Cell to bedsideMyofibroblasts in diseased hearts: New players in cardiac arrhythmias?
Introduction
Although a wealth of information exists regarding the role of abnormal cardiomyocyte electrophysiology in arrhythmogenesis, much less is known about whether stromal cells of the heart in general and cardiac fibroblasts in particular might be actively involved in arrhythmogenesis. This is surprising insofar as that fibroblasts represent the most numerous cell population in normal human hearts, with individual cells being in intimate contact with cardiomyocytes. In fact, cardiac fibroblasts outnumber cardiomyocytes by a factor of 2–3 while occupying approximately 20% of the volume of the working myocardium.1 Under physiologic conditions, fibroblasts produce and maintain a three-dimensional network of collagen and elastin fibers, which acts as a scaffold for cardiomyocytes and integrates the mechanical forces of individual cells, thus resulting in an efficient pump function of the entire organ. Moreover, by providing the structural backbone for the regular three-dimensional assembly of cardiomyocytes, fibroblasts contribute importantly to the uniformity of the excitable substrate and, thus, to continuous and fast electrical activation of the working myocardium under physiologic conditions. Given that the fibrillar components of the scaffold are subject to constant turnover, which amounts up to approximately 5% per day,2 it is evident that formation and degradation of these fibers needs to be closely controlled in order to maintain the structural and functional integrity of the myocardium over time. This control is exerted by a large number of biophysical and molecular signaling events that control fibroblast growth and function. If the delicate balance between extracellular matrix (ECM) production and degradation is lost, the working myocardium undergoes structural remodeling that has far-reaching adverse consequences for both the electrical and the pump function of the heart.
Section snippets
Structural remodeling and arrhythmogenesis
Structural remodeling of the myocardium is the result of a variety of complex cellular reactions to injury and involves both cardiomyocytes and noncardiomyocytes. Histologically, it is characterized by cardiomyocyte hypertrophy, activation and proliferation of fibroblasts, increased ECM deposition, and cell death.3 The leading causes of structural remodeling are pressure overload, volume overload, ischemic heart disease, and genetics and old age, which result in changes of the size and shape of
Cardiac fibrosis and the appearance of myofibroblasts
The absence of arrhythmias in healthy hearts suggests that fibroblasts, even though they greatly outnumber cardiomyocytes, exert no arrhythmogenic effects per se under physiologic conditions. However, under pathologic conditions such as hypertensive heart disease and infarction, an additional type of cell makes its appearance in the working myocardium. These so-called myofibroblasts (sometimes termed activated fibroblasts) are considered to be importantly involved in the establishment of
Gap junctional coupling of myofibroblasts to cardiomyocytes
Given the close apposition between cardiomyocytes and myofibroblasts in diseased myocardia, the question arises as to whether gap junctions might electrically interconnect the two cell types. Whereas connexin (Cx) expression is a well-established feature of myofibroblasts in tissues different from heart, such as suburothelial tissue,22 intestine,23 breast cancer stroma,24 and healing skin wounds,25 the question of gap junctional coupling between myofibroblasts and cardiomyocytes in diseased
Myofibroblast mend broken pathways of impulse conduction
It is generally assumed that cardiac impulse conduction is blocked at sites where the cardiomyocyte network is disrupted by collagenous septa or at sites of sutures following heart transplantation. Interestingly, for the latter case, it has been reported that recipient and donor atria are sporadically capable of establishing electrical synchronization despite scar formation in the region of the suture.30 Because myofibroblasts are a typical cellular component of scar tissue, we tested the
Myofibroblasts induce slow conduction
Structurally, the border zone of healing infarcts is characterized by surviving cardiomyocytes in close contact with a large number of myofibroblasts (cf. Figure 2). Functionally, this very same region is known to contribute significantly to postinfarction arrhythmogenesis based on remodeling of the cellular microarchitecture, modifications of gap junctional coupling among cardiomyocytes, and changes in the electrophysiology of border zone cardiomyocytes (for review see Peters and Wit34). Given
Myofibroblasts induce abnormal automaticity
In diseased hearts, cardiac fibrosis not only induces arrhythmogenic slow and discontinuous conduction; it also is suspected to promote ectopic activity, which is central to the generation of focal and reentrant tachyarrhythmias.35 The presence of ectopic activity under these conditions is thought to be favored by anisotropies in tissue structure and in electrical coupling that ultimately permits a few cardiomyocytes exhibiting abnormal automaticity to drive the surrounding myocardium.36 Given
Conclusions and perspectives
The findings presented demonstrate that myofibroblasts, as schematically summarized in Figure 7, are capable of exerting highly arrhythmogenic effects following heterocellular electrotonic coupling to cardiomyocytes. By inducing (dis)continuous slow conduction as well as ectopic activity, myofibroblasts are, in fact, capable of launching the main mechanisms driving focal and reentrant tachyarrhythmias, that is, abnormal impulse conduction and abnormal impulse formation.39 Although this finding
Acknowledgment
I wish to thank Dr. Christian Mühlfeld for providing sections of infarcted rat hearts.
References (41)
- et al.
Collagen synthesis and degradation in vivoEvidence for rapid rates of collagen turnover with extensive degradation of newly synthesized collagen in tissues of the adult rat
Coll Relat Res
(1987) - et al.
The perplexing complexity of cardiac arrhythmias: beyond electrical remodeling
Heart Rhythm
(2005) - et al.
Angiotensin converting enzyme and myofibroblasts during tissue repair in the rat heart
J Mol Cell Cardiol
(1996) - et al.
Homo- and heterocellular junctions in cell cultures: an electrophysiological and morphological study
Prog Brain Res
(1969) - et al.
Recipient-to-donor atrioatrial conduction after orthotopic heart transplantation: surface electrocardiographic features and estimated prevalence
Am J Cardiol
(1998) - et al.
Optical recording system based on a fiber optic image conduit: assessment of microscopic activation patterns in cardiac tissue
Biophys J
(1998) - et al.
Three-dimensional anatomic structure as substrate for ventricular tachycardia/ventricular fibrillation
Heart Rhythm
(2005) - et al.
Electrotonic myofibroblast-to-myocyte coupling increases propensity to reentrant arrhythmias in two-dimensional cardiac monolayers
Biophys J
(2008) Extracellular matrix and cardiac interstitium: restriction is not a restricted phenomenon
Herz
(1995)Molecular mechanisms of myocardial remodeling
Physiol Rev
(1999)
Microfibrosis produces electrical load variations due to loss of side-to-side cell connections: a major mechanism of structural heart disease arrhythmias
Pacing Clin Electrophysiol
Slow conduction in the infarcted human heart: zigzag course of activation
Circulation
Extracellular matrix remodeling in heart failure: a role for de novo angiotensin II generation
Circulation
Fibrosis in hypertensive heart disease: focus on cardiac fibroblasts
J Hypertension
The myofibroblast in wound healing and fibrocontractive diseases
J Pathol
Fibrogenesis of parenchymal organs
Proc Am Thorac Soc
Human semilunar cardiac valve remodeling by activated cells from fetus to adult: implications for postnatal adaptation, pathology, and tissue engineering
Circulation
Cardiac myofibroblasts express alpha smooth muscle actin during right ventricular pressure overload in the rabbit
Am J Pathol
Transforming growth factor function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats
Circ
Expression of Gi-2α and Gsα in myofibroblasts localized to the infarct scar in heart failure due to myocardial infarction
Cardiovasc Res
Cited by (161)
A model for positive feedback control of the transformation of fibroblasts to myofibroblasts
2019, Progress in Biophysics and Molecular BiologyStraight to the heart: Pleiotropic antiarrhythmic actions of oral anticoagulants
2019, Pharmacological ResearchObesity and atrial fibrillation: a narrative review from arrhythmogenic mechanisms to clinical significance
2023, Cardiovascular DiabetologyThe scar: the wind in the perfect storm—insights into the mysterious living tissue originating ventricular arrhythmias
2023, Journal of Interventional Cardiac Electrophysiology
This work was supported by the Swiss National Science Foundation (Grant 320000-118247/1).