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S100A1 in human heart failure: lack of recovery following left ventricular assist device support
Mosi K Bennett1, Wendy E Sweet1, Sara Baicker-McKee1
1From the Kaufman Center for Heart Failure, Department of Cardiovascular Medicine, Cleveland Clinic, OH.
Insights
S100A1 protein levels decrease in human heart failure but do not recover after left ventricular assist device support. This suggests S100A1 may play a role in heart remodeling and recovery.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- S100A1 protein is crucial for cardiac function.
- S100A1 levels are reduced in heart failure.
- Restoring S100A1 shows promise for cardiac recovery in models.
Purpose of the Study:
- Investigate S100A1 regulation in human heart hypertrophy and failure.
- Determine S100A1's role in cardiac remodeling after left ventricular assist device (LVAD) support.
Main Methods:
- Quantified S100A1, SERCA, phospholamban, ryanodine receptor, and beta-adrenergic receptors in human hearts.
- Assessed protein alterations' functional impact on isolated muscle contractions.
- Compared protein levels and function in nonfailing, hypertrophied, failing, and LVAD-supported failing hearts.
Main Results:
- S100A1 and SERCA decreased in failing hearts but not in hypertrophy.
- Ryanodine receptor levels remained unchanged across groups.
- In failing hearts supported by LVAD, S100A1 and SERCA did not recover.
- Phospholamban, beta-adrenergic receptors, and inotropic response recovered fully post-LVAD.
Conclusions:
- S100A1 and SERCA, key calcium regulators, are diminished in human heart failure.
- These reductions are not reversed by LVAD support.
- The clinical implications for cardiac recovery warrant further investigation.
Background:
We hypothesized that S100A1 is regulated during human hypertrophy and heart failure and that it may be implicated in remodeling after left ventricular assist device. S100A1 is decreased in animal and human heart failure, and restoration produces functional recovery in animal models and in failing human myocytes. With the potential for gene therapy, it is important to carefully explore human cardiac S100A1 regulation and its role in remodeling.
Methods And Results:
We measured S100A1, the sarcoplasmic endoplasmic reticulum Ca(2+)ATPase, phospholamban, and ryanodine receptor proteins, as well as β-adrenergic receptor density in nonfailing, hypertrophied (left ventricular hypertrophy), failing, and failing left ventricular assist device-supported hearts. We determined functional consequences of protein alterations in isolated contracting muscles from the same hearts. S100A1, sarcoplasmic endoplasmic reticulum Ca(2+)ATPase and phospholamban were normal in left ventricular hypertrophy, but decreased in failing hearts, while ryanodine receptor was unchanged in either group. Baseline muscle contraction was not altered in left ventricular hypertrophy or failing hearts. β-Adrenergic receptor and inotropic response were decreased in failing hearts. In failing left ventricular assist device-supported hearts, S100A1 and sarcoplasmic endoplasmic reticulum Ca(2+)ATPase showed no recovery, while phospholamban, β-adrenergic receptor, and the inotropic response fully recovered.
Conclusions:
S100A1 and sarcoplasmic endoplasmic reticulum Ca(2+)ATPase, both key Ca(2+)-regulatory proteins, are decreased in human heart failure, and these changes are not reversed after left ventricular assist device. The clinical significance of these findings for cardiac recovery remains to be addressed.