Chronic heart failure (CHF) is a disease affecting 26 million people worldwide. The increasing prevalence of CHF is related to the aging of the susceptible population and the improvement in the treatment of acute cardiovascular events. Although current therapies improve the symptoms associated with reduced ejection fraction (HFrEF) to a certain extent, much more efficacious therapies are required to greatly improve the quality of life and extend the life span of heart failure patients. Furthermore, there is an urgent need to explore novel therapeutic strategies for heart failure with preserved ejection fraction (HFpEF), which usually does not respond to the conventional therapies.
Translatable animal models are highly desirable to better understand the pathophysiology and pharmacology of heart failure. Rodent models of heart failure, which are caused either by artificial stress or single gene deficiency, have been widely used for drug discovery for decades. Those models have obvious issues of translatability.
Unlike rodents, non-human primates (NHPs) have advantage of significant similarities to humans in histology, biochemistry, physiology and genetics. Cynomolgus monkeys with metabolic dysfunctions share risk factors of heart failure with susceptible patients and progress to CHF spontaneously (Fig 1).
To screen for heart failure monkeys, over 1000 monkeys fed HFD for two years or longer and have more severe metabolic syndrome are selected for the cardiac functional assessment by echocardiography. About 38% of the selected monkeys with severe metabolic dysfunction were found to have different extents of either systolic or diastolic dysfunction (Fig2, 3, 4).
N-terminal pro-brain natriuretic peptide (NT-proBNP), a CHF specific biomarker, has been demonstrated to be valuable in primary care and clinical studies, and also for assessment of drug efficacy. In the CHF monkeys, NT-proBNP is significantly elevated (Fig5), which provides us an advantage when assessing efficacy and toxicity of drugs.
MRI T1 mapping for determination of extracellular matrix volume (ECV) as a surrogate for the interstitial cardiac fibrosis is evolving as a non-invasive diagnosis approach for HF patients, especially those with HFpEF. We are validating the assay at KBI in the HFpEF monkeys (Fig6).
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