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The role of the cytoskeleton in heart failure
Abstract:
The cytoskeleton of cardiac myocytes consists of actin, the intermediate filament desmin and of alpha- and beta-tubulin that form the microtubules by polymerization. Vinculin, talin, dystrophin and spectrin represent a separate group of membrane-associated proteins. In numerous experimental studies, the role of cytoskeletal alterations especially of microtubules and desmin, in cardiac hypertrophy and failure (CHF) has been described. Microtubules were found to be accumulated thereby posing an increased load on myocytes which impedes sarcomere motion and promotes cardiac dysfunction. Other groups were unable to confirm microtubular densification. The possibility exists that these changes are species, load and chamber dependent. Recently, damage of the dystrophin molecule and MLP (muscle LIM protein) were identified as possible causes of CHF. Our own studies in human hearts with chronic CHF due to dilated cardiomyopathy (DCM) showed that a morphological basis of reduced contractile function exists: the cytoskeletal and membrane-associated proteins are disorganized and increased in amount confirming experimental reports. In contrast, the contractile myofilaments and the proteins of the sarcomeric skeleton including titin, alpha-actinin, and myomesin are significantly decreased. These changes can be assumed to occur in stages and are here presented as a testable hypothesis: (1) The early and reversible stage as present in animal experiments is characterized by accumulation of cytoskeletal proteins to counteract an increased strain without loss of contractile material. (2) Further accumulation of microtubules and desmin to compensate for the increasing loss of myofilaments and titin represents the late clinical and irreversible state. We suggest, based on a structural basis for heart failure, an integrative view which closes the gap between changes within cardiac myocytes and the involvement of the extracellular matrix, including the development of fibrosis. These factors contribute significantly to structural ventricular remodeling and dilatation finally resulting in reduced cardiac function.
Insights
Cardiac cytoskeleton changes, including microtubule and desmin accumulation, contribute to heart failure. Early stages are reversible, while late stages involve myofilament loss and fibrosis, leading to irreversible cardiac dysfunction.
Area of Science:
- Cardiovascular Biology
- Cellular Biology
- Biochemistry
Background:
- Cardiac myocyte cytoskeleton comprises actin, desmin, tubulin, and membrane-associated proteins.
- Cytoskeletal alterations, particularly in microtubules and desmin, are implicated in cardiac hypertrophy and failure (CHF).
- Previous studies show conflicting results regarding microtubule accumulation in CHF.
Purpose of the Study:
- To investigate the morphological basis of reduced contractile function in human hearts with chronic CHF due to dilated cardiomyopathy (DCM).
- To propose a staged hypothesis for cytoskeletal changes in heart failure.
- To integrate myocyte-level changes with extracellular matrix involvement in cardiac remodeling.
Main Methods:
- Analysis of cytoskeletal and sarcomeric proteins in human hearts with DCM.
- Morphological assessment of myocyte structure and protein organization.
- Comparison with experimental findings in animal models of heart failure.
Main Results:
- Disorganization and increased amounts of cytoskeletal and membrane-associated proteins in human hearts with CHF.
- Significant decrease in contractile myofilaments and sarcomeric skeleton proteins (titin, alpha-actinin, myomesin).
- Evidence supporting a staged progression of cytoskeletal changes in heart failure.
Conclusions:
- A structural basis for reduced contractile function in CHF involves cytoskeletal disorganization and myofilament loss.
- Early, reversible stages involve cytoskeletal protein accumulation; late, irreversible stages involve myofilament loss and compensatory protein accumulation.
- An integrative view connecting myocyte changes, extracellular matrix, and fibrosis is crucial for understanding ventricular remodeling and heart failure progression.