© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
A Whisper on the wind spawns a storm
Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, Memphis College of Medicine, Memphis, TN USA
* Corresponding author. Tel.: +901-448-5759; fax: +901-448-8084 KTWeber{at}utmem.edu
Received 11 February 2000; accepted 14 February 2000
The heart, like many other organs, is composed of parenchyma surrounded by stroma. In this case, highly differentiated and very specialized cardiac myocytes are connected to and tethered within a three dimensional scaffolding of structural protein. Cardiac myocytes number one-third of cells found in the heart. Noncardiomyocytes, such as fibroblasts, endothelial and vascular smooth muscle cells, account for the majority of the remaining two-thirds. Interstitial fibroblasts are responsible for normal synthesis and degradation of this extracellular network, an albeit slow yet nonetheless ongoing process [1]. Fibroblasts are undifferentiated and pluripotent with a diverse portfolio of phenotypic expressions and functions. Myofibroblasts are an example of specialized fibroblast-like cells that appear at sites of tissue repair to carry out fibrogenesis and other functions [2].
Type I collagen is the dominant fibrillar collagen of the heart’s extracellular matrix. Its tensile strength of steel imparts cardiac tissue with an ability to resist deformation. Type III collagen, a more flexible fibrillar collagen, is present in lesser proportion while the heart’s concentration of elastin is modest, quite unlike normally distensible blood vessels. Various functions of this structural protein network in health and disease have been reviewed previously [3].
Matrix and fibroblasts are bathed by tissue fluid that contains a filtrate of blood as well as substances derived from myocytes and noncardiomyocytes. Circulating and locally generated substances may serve as signals that govern cell differentiation, growth, apoptosis, and metabolic behavior. Also present in the interstitial space are glycosaminoglycans, proteoglycans and self-aggregating molecules called into play following injury. Such molecules include a family of transforming growth factor-β polypeptides and matrix metalloproteinases, each of which reside in latent form their activity held in abeyance by respective inhibitors. Stroma is the heart’s interstitial compartment. By definition this implies it is merely supporting tissue, a bit player in the heart’s impressive panoply of functions and capacity for self-determination of its structure and composition. This is a misrepresentation. Stroma is a dynamic entity. Until recently, it attracted little attention — it represented a mere whisper on the wind. Overlooked was its important contribution to cardiovascular disease. Why? Several possibilities come to mind.
The 20th century nurtured and accelerated the development of cardiac muscle physiology as a discipline. There appeared an explosion of information drawn from in vivo and in vitro studies of the intact heart and tissue fragments taken from its myocardium. Born of these studies some 40 years ago was the concept of contractility, a biochemical property of cardiac myocytes that determines shortening independent of myocyte length or shortening load. From this collective perspective it perhaps naturally followed that ventricular systolic dysfunction was viewed as originating solely within parenchyma, the heart’s functional (contractile) element. Intrinsic abnormalities in myocyte biochemistry, such as defective or maladaptive contractile proteins and/or intracellular handling of calcium, were proposed as accounting for such impaired shortening [4]. This paradigm was viewed as applicable to both acute and chronic forms of cardiac failure. Stroma was not considered culpable in faulty behavior of hypertrophied cardiac myocytes. Yet giant mastodons, trapped in tar, do not move well in this unfriendly environment. Years later, ventricular diastolic dysfunction with impaired relaxation and increased resistance to filling was recognized as a determinant of acute and chronic cardiac failure. Once again a biochemical perspective, such as altered intracellular calcium homeostasis, would often be invoked as the cellular mechanism responsible for this entity [5]. Not considered is the active relengthening of myocytes and ventricular tissue provided by energy stored in coiled collagen fibers during systole to create diastolic suction, a mechanism analogous to the manner in which a squid propels itself through water [6]. A structural remodeling of matrix could interfere not only with this efficient mechanism contributing to relaxation and early filling but also to abnormal tissue stiffness that impedes filling.
Classic models of cardiac muscle mechanics included a contractile element tethered to an in-series elastic element and surrounded by an in-parallel elastic element. These latter components, however, were considered of lesser importance to overall mechanical behavior of cardiac tissue in normal and diseased hearts and therefore received less attention. Moreover, these elastic elements had no clear anatomic correlate. The advent of scanning electron microscopy broadened the perspective. Pioneering morphologic studies by James Caulfield, Thomas Borg and the late Thomas Robinson provided compelling evidence that fibrillar collagen represented an important structural correlate of these elastic elements [6,7]. The work of these investigators would identify a number of its functional features and iterations in matrix structure that appeared in different disease states. The functional significance of derangements in matrix architecture and composition has been reviewed elsewhere [8].
A second explanation related to the shunning of stroma was collagen’s stability as a structural protein — ‘hemp rope’ with a slow turnover rate. Pathologic accumulations of fibrillar collagen in the heart, also referred to as fibrous tissue (including scar tissue), were likewise presumed inert and routine histochemistry would imply they were acellular — ‘dead meat’. Recent studies employing immunohistochemistry, in situ hybridization and quantitative in vitro autoradiography would indicate otherwise.
Finally, there was the presumption that the mere presence of fibrous tissue in the diseased heart was nothing but a sequelae to and therefore a sine qua non of myocyte necrosis. Little consideration was given to the possibility that its accumulation could be reactive and progressive in the absence of myocyte loss. In like manner, active proteolytic digestion of fibrillar collagen was not addressed in the pathogenesis of various forms of heart disease. It therefore followed that little was to be gained using microscopy to examine diseased tissue and to assess the potential for a structural basis of heart disease, except of course to exclude an inflammatory process. After all, it was reasoned, most secrets to ventricular dysfunction resided within presumptive derangements in parenchymal biochemistry. This view has persisted amongst cardiologists despite advances made by other disciplines, who came to recognize the important contribution of matrix accumulation and its dynamic cellular nature in such entities as cirrhosis, nephrosclerosis and interstitial lung disease and an important role for matrix degradation in emphysema, rheumatoid arthritis and blistering skin diseases. Other specialties of medicine fully utilize such tissue-based microscopic evaluation in assigning diagnosis, assessing disease activity and predicting progression, and formulating management plans.
Studies drawing on technologies of cellular and molecular biology are beginning to broaden the perspective in cardiology, to clear the air of this lingering, at times stupefying biochemical miasma of parenchyma. Evidence accumulated to date is both compelling and persuasive as to the importance of matrix in the pathophysiologic expressions of various cardiovascular diseases. The involvement of the heart’s extracellular matrix in heart disease may present as either an adverse accumulation of fibrillar collagen or inappropriate degradation [3]. For example, a reactive interstitial fibrosis is found in noninfarcted myocardium of the infarcted heart and a perivascular/interstitial fibrosis in both nonhypertrophied right and hypertrophied left ventricles in hypertensive heart disease. Examples involving fibrillar collagen degradation include dilated (idiopathic) cardiomyopathy, infarct expansion, ventricular rupture and aortic aneurysm. A structural remodeling of great vessels, conduit arteries and arterioles by adverse accumulation of fibrillar collagen has now also gained a fuller measure of understanding as has a role for matrix metalloproteinases in rupture of an atherosclerotic plaque. What remains is a deciphering of fundamental molecular and cellular events involved in pathologic abnormalities of matrix remodeling in these entities. Such information will permit the introduction of either protective or reparative strategies that will respectively prevent or regress such remodeling [9]. Several such strategies may already be in hand.
Evidence that a recognition of the heart’s extracellular matrix has indeed come of age worldwide — that a whisper on the wind has spawned a storm — is witnessed by: an ever increasing number of studies devoted to this topic which now appear annually throughout the scientific literature; a National Heart, Lung and Blood Institute sponsored workshop on the importance of matrix remodeling in heart failure [10]; and this focused issue of Cardiovascular Research that features original contributions and mini-reviews on topics identified in this brief overview. It is an honor to serve as guest editor.
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 Top References |
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- Laurent G.J. Dynamic state of collagen: pathways of collagen degradation in vivo and their possible role in regulation of collagen mass. Am J Physiol (1987) 252:C1–9.[Web of Science][Medline]
- Gabbiani G. Evolution and clinical implications of the myofibroblast concept. Cardiovasc Res (1998) 38:545–548.
[Free Full Text] - Weber K.T. Cardiac interstitium in health and disease: the fibrillar collagen network. J Am Coll Cardiol (1989) 13:1637–1652.[Abstract]
- Katz A.M. Cardiomyopathy of overload: a major determinant of prognosis in congestive heart failure. N Engl J Med (1990) 322:100–110.[Web of Science][Medline]
- Grossman W. Diastolic dysfunction in congestive heart failure. N Engl J Med (1991) 325:1557–1564.[Web of Science][Medline]
- Robinson T.F., Factor S.M., Sonnenblick E.H. The heart as a suction pump. Sci Am (1986) 254:84–91.[Web of Science][Medline]
- Caulfield J.B., Borg T.K. The collagen network of the heart. Lab Invest (1979) 40:364–372.[Web of Science][Medline]
- Weber K.T., Brilla C.G., Janicki J.S. Myocardial fibrosis: functional significance and regulatory factors. Cardiovasc Res (1993) 27:341–348.
[Free Full Text] - Weber K.T., Anversa P., Armstrong P.W., Bauer J.H., Brilla C.G., Burnett J.C., et al. Remodeling and reparation of the cardiovascular system. J Am Coil Cardiol (1992) 20:3–16.
- Weber K.T., Hsueh W.A., Watson J.T., Goldman S.S. Workshop on diagnosis and treatment of cardiac maladaptive remodeling. Heart Failure Rev (1999) 4:97–100.[CrossRef]
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