13 Nov Echocardiography in rodents to track dimorphism in heart failure
Heart failure (HF) occurs in women as frequently as in men, but the events tend to happen later in life for women and less often from ischaemic causes. This is reflected in pre-clinical heart disease models in rodents (either rat or mouse), where oestrogens have been shown to slow the development of left ventricle hypertrophy (LVH), a prognostic indicator of progression towards heart failure, delay HF and improve survival. Indeed, LVH becomes more prevalent in women after menopause and constitutes the strongest mortality predictor from HF. Volume overload (VO) diseases such as heart/aortic valve regurgitations (AR), typically induce eccentric LVH, as in pressure overload (PO) diseases such as aortic valve stenosis or arterial hypertension. Sex differences of HF in both VO and PO diseases remain mostly unstudied.
In both pre-clinical PO and VO rodent models, the development of HF in males usually progresses more quickly towards heart failure than in females, but this may not be directly linked to levels of cardiac hypertrophy. Researchers looked into sexual dimorphism in myocardial transcriptional adaptations to severe VO from severe Aortic valve regurgitation. They showed that LV gene expression in rats with severe AR is significantly less altered in females, although they developed significantly more cardiac hypertrophy than males in response to volume overload.
The rats were also examined using echocardiography, which allowed to further understand the mechanisms at play and the morphological differences between males and females. The results showed as expected that volume overload caused marked LV dilatation that was similar for both sexes and an increase in end-systolic diameters in males (+59%) and female (+43%) AR rats, resulting in a larger decrease in LV fractional shortening (FS) in males (−20%) than in females (-11%). Moreover, the LV mid-wall velocity was lower in the males than in the females, a good index of systolic function, and septal wall thickness increased in females but not in males with AR. It was also evident that both AR males and females displayed eccentric LV remodelling, a little less in females, as a decrease in relative wall thickness was visible with the echocardiography.
Overall, the data showed that there was more LV wall thickening in AR female, whereas chamber dilation was relatively similar, resulting in less eccentric LV remodelling compared to males. This remodelling was accompanied by lower levels of wall stress in females despite higher levels of hypertrophy and a similar degree of aortic valve regurgitation. Echocardiographic data helped further show evidence of these mechanical and morphological sexual difference, and is a useful tool for the study of heart failure in general, in humans and evidently in animal models, as small as the rat or the mouse.
Syncrosome, a scientific preclinical CRO based in France, uses echocardiography in animal models to study conditions linked to heart failure. With the device, they can monitor Coronary artery ligation, reperfusion, blood pressure, heart rate, planimetry, histology and morphological and functional biomarkers. By combining all these parameters, they can most reliably test for appropriate reaction.
Adult Wistar male and female rats either underwent a sham operation or were induced with AR and then followed for 26 weeks. Female AR rats gained relatively more LV mass than males (75 vs. 42%). They had a similar increase in LV chamber dimensions compared to males but more wall thickening. On the other hand, fatty acid oxidation (FAO)-related LV enzyme activity was only decreased in AR males. The expression of genes encoding FAO-related enzymes was only reduced in AR males and not in females. A similar situation was observed for the expression of genes involved in mitochondrial biogenesis or function as well as for genes encoding for transcription factors implicated in the control of bioenergetics and mitochondrial function (Errα, Errγ or Pgc1α). Although females develop more LV hypertrophy from severe VO, their myocardial gene expression remains closer to normal. This could provide survival benefits for females with severe VO.
Key words: preclinical CRO, preclinical study, animal model, animal research, myocardial, ischemia, infarction, reperfusion, heart, rat model, mouse model, inflammation, heart failure, sex dimorphism, echocardiography, heart disease, pressure overload, volume overload