Persistent Fibrosis in Heart Failure With a Reduced Ejection Fraction Linked to Phenotypic Differences in Human...

Area of Science:

• Cardiology
• Biomedical Engineering
• Translational Medicine

Background:

• Myocardial fibrosis is a common characteristic of cardiomyopathies leading to heart failure with reduced ejection fraction.
• Left ventricular assist device (LVAD) therapy unloads the heart but has not consistently reduced fibrosis in previous studies.
• This study investigates persistent fibrosis and fibroblast activation despite LVAD treatment.

Purpose of the Study:

• To test if fibrosis and fibroblast activation persist after LVAD implantation, leading to sustained myocardial stiffness.
• To understand the role of fibroblast mechanosensitivity in the context of heart failure and LVAD support.

Main Methods:

• Collected myocardial tissues from heart failure patients pre-LVAD, post-LVAD, and controls.
• Quantified myocardial stiffness, collagen content, and fibroblast populations.
• Isolated fibroblasts and assessed their response to varying substrate stiffness, analyzing gene expression via bulk-RNA sequencing.

Main Results:

• Pre- and post-LVAD hearts showed increased myocardial stiffness and collagen content compared to controls.
• Fibroblast populations were elevated in pre- and post-LVAD hearts.
• While control fibroblasts adapted to substrate stiffness, pre- and post-LVAD fibroblasts did not, showing altered gene expression in mechano-sensitive pathways.

Conclusions:

• Sustained hemodynamic overload causes a fibroblast phenotype change, reducing their ability to sense mechanical input.
• This fibroblast reprogramming contributes to persistent collagen deposition and myocardial stiffness even after LVAD support.