Cardiomyopathy
Fibroblast-Cardiomyocyte Interaction in Pediatric Restrictive Cardiomyopathy
2021 Volume 85 Issue 5 Pages 687-689
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2021 Volume 85 Issue 5 Pages 687-689
Pediatric restrictive cardiomyopathy (RCM) is a cardiac muscle disorder characteristic of severe diastolic dysfunction with preserved systolic function. RCM is a rare disease, affecting less than 1 in 100,000 children, but is progressive and has an exceptionally high mortality. Most RCM patients require cardiac transplantation within 10 years of the diagnosis.1 No drugs are available for the disease; therefore, there is an urgent need to elucidate its pathophysiology.
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The most common causes of idiopathic RCM in children are mutations in the sarcomere genes, such as troponin I3, cardiac type (TNNI3).2 Although detailed mechanisms underlying the diastolic dysfunction with these mutations are unknown, studies in animal models suggest that the gene mutations cause myofibril calcium hypersensitivity resulting in delayed calcium dissociation and impaired active relaxation.3 Mutations in other genes whose proteins are not directly involved in the contractile apparatus, such as desmin, have also been reported. These mutations are likely to cause disorders in protein complex assembly and accumulation of the protein aggregates, leading to diastolic dysfunction.4
Fibrosis is a pathological hallmark of RCM. However, detailed physiological analysis of RCM patients suggests that increased intrinsic stiffness of the ventricular wall caused by fibrosis per se has little effect on diastolic function.5 Hence, the relationship between the sarcomere mutations and active relaxation has been the main focus of RCM research, and the role of cardiac fibroblasts in the pathophysiology of RCM has received little attention.
In this issue of the Journal, Tsuru et al challenged this idea by investigating the interaction between cardiac fibroblasts and cardiomyocytes independent of tissue fibrosis.6 These authors established multiple cell lines of pediatric RCM patient-derived cardiac fibroblasts (RCM-CF) and evaluated the effect of RCM-CF-derived paracrine factors on cardiomyocyte function. Tsuru et al determined that: (1) RCM-CF have distinct gene expression profiles compared with fibroblasts from healthy individuals; and (2) paracrine factors secreted from RCM-CF exacerbate cardiomyocyte relaxation.6
The results of the study of Tsuru et al6 are consistent with the results of recent studies that have shown that cardiac fibroblasts secrete a myriad of paracrine factors and actively modulate cardiac function. The most well studied is transforming growth factor-β (TGF-β), upregulation of which was observed in RCM-CF in the present study.6 C-X-C motif chemokine ligand 12 (CXCL12) and interleukin (IL)-33, which Tsuru et al reported to be downregulated in RCM-CF,6 have also been reported to alter cardiomyocyte morphology and function. For example, CXCL12 attenuated the intracellular calcium transient in isolated adult rat cardiomyocytes,7 and IL-33 antagonized angiotensin II- and phenylephrine-induced cardiomyocyte hypertrophy.8 The present study followed these findings and suggested that fibroblast-cardiomyocyte interaction plays a crucial role in the pathophysiology of the relaxation disorder observed in RCM6 (Figure 1). These paracrine factors can be a biomarker for clinical evaluation and a possible treatment target for pediatric RCM.
Schematic diagram of the pathogenesis of restrictive cardiomyopathy (RCM): cardiomyocytes, cardiac fibroblasts, and their interaction. Bolded text indicates findings reported by Tsuru H, et al.6 COL16A1, collagen type XVI α 1 chain; CXCL12, C-X-C motif chemokine ligand 12; ECM, extracellular matrix; IL33, interleukin-33; ITGA11, integrin subunit α 11; MMP1, matrix metalloproteinase 1; TGFB1, transforming growth factor-β1; TNNI3, troponin I3, cardiac type; TNNT2, troponin T2, cardiac type.
In the heart, quiescent resident cardiac fibroblasts become activated upon stress, such as myocardial infarction, and differentiate into myofibroblasts. Myofibroblast is an activated form of fibroblasts with the following two key characteristics: (1) They produce large amounts of extracellular matrix (ECM) proteins and cytokines; and (2) they express α-smooth muscle actin (α-SMA) and actively contract.9 These unique features of myofibroblasts are essential to form a stable scar in the infarcted myocardium and prevent cardiac rupture. Myofibroblasts can also be found in the hearts of patients with heart failure with reduced ejection fraction (HFrEF), possibly contributing to interstitial fibrosis formation.10
It is intriguing that although RCM-CFs had increased expression of ECM proteins and cytokines akin to myofibroblasts, the number of α-SMA-positive cells was comparable to that in healthy cardiac fibroblasts.6 Similar findings were reported in an obesity-induced rodent model of heart failure with preserved ejection fraction (HFpEF).11 A different study using fibroblast cell lines showed that nutrition deprivation accelerated ECM protein production without increasing α-SMA expression.12 Although myofibroblasts and activated fibroblasts are often used interchangeably, these studies indicate a non-myofibroblast mode of fibroblast activation (Figure 2). The study of Tsuru et al provides novel evidence to these previous studies and opens a path for further investigation of a previously overlooked mode of fibroblast activation, which may contribute to a better understanding of the molecular mechanisms underlying RCM and HFpEF.
Characteristics of cardiac fibroblasts from restrictive cardiomyopathy (RCM) patients and traditional myofibroblasts. α-SMA, α-smooth muscle actin; ECM, extracellular matrix; TGF-β, transforming growth factor-β.
The study of Tsuru et al raises the question as to how the RCM-CFs were activated in a manner distinct from that of traditional myofibroblasts. The signaling transduction system that differentiates cardiac fibroblasts into myofibroblasts can be roughly categorized into two: One is through conventional ligand-receptor interactions, such as TGF-β signaling, and the other is mechanical signal transduction via mechanosensitive channels, such as transient receptor potential (TRP) channels.13 However, the signaling pathway that induces the non-myofibroblast mode of fibroblast activation is unknown. The aforementioned studies of non-myofibroblast type fibroblast activation involved metabolic changes as a trigger,11,12 and similar mechanisms may underlie the activation of RCM-CF. Metabolic changes in the heart have been observed in dilated cardiomyopathy and hypertrophic cardiomyopathy,14 but data are scarce for RCM. Further studies are required to clarify how RCM-CFs develop within the RCM heart.
Tsuru et al show, for the first time, that fibroblast-cardiomyocyte interaction may play an essential role in the pathophysiology of pediatric RCM and that RCM-CF is activated in a way distinct from traditional myofibroblasts.6 Although the study was conducted thoroughly in vitro and lacked in vivo evaluation, the results provide a novel concept of targeting fibroblast as a possible treatment strategy for RCM. Further research focusing on RCM-CF is warranted.
T.S. has received research grants from Suzuken Memorial Foundation and The Kidney Foundation. M.I. has received the following research grants: the Grant for Basic Research of the Japanese Circulation Society, Japan Heart Foundation Research Grant, and Research Grant of the Kanae Foundation for the Promotion of Medical Science. In addition, M.I. belongs to an endowed department (Department of Advanced Clinical Science and Therapeutics) sponsored by Anges Inc. (Tokyo, Japan).
