Cellular, structural and functional cardiac remodelling following pressure overload and unloading
Keith Dadson1, Vera Kovacevic1, Palanivel Rengasamy1
1Department of Biology, York University, Toronto, Canada.
Insights
Left ventricular unloading improves heart function and cardiac remodelling in heart failure. While fibrosis markers decrease, collagen disorganization persists, suggesting potential therapeutic targets.
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.
Background:
The cardiac remodelling process in advanced heart failure due to pressure overload has not been clearly defined but likely involves mechanisms of cardiac fibrosis and cardiomyocyte hypertrophy. The aim of this study was to examine pressure overload (PO)-induced cardiac remodelling processes and their reversibility after unloading in both humans with heart failure and a mouse model of PO induced by aortic constriction.
Methods & Results:
Speckle tracking echocardiography showed PO-induced cardiac dysfunction in mice was reversible after removal of aortic constriction to unload. Masson's Trichrome staining suggested that PO-induced myocardial fibrosis was reversible, however detailed analysis of 3-dimensional collagen architecture by scanning electron microscopy demonstrated that matrix remodelling was not completely normalised as a disorganised network of thin collagen fibres was evident. Analysis of human left ventricular biopsy samples from HF patients revealed increased presence of large collagen fibres which were greatly reduced in paired samples from the same individuals after unloading by left ventricular assist device implantation. Again, an extensive network of small collagen fibres was still clearly seen to closely surround cardiomyocytes after unloading. Other features of PO-induced remodelling including increased myofibroblast content, cardiomyocyte disarray and hypertrophy were largely reversed upon unloading in both humans and mouse model. Previous work in humans demonstrated that receptors for adiponectin, an important mediator of cardiac fibrosis and hypertrophy, decreased in heart failure patients and returned to normal after unloading. Here we provide novel data showing a similar trend for adiponectin receptor adaptor protein APPL1, but not APPL2 isoform.
Conclusions:
LV unloading diminishes PO-induced cardiac remodelling and improves function. These findings add new insights into the cardiac remodelling process, and provide novel targets for future pharmacologic therapies.
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