Cellular and Molecular Differences between HFpEF and HFrEF: A Step Ahead in an Improved Pathological Understanding

Steven J Simmonds, Ilona Cuijpers, Stephane Heymans, Elizabeth A V Jones, Steven J Simmonds, Ilona Cuijpers, Stephane Heymans, Elizabeth A V Jones

Abstract

Heart failure (HF) is the most rapidly growing cardiovascular health burden worldwide. HF can be classified into three groups based on the percentage of the ejection fraction (EF): heart failure with reduced EF (HFrEF), heart failure with mid-range-also called mildly reduced EF- (HFmrEF), and heart failure with preserved ejection fraction (HFpEF). HFmrEF can progress into either HFrEF or HFpEF, but its phenotype is dominated by coronary artery disease, as in HFrEF. HFrEF and HFpEF present with differences in both the development and progression of the disease secondary to changes at the cellular and molecular level. While recent medical advances have resulted in efficient and specific treatments for HFrEF, these treatments lack efficacy for HFpEF management. These differential response rates, coupled to increasing rates of HF, highlight the significant need to understand the unique pathogenesis of HFrEF and HFpEF. In this review, we summarize the differences in pathological development of HFrEF and HFpEF, focussing on disease-specific aspects of inflammation and endothelial function, cardiomyocyte hypertrophy and death, alterations in the giant spring titin, and fibrosis. We highlight the areas of difference between the two diseases with the aim of guiding research efforts for novel therapeutics in HFrEF and HFpEF.

Keywords: cardiomyocyte alterations; endothelial dysfunction; heart failure with preserved ejection fraction; heart failure with reduced ejection fraction; inflammation.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Risk factors and comorbidities involved in the development of either heart failure with reduced ejection fraction, heart failure with preserved ejection fraction or both. Image created using artwork from Servier medical art.
Figure 2
Figure 2
Schematic of sterile-, metabolic risk-, and non-sterile-induced inflammation in the development of heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. HFpEF (heart failure with preserved ejection fraction), HFrEF (heart failure with reduced ejection fraction), HSC (haemopoietic stem cell), IFN1 (interferon 1), IL-10 (interleukin 10), MAPK (mitogen-activated protein kinase), NFκB (nuclear factor kappa B), PRR (pathogen recognition receptor), T2DM (type 2 diabetes mellitus), ROS (reactive oxygen species), TGFβ (transforming growth factor beta) Image created using artwork from Servier medical art.
Figure 3
Figure 3
The role of titin in left ventricular stiffness. (A) Diagram of the alternative isoforms of titin. (B) Post-translational modifications of Titin and their effect on left ventricular stiffness in HFrEF and HFpEF.

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