Molecular Biomarkers of Ventricular Remodeling in Advanced Heart Failure Patients

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Summary of  Journal of the American Heart Association https://doi.org/10.1161/JAHA.125.044558
Dr. Karthi Sreedevi et al.

Points

Researchers evaluated tissue from 19 advanced heart failure patients to determine why only a specific subset of individuals experience meaningful myocardial recovery after receiving mechanical circulatory support.
Baseline measurements across all 19 enrolled subjects showed severely reduced levels of the muscle-specific protein PERM1 prior to the initiation of left ventricular assist device support.
Following mechanical unloading, PERM1 expression was restored to near-normal levels exclusively in clinical responders who demonstrated significant improvements in left ventricular systolic function and structural remodeling.
The protein acts at the center of a metabolic cycle by regulating how heart muscle cells produce energy and manage stress-related cellular pathways during advanced heart failure.
These findings position PERM1 as a promising therapeutic target for gene therapies aimed at repairing failing cardiomyocytes rather than simply managing chronic symptoms of the disease.

Summary

This study evaluated the molecular mechanisms driving myocardial recovery in patients with advanced chronic heart failure (HF) with reduced left ventricular ejection fraction (HFrEF) undergoing left ventricular assist device (LVAD) support. Heart failure impacts approximately 6.5 million individuals in the United States, with half exhibiting reduced ejection fraction. While mechanical unloading via LVADs can reverse structural remodeling and restore systolic function, clinical recovery occurs only in a specific subset of responders. The research sought to determine the role of the muscle-specific protein PERM1 in modulating cardiomyocyte metabolism and contractile function during mechanical circulatory rest.

Using a translational approach approved under University of Utah IRB00030622, researchers analyzed paired myocardial tissue samples from 19 patients with chronic advanced HFrEF enrolled in the UTAH Cardiac Transplant Program, defined by continuous symptoms for over 3 months. Tissue specimens were harvested from the left ventricular apex during primary device implantation and subsequently during explantation or cardiac transplantation. Quantifications revealed that baseline PERM1 expression was uniformly suppressed across all 19 patients prior to mechanical support. Following longitudinal LVAD therapy, PERM1 expression was fully restored to near-normal physiological levels exclusively within the cohort of clinical responders, whereas expression remained chronically suppressed in non-responders.

Mechanistically, PERM1 serves as a vital regulator of cardiomyocyte bioenergetics and cellular stress-related metabolic pathways. The normalization of this protein strongly correlates with the reversal of the energy-depletion and contractile-deficit cycle characteristic of advanced cardiomyopathy. Preclinical models indicate that therapeutic upregulation of PERM1 can mitigate structural failure and preserve baseline ejection fraction, positioning this protein as both a prognostic biomarker and a viable target for gene therapy. The findings suggest that targeting muscle-specific bioenergetic pathways can actively repair myocardial tissue, though larger trials are required to establish specific hazard ratios for long-term explantation success.

Link to the article: https://www.ahajournals.org/doi/10.1161/JAHA.125.044558

References

Sreedevi, K., Shankar, T. S., Zaitsev, A. V., Korte, A., Tseliou, E., Kyriakoulis, I., Selzman, C. H., Drakos, S. G., & Warren, J. S. (2026). Perm1 is selectively restored in left ventricular assist device–mediated myocardial recovery in heart failure. Journal of the American Heart Association, 15(9), e044558. https://doi.org/10.1161/JAHA.125.044558