KBI has various NHP models of cardiovascular disease including prolonged feeding with high fat diet (HFD), high fat and high fructose diet (HFHFrD) with added cholesterol and spontaneous hypertension with ageing. Hypertension is screened by the measurement of blood pressure (BP) with High Definition Oscillometry (HDO).
Myocardial infarction and heart failure are leading causes of the mortality worldwide. The NHP model of myocardial ischemia/reperfusion injury is very unique for the evaluation of new therapeutics (particularly protein products and gene therapies) to clinical application devoid of inter-species variations.
KBI has various models of ischemic-reperfusion by blocking and releasing the left anterior descending (LAD) artery. The ischemia and reperfusion injury is monitored by the ST elevation (STEMI) in ECG, plasma levels of creatine kinase (CK) and lactate dehydrogenase (LDH), and can be further examined by gross morphology and histopathology.
Chronic heart failure (CHF) affects 26 million people worldwide and it increases with aging and acute cardiovascular events. Current therapies for the reduced ejection fraction (HFrEF) are inadequate and almost no effect to preserve ejection fraction (HFpEF). Rodent models of heart failure have been widely used for drug discovery and significantly advanced the understanding of the mechanisms. Cynomolgus monkeys with metabolic dysfunctions are ideal models to verify these findings prior to the trial in humans because the monkey species are much closer to patients and can spontaneously progress to CHF (Fig 1).
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).