Ultrasound evaluation of cardiovascular function in male and female APOE3 and APOE4 mice

Abstract

Introduction Alzheimer's disease (AD) is the most common form of dementia and is the 6th leading cause of death in the US. Growing evidence supports a link between AD and cardiovascular disease (CVD). Variant isoforms of apolipoprotein E (APOE) are risk factors for both AD and CVD. The most common APOE isoform, APOE3, has neutral risk for developing AD, whereas APOE4 increases AD risk. Pathogenic alterations in cardiac (C), aortic (TA) and carotid artery (CA) function are known to contribute to neurodegenerative diseases including AD. Previous studies in our lab have demonstrated cerebral arteries from APOE3 mice exhibit “normal” aging characteristics, whereas cerebral arteries from APOE4 mice exhibited a delay in age-related changes in vascular structure and function. Because of this observation, we investigated whether age-related changes in cardiac structure/function (in vivo) mirrored in vitro experiments of isolated cerebral arteries. Here, we evaluated age-related changes in cardiac structure/function, in mice expressing human-ApoE targeted replacement of APOE3 (B6.129P2-Apoetm2(APOE*3)Mae N8) or APOE4 (B6.129P2-Apoetm3(APOE*4)Mae N8)(Taconic Labs). We hypothesized that mice expressing APOE4 would have delayed age-related changes in cardiac structure/function compared to age matched APOE3 mice. Methods In vivo high-resolution ultrasound (U/S) imaging was performed to evaluate the structure and function of cardiac, thoracic aorta (TA), carotid artery (CA), and cerebral blood flow in young (3-4 months), adult (12-14 months) and aged (18-20 months), APOE3 and APOE4 mice. Male and female mice were used. Blood pressure (BP) was determined using the tail-cuff method. All U/S and BP values were collected under isoflurane anesthesia. Results were considered significant at p<0.05. Results Both hAPOE3 and hAPOE4 mice exhibited age-related increase in body weight. The peak velocity measurements of the posterior cerebral artery showed no statistical difference between the groups. CA structure and function was assessed by wall thickness (WT) and pulse wave velocity (PWV) respectively. Our data showed an age-related increase in CA PWV and WT in hAPOE3 and hAPOE4 mice. TA PWV also showed an age-related increase in both hAPOE3 and hAPOE4 mice (P<0.05). The indices of cardiac function, cardiac output (CO), ejection fraction (EF), stroke volume (SV) showed no significant difference between the groups. The left ventricle mass increased with age in both hAPOE3 and hAPOE4 mice. And finally, the systolic and diastolic BP values showed no significance difference between groups. Conclusion These data suggest that hAPOE3 and hAPOE4 mice show similar age-related cardiac and vascular changes. Future studies have been designed to assess whether psycho-social stress and/or diet are involved in APOE4 allele related development of CVD and AD/dementia.