Author + information
- Nathan O. Stitziel, MD, PhD∗ (, )
- Kiran Musunuru, MD, PhD, MPH and
- Sekar Kathiresan, MD
- ↵∗Cardiovascular Division, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8086, St. Louis, Missouri 63110
In their response to our recent paper in the Journal (1), Dr. Luo and colleagues comment that circulating ANGPTL3 concentrations may be affected by an acute myocardial infarction. They also raise the possible role of ANGPTL3 in angiogenesis as a consideration for anti-ANGPTL3 therapeutics.
We agree that the acute phase of myocardial injury can affect levels of circulating proteins. However, we do not have plasma ANGPTL3 concentration measured at other time points (e.g., preceding or following the acute phase of injury) to determine if its concentration is also affected by an acute myocardial infarction. Regardless, individuals with loss-of-function mutations in ANGPTL3 have lifelong reductions in circulating ANGPTL3 protein concentration (2,3) along with reduced risk of coronary artery disease (1,2), supporting the association between ANGPTL3 plasma concentration and risk of disease. Although ANGPTL3 may play a role in angiogenesis, humans without circulating ANGPTL3 do not appear to have defective wound healing or other signs of impaired angiogenesis. The number of such humans is limited, however, and further studies may clarify the role of ANGPTL3 in angiogenesis.
Dr. Guo and colleagues request additional data on the potential relationship of ANGPTL3 deficiency with obesity and normal physiological functions. In addition, they wonder if ANGPTL3 deficiency may differ from anti-ANGPTL3 therapies.
Our current study included 3 participants with complete ANGPTL3 deficiency, effectively precluding any conclusions on differences in these individuals with respect to body mass index or other phenotypes. These participants were included in a previous study (2), however, which reported on the clinical phenotypes of 22 individuals with complete ANGPTL3 deficiency, 93 individuals with partial ANGPTL3 deficiency, and 402 control subjects without ANGPTL3 deficiency. Body mass index did not differ according to ANGPTL3 deficiency status in that study.
Ongoing studies of humans with loss-of-function mutations may provide additional data to address questions regarding the broader potential physiological impact of therapeutically targeting ANGPTL3. However, as Dr. Guo and colleagues suggest, loss-of-function mutations differ from pharmacological inhibition in important ways. For example, pharmacological therapy is associated with a shorter duration of inhibition (several years compared with a lifetime in mutation carriers) and may be associated with off-target effects. As such, randomized controlled trials will be required to provide definitive answers regarding the efficacy and safety of therapies targeting ANGPTL3.
Please note: Dr. Stitziel has received a research grant from AstraZeneca and consulting fees from Aegerion Pharmaceuticals. Dr. Kathiresan has received grants from Bayer Healthcare, Aegerion Pharmaceuticals, and Regeneron Pharmaceuticals; has received consulting fees from Merck, Novartis, Sanofi, AstraZeneca, Alnylam Pharmaceuticals, Leerink Partners, Noble Insights, Quest Diagnostics, Genomics PLC, and Eli Lilly; and holds equity in San Therapeutics and Catabasis Pharmaceuticals. Dr. Musunuru has reported that he has no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation
- Stitziel N.O.,
- Khera A.V.,
- Wang X.,
- et al.
- Minicocci I.,
- Santini S.,
- Cantisani V.,
- et al.
- Dewey F.E.,
- Gusarova V.,
- Dunbar R.L.,
- et al.