Apolipoprotein E4 Is Associated with Right Ventricular Dysfunction in Dilated Cardiomyopathy—An Animal and In-Human Comparative Study

Abstract

ApoE abnormality represents a well-known risk factor for cardiovascular diseases. Beyond its role in lipid metabolism, novel studies demonstrate a complex involvement of apoE in membrane homeostasis and signaling as well as in nuclear transcription. Due to the large spread of apoE isoforms in the human population, there is a need to understand the apoE’s role in pathological processes. Our study aims to dissect the involvement of apoE in heart failure. We showed that apoE-deficient rats present multiple organ damages (kidney, liver, lung and spleen) besides the known predisposition for obesity and affected lipid metabolism (two-fold increase in tissular damages in liver and one-fold increase in kidney, lung and spleen). Heart tissue also showed significant morphological changes in apoE−/− rats, mostly after a high-fat diet. Interestingly, the right ventricle of apoE−/− rats fed a high-fat diet showed more damage and affected collagen content (~60% less total collagen content and double increase in collagen1/collagen3 ratio) compared with the left ventricle (no significant differences in total collagen content or collagen1/collagen3 ratio). In patients, we were able to find a correlation between the presence of ε4 allele and cardiomyopathy (χ2 = 10.244; p = 0.001), but also with right ventricle dysfunction with decreased TAPSE (15.3 ± 2.63 mm in ε4-allele-presenting patients vs. 19.8 ± 3.58 mm if the ε4 allele is absent, p < 0.0001*) and increased in systolic pulmonary artery pressure (50.44 ± 16.47 mmHg in ε4-allele-presenting patients vs. 40.68 ± 15.94 mmHg if the ε4 allele is absent, p = 0.0019). Our results confirm that the presence of the ε4 allele is a lipid-metabolism-independent risk factor for heart failure. Moreover, we show for the first time that the presence of the ε4 allele is associated with right ventricle dysfunction, implying different regulatory mechanisms of fibroblasts and the extracellular matrix in both ventricles. This is essential to be considered and thoroughly investigated before the design of therapeutical strategies for patients with heart failure.

Screening of Lipid Metabolism-Related Gene Diagnostic Signature for Patients With Dilated Cardiomyopathy

“…During the progression of heart failure, the transcription level of fatty acid oxidation is gradually down-regulated (3). ApoE abnormality is a well-known risk factor for cardiovascular disease, and rats lacking ApoE showed cardiac dysfunction after high-fat diet (4). Accumulating evidence shows that fatty acid oxidation disorders can worsen heart function and lead to decreased contractility (5,6).…”

Human ApoE2 Endows Stronger Contractility in Rat Cardiomyocytes Enhancing Heart Function

“…In hApoE2 Whether and how the ApoE2 allele is associated with susceptibility to CHD remains uncertain. Most studies believe the protective effect of ApoE2 on CHD [19,[50][51][52], while others show ambiguous and opposite opinions [51,[53][54][55]. The rarity of ApoE2 homozygous as ideal study objects makes it hard to conclude.…”

Testosterone and quality of life in patients with dilated cardiomyopathy

“…Routine echocardiographic examinations were performed blindly by experienced echocardio-graphers with standard techniques at the echo-cardiography core facility 11,12 .…”