1. Less inflamed
2. Lipid core less
3. Fibrous tissue up
4. Calcified tissue up
Understand this process a lot less than plaque rupture.
Small provocative study: ACS with erosion may not require stent but just intense antiplatelet
Large atherosclerosis plaque biobank
Underlying pathology of plaque changing over time.
in collaboration with Staten Biotech, New Haven
Developed monoclonal antibody that promotes dissociation of apoc3 from TRLs
Now, developed recycling antibody (STT508)
Single injection antibody, drop apoc3 for 4 weeks
Cholesterol efflux capacity, in vitro measure in humans
Inverse correlation with CAD, even after adjusting for plasma HDL-C
Consortium to look at genetics of this phenotype (n~13K)
Promoting cholesterol efflux by infusing ApoAI protein complexed with phospholipids may ameliorate CAD
Human tests of hypothesis
1. CER001 - failed IVUS trial, discontinued
2. MDC0216 - failed IVUS trial, discontinued
3. CSL112 - AEGIS-II trial ongoing
@CSLBehring has bet big on this hypothesis.
Protective role of brown adipose in atherosclerosis development
In mice, brown adipose tissue activity controls triglyceride clearance
What are interventions to activate brown adipose tissue in rodents?
1. Acute cold exposure: 24h mice at 6 degrees
2. Chronic cold exposure
3. BAT activation by β3-adrenergic receptor stimulation
Anti-diabetic agents that have been/are being studied for CVOT:
Adipose knockout tribbles-1, GWAS locus CAD, reduces plasma lipids & increases adiponectin
Why study tribbles1 (TR1B1) - one of only 2 loci from GWAS to associate with all 4 lipid traits (LDL, HDL, TG, TC) *AND* CAD; also associates adiponectin in humans
higher plasma adiponectin levels
no difference in insulin sensitivity
plasma TG down (but liver-specific KO had increased TG)
Journal of Lipid Research Junior Investigator Award recipient 👏
Leveraging mouse liver co-expression networks and human lipid GWAS data to identify and validate cholesterol metabolism genes
integrated mouse co-expression with (publicly available) lipids GWAS data
prioritized candidate genes
laboratory in vitro validation
in vivo validation
in depth analysis of one gene: sestrin-1
B cell depletion with rituximab in acute STEMI!
Doing proof of concept studies for this hypothesis
ApoB peptide based vaccines reduce athero mice.
Talking about 15y, why no trials?
Lack robust effect of GMP grade formulations
Presumed tolerance difficult to monitor in clinic
Ph2 lack good surrogate measures
Little experience vaccine chronic diseases
Chose IL1-beta antagonist (canakinumab) to test inflammation CVD hypothesis
Dose dependent decreases CRP 35-40%
Placebo event rate: 4.5% per y
150mg dose: 3.9% per y
HR 0.85 for MACE
IL1beta antagonism ‘worked’
What didn’t work/in progress
He suggests things that work primarily target IL1-beta pathway
Basically, this is observational analysis with all its attendant limitations re causal inference.