Figure 2. Small animal models are beginning to identify key cellular events in the progression of adverse cardiac remodeling linked to diastolic dysfunction in heart failure with preserved ejection fraction.

A key initiating factor is thought to be microvascular inflammation, an event linked to diastolic dysfunction or impaired contractile relaxation by 2 means: via increased fibrosis and by impairing normal NO/cGMP/PKG signaling and altering titin phosphorylation. In addition, the upregulation of iNOS leads to an impaired unfolded protein response, resulting from impaired IRE1α (inositol requiring transmembrane kinase endoribonuclease 1α) splicing activity and diminished Xpb1s levels, in cardiomyocytes that are subjected to endoplasmic reticulum stress attributable to hypertrophic pressures. Exacerbation of endoplasmic reticulum stress leads to oxidative stress, mitochondrial dysfunction, and impaired Ca²⁺ handling that can feedback to worsen diastolic function. Some content is adapted from Servier Medical Art (https://smart.servier.com/) under the terms of the Creative Commons Attributions 3.0 Unported License. AIU, aldosterone‐infused uninephrectomy; cGMP, cyclic guanosine monophosphate; ER, endoplasmic reticulum; iNOS, inducible nitric oxide synthase; NO, nitric oxide; NOS2, nitric oxide synthase 2; PKG, protein kinase G; and UPR, unfolded protein response.