14 Invited for Debate: Is There a Virus-Specific Matrix Destruction in the Course of Disease
in Dilated Cardiomyopathy?
F. Waagstein
14.1 Conclusion . . . 257 References . . . 257
In the normal myocardium there is a equilibrium between degrading and
rebuilding of the matrix (Fig. 1) which during the remodeling process in
chronic heart failure is displaced by an increase in degrading of matrix
in the early phase leading to slipping of myocytes and dilatation of
ventricles (Fig. 2) later followed by increase in fibrosis and myocardial
stiffness (Tsuruda et al. 2004). In inflammatory viral cardiomyopathy,
the question is whether this process is mediated by a specific virus-
induced process due to loss of myocytes and depression of contractility
or mediated by an increase in inflammatory cytokines, which indirectly
leads to a cascade of events resulting in upregulation of metallopro-
teinases.
Fig. 1. Adequate extracellular matrix metabolism
Fig. 2. Inadequate extracellular matrix metabolism
Figure 3 illustrates a hypothetical series of events leading to matrix destruction during chronic virus infection.
When the time course of matrix destruction is studied in an ani-
mal model it is obvious that a bimodal pattern is present. Early during
stretch – after a few hours – there is an activation of angiotensin II that
slows down after 24 h (Wang et al. 2004; Fig. 4).
Virus-Specific Matrix Destruction? 253
Fig. 3. Possible mechanism for developing heart dilatation in inflammatory myocardial disease
Fig. 4. Cyclic stretch of myocytes induces angiotensin II (Wang et al. 2004)
In a volume overload model of heart failure, there is an early activation of metalloproteinases followed by downregulation, and then upregula- tion again, during the phase of decompensation (Fig. 5). In the early phase, downregulation of collagen volume fraction is seen, followed by upregulation in the late phase of decompensation (Janicki et al. 2004;
Fig. 6).
Fig. 5. Activation of matrix metalloproteinase (MMP) in a heart failure volume overload model (Janicki et al. 2004)
Fig. 6. Effects of activation and deactivation of MMP on left ventricular (LV) collagen in a volume overload model of heart failure (Janicki et al. 2004)
This process could be reversed by unloading the failing heart by left
ventricular assist, which downregulates metalloproteinases (Fig. 7) and
upregulates tissue inhibitors of matrix metalloproteinase (TIMP) (Li
et al. 2001; Fig. 8).
Virus-Specific Matrix Destruction? 255
Fig. 7. Downregulation of MMP-9 after LV assist device (LVAD) in severe heart failure (Li et al. 2001)
Fig. 8. Effect of LVAD on TIMP-3 expression in dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) (Lin et al. 2001)
Additionally, pharmacotherapy, such as beta-blockade, could reverse
the inflammatory response (Fig. 9) and downregulate metalloproteinases
(Ohtsuka et al. 2003; Fig. 10).
10
0 Baseline 6 months
TNF-
Fig. 9. Serum tumor necrosis factor (TNF)-α in DCM treated with carvedilol (Ohtsuka et al. 2003)
Fig. 10. Serum MMP-9 in DCM treated with carvedilol (Ohtsuka et al. 2003)
Virus-Specific Matrix Destruction? 257
14.1 Conclusion
There is more evidence that matrix destruction in inflammatory car- diomyopathy is a secondary event to virus infection caused by a cascade of processes induced by the inflammatory response to virus infection and loss of myocytes than matrix destruction is a specific process caused by virus proteases.
It is, however, possible that both processes, a direct virus effect and an indirect effect from virus infection, act in cooperation. Future treat- ment with specific antiviral therapy may show which mechanism is the dominating factor in inflammatory cardiomyopathy causing matrix destruction.
References
Janicki JS, Brower GL, Gardner JD, Chancey AL, Stewart JA Jr (2004) The dynamic interaction between matrix metalloproteinase activity and adverse myocardial remodeling. Heart Fail Rev 9:33–42
Li YY, Feng Y, McTiernan CF, Pei W, Moravec CS, Wang P, Rosenblum W, Kormos RL, Feldman AM (2001) Down regulation of matrix metallopro- teinases and reduction in collagen damage in the failing human heart after support with left ventricular assist devices. Circulation 104:1147–1152 Ohtsuka T, Hamada M, Saeki H, Ogimoto A, Hara Y, Shigematsu Y, Hi-
gaki J (2003) Serum levels of serum metalloproteinases and tumour necrosis factor-alpha in patients with idiopathic dilated cardiomyopathy and effect of carvedilol on these levels. J Am Coll Cardiol 91:1024–1027
Tsuruda T, Costello-Boerrigter LC, Burnett JC Jr (2004) Matrix metallopro- teinases: pathways of induction by bioactive molecules. Heart Fail Rev 9:53–61
Wang TL, Yang YH, Chang H, Hung CR (2004) Angiotensin II signals me- chanical stretch-induced cardiac matrix metalloproteinase expression via JAK-STAT pathway. J Mol Cell Cardiol 37:785–794
