Cellular, structural and functional cardiac remodelling following pressure overload and unloading.

Area of Science:

• Cardiovascular Research
• Heart Failure Pathophysiology
• Cardiac Remodeling

Background:

• Pressure overload (PO) induces cardiac remodeling, involving fibrosis and cardiomyocyte hypertrophy, but its reversibility is unclear.
• Understanding PO-induced cardiac remodeling is crucial for advanced heart failure treatment.
• This study investigates PO-induced cardiac remodeling and its reversal after unloading in humans and a mouse model.

Purpose of the Study:

• To examine pressure overload (PO)-induced cardiac remodeling processes.
• To assess the reversibility of cardiac remodeling after unloading.
• To investigate the role of adiponectin receptor adaptor proteins in cardiac remodeling.

Main Methods:

• Utilized a mouse model of pressure overload induced by aortic constriction.
• Analyzed human left ventricular biopsy samples from heart failure patients.
• Employed speckle tracking echocardiography, Masson's Trichrome staining, and scanning electron microscopy.
• Assessed myofibroblast content, cardiomyocyte disarray, hypertrophy, and adiponectin receptor adaptor protein expression (APPL1, APPL2).

Main Results:

• Left ventricular unloading reversed cardiac dysfunction and largely normalized fibrosis, cardiomyocyte hypertrophy, and disarray in both mice and humans.
• Scanning electron microscopy revealed persistent disorganization of collagen fibers despite reduced overall fibrosis.
• Human samples showed reduced large collagen fibers after unloading, but a network of small fibers remained around cardiomyocytes.
• APPL1 expression trended towards normalization after unloading, unlike APPL2.

Conclusions:

• Left ventricular unloading effectively diminishes pressure overload-induced cardiac remodeling and improves cardiac function.
• Persistent collagen disorganization after unloading highlights the complexity of matrix remodeling.
• Findings provide novel insights into cardiac remodeling and identify potential targets for future pharmacologic therapies.