Spontaneous Degenerative Aortic Valve Disease in New Zealand Obese Mice.
Christiane OttKathleen PappritzNiklas HegemannCathleen JohnSarah JeutheCameron S McAlpineYoshiko IwamotoJonathan H LaurynJan KlagesRobert KlopfleischSophie Van LinthoutFilip K SwirskiMatthias NahrendorfUlrich KintscherTilman GruneWolfgang M KueblerJana GrunePublished in: Journal of the American Heart Association (2021)
Background Degenerative aortic valve (AoV) disease and resulting aortic stenosis are major clinical health problems. Murine models of valve disease are rare, resulting in a translational knowledge gap on underlying mechanisms, functional consequences, and potential therapies. Naïve New Zealand obese (NZO) mice were recently found to have a dramatic decline of left ventricular (LV) function at early age. Therefore, we aimed to identify the underlying cause of reduced LV function in NZO mice. Methods and Results Cardiac function and pulmonary hemodynamics of NZO and age-matched C57BL/6J mice were monitored by serial echocardiographic examinations. AoVs in NZO mice demonstrated extensive thickening, asymmetric aortic leaflet formation, and cartilaginous transformation of the valvular stroma. Doppler echocardiography of the aorta revealed increased peak velocity profiles, holodiastolic flow reversal, and dilatation of the ascending aorta, consistent with aortic stenosis and regurgitation. Compensated LV hypertrophy deteriorated to decompensated LV failure and remodeling, as indicated by increased LV mass, interstitial fibrosis, and inflammatory cell infiltration. Elevated LV pressures in NZO mice were associated with lung congestion and cor pulmonale, evident as right ventricular dilatation, decreased right ventricular function, and increased mean right ventricular systolic pressure, indicative for the development of pulmonary hypertension and ultimately right ventricular failure. Conclusions NZO mice demonstrate as a novel murine model to spontaneously develop degenerative AoV disease, aortic stenosis, and the associated end organ damages of both ventricles and the lung. Closely mimicking the clinical scenario of degenerative AoV disease, the model may facilitate a better mechanistic understanding and testing of novel treatment strategies in degenerative AoV disease.
Keyphrases
- aortic valve
- aortic stenosis
- transcatheter aortic valve replacement
- aortic valve replacement
- transcatheter aortic valve implantation
- left ventricular
- ejection fraction
- pulmonary hypertension
- high fat diet induced
- heart failure
- adipose tissue
- mitral valve
- cardiac resynchronization therapy
- pulmonary artery
- mental health
- stem cells
- single cell
- mesenchymal stem cells
- acute myocardial infarction
- blood flow
- cell therapy
- pulmonary arterial hypertension
- hypertrophic cardiomyopathy
- computed tomography
- type diabetes
- coronary artery disease
- obese patients
- skeletal muscle
- climate change
- risk assessment