Related Experiment Videos
Novel approaches to retard ventricular remodeling in heart failure
Insights
Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) play a crucial role in congestive heart failure (CHF) by contributing to left ventricular (LV) remodeling. Targeting MMP and TIMP activity offers a novel therapeutic strategy for CHF.
Area of Science:
- Cardiovascular Biology
- Biochemistry
- Pathophysiology
Background:
- Congestive heart failure (CHF) commonly involves left ventricular (LV) remodeling, increased wall stress, and impaired pump function.
- Current therapies focus on reducing LV afterload or blocking neurohormonal effects.
- Direct intervention in the LV remodeling process presents a potential new therapeutic avenue.
Discussion:
- The fibrillar collagen matrix is vital for myocyte structure and cardiac function.
- LV remodeling in CHF is associated with alterations in collagen matrix structure and composition.
- Matrix metalloproteinases (MMPs) are key enzymes in matrix remodeling, with altered expression and activity observed in CHF.
- Tissue inhibitors of MMPs (TIMPs) also show altered expression in end-stage CHF myocardium.
Key Insights:
- Increased MMP activity and reduced TIMP control likely contribute to LV remodeling in CHF.
- Bioactive peptides and cytokines influence MMP and TIMP expression and activity.
- Pharmacological MMP inhibitors are under investigation.
Outlook:
- Controlling MMP and TIMP expression and activity in the failing myocardium is a promising therapeutic target for CHF.
- Further research into MMP/TIMP modulation could lead to novel CHF treatments.
- This approach may offer a new strategy beyond traditional vasodilator and neurohormonal therapies.
Abstract:
While the etiologies of congestive heart failure (CHF) are diverse, a common event in the progression of this disease process is LV remodeling, increased wall stress, and subsequent pump dysfunction. Therapeutic approaches for CHF have been focused upon reducing LV afterload through vasodilator therapy, or by blocking/interrupting the effects of neurohormonal stimuli. However, another therapeutic approach would be to directly intervene in the LV remodeling process with CHF. An important determinant in the maintenance of myocyte shape, alignment and transduction of myocyte shortening into an overall ejection is the structural support provided by the fibrillar collagen matrix. As in most tissue remodeling processes, LV myocardial remodeling with CHF is accompanied by changes in the structure and composition of the collagen matrix. Matrix metalloproteinases (MMPs) are an endogenous family of zinc-dependent enzymes which have been identified to be responsible for matrix remodeling and alterations in MMP expression and activity have been identified in clinical and animal models of CHF. Moreover, alterations in the tissue inhibitors of MMPs (TIMPs) have also been identified to occur in the end-stage CHF myocardium. Thus, it is very likely that increased MMP activity and reduced inhibitory control of the TIMPs contribute to the LV remodeling process with CHF. A number of bioactive peptides and cytokines influence MMP and TIMP expression and activity. In addition, pharmacologically active MMP inhibitors have been synthesized and are currently under study. Accordingly, the control of MMP and TIMP expression and activity within the failing myocardium represents a new and potentially significant therapeutic target for CHF.