Author + information
- Received August 22, 2017
- Revision received November 3, 2017
- Accepted November 4, 2017
- Published online April 30, 2018.
- Jamie Morton, MBBS, PhDa,b,
- Shisan Bao, MD, PhDc,
- Laura Z. Vanags, BSc, PhDa,b,
- Tania Tsatralis, BSca,
- Anisyah Ridiandries, BSc, PhDa,b,
- Chung-Wah Siu, MBBS, MDd,
- Kwong-Man Ng, BSc, PhDd,
- Joanne T.M. Tan, BSc, PhDa,b,
- David S. Celermajer, MBBS, PhDa,b,e,
- Martin K.C. Ng, MBBS, PhDa,b,e and
- Christina A. Bursill, BSc, PhDa,b,∗ ()
- aImmunobiology Group, The Heart Research Institute, Sydney, Australia
- bDepartment of Medicine, Sydney Medical School, University of Sydney, Sydney, Australia
- cDiscipline of Pathology, University of Sydney, Sydney, Australia
- dDivision of Cardiology, Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
- eDepartment of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia
- ↵∗Address for correspondence:
Dr. Christina Bursill, Heart Health Theme, SAHMRI, North Terrace, Adelaide, SA 5000, Australia.
• The atheroprotective effects of apoA-I are dependent on the plaque stage from which apoA-I is infused.
• The atheroprotective effects of apoA-I infusions are also impaired in older mice with a greater disease milieu.
• Ex vivo studies with mouse HDL found an impairment in HDL functionality with increasing disease/age of the mice as well as a reduced ability of apoA-I infusions to improve the atheroprotective functions of HDL.
• Our study provides understanding regarding the disparity between the very positive results of HDL/apoA-I raising in preclinical studies, largely performed in younger animals with early-stage disease, and the large-scale HDL-raising clinical trials in more elderly patients with established plaque that have failed to show benefit.
Preclinical studies have shown benefit of apolipoprotein A-I (apoA-I)/high-density lipoprotein (HDL) raising in atherosclerosis; however, this has not yet translated into a successful clinical therapy. Our studies demonstrate that apoA-I raising is more effective at reducing early-stage atherosclerosis than late-stage disease, indicating that the timing of HDL raising is a critical factor in its atheroprotective effects. To date, HDL-raising clinical trials have only been performed in aged patients with advanced atherosclerotic disease. Our findings therefore provide insight, related to important temporal aspects of HDL raising, as to why the clinical trials have thus far been largely neutral.
This work was supported by a post-graduate scholarship from the National Medical Research Council of Australia (NHMRC) (#598402) and the Heart Foundation (HF) [PC09S4757] to Dr. Morton; and the NHMRC Project Grant (#632512) to Drs. Ng and Bursill. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Ng and Bursill contributed equally to this work.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received August 22, 2017.
- Revision received November 3, 2017.
- Accepted November 4, 2017.
- 2018 The Authors