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Review
. 2014 Dec;11(4):436-44.
doi: 10.1007/s11897-014-0219-3.

New insights in (inter)cellular mechanisms by heart failure with preserved ejection fraction

Carsten Tschöpe  1 , Sophie Van Linthout
Affiliations
Review

New insights in (inter)cellular mechanisms by heart failure with preserved ejection fraction

Carsten Tschöpe et al. Curr Heart Fail Rep. 2014 Dec.

Abstract

Recently, a new paradigm for the development of heart failure with preserved ejection fraction (HFpEF) has been proposed, which identifies a systemic pro-inflammatory state induced by comorbidities as the origin of microvascular endothelial cell inflammation and subsequent concentric cardiac remodeling and dysfunction. This review further discusses the pivotal role of the inflamed endothelium in the pathogenesis of HFpEF-specific cardiac remodeling. The potential importance of reciprocal interactions of the endothelium with cardiac fibroblasts and cardiomyocytes and with the cardiac neurohumoral response in this cardiac remodeling process is outlined.

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Conflict of interest statement

Carsten Tschöpe and Sophie Van Linthout declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Impact of endothelial dysfunction on the pathogenesis of HFpEF. Comorbodities such as obesity, hypertension, diabetes mellitus, microalbuminuria, iron deficiency, and hypercoagulability induce a systemic inflammatory state leading to increased VCAM-1 expression, subsequent monocyte adhesion, and infiltration of inflammatory cells releasing pro-inflammatory factors including interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, and soluble ST2 (sST2), which promote endothelial dysfunction. The resulting endothelial dysfunction is associated with impaired NO bioavailibilty and ROS production, leading to the formation of peroxynitrite (ONOO−), all of which induce lowering of protein kinase G (PKG) activity and subsequently titin hypophosphorylation and an increased resting tension (F passive) of cardiomyocytes. Intracellular calcium dysregulation involving dysfunction of the sarcoplasmic reticular adenosine triphosphate (ATP)-driven pump (SERCA), phospholamban (PLB), and/or ryanodine receptors (RYR) 2 further participates to cardiomyocyte stiffness. Low PKG activity and, among others, the release of endothelin-1 by activated endothelial cells, contribute to cardiomyocyte hypertrophy. Furthermore, NO deprivation results in endothelial-to-mesenchymal transition (EndMT), a process by which endothelial cells transdifferentiate into (myo)fibroblasts. VCAM-1 and E-selectin expression on endothelial cells favors the adhesion of leukocytes, which by releasing transforming growth factor β (TGF-β) stimulate EndMT and the conversion of fibroblasts to myofibroblasts and hereby cardiac fibrosis. By the release of, among others, chemokines (monocyte chemotractant protein-1) and the induction of matrix metalloproteinases, (myo)fibroblasts stimulate the inflammatory process. Cardiac fibrosis, cardiomyocyte hypertrophy, and/or cardiomyocyte stiffness contribute to wall stress and diastolic dysfunction
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