Thread by @skathire

Terrific week ahead:

@KeystoneSymp on atherosclerosis

Will be live-tweeting as appropriate.

#KSathero

atherosclerosis
1st keynote: Peter Libby @BrighamWomens

“Is the vulnerable plaque a valid concept in 2018?”

academic.oup.com/eurheartj/arti…

Libby: in vivo imaging, few thin-capped fibroatheromas actually rupture

Libby: argues that with pervasive LDL lowering, leading to different types plaques
1. Less inflamed
2. Lipid core less
3. Fibrous tissue up
4. Calcified tissue up

Libby: arguing that superficial erosion becoming a more impt process than plaque rupture.

#KSathero

academic.oup.com/eurheartj/adva…

Libby: what is the mechanistic basis for superficial plaque erosion?

Understand this process a lot less than plaque rupture.

#KSathero

Libby: study superficial erosion, new animal models, lesions rich in glycosaminoglycans.

circres.ahajournals.org/content/early/…

#KSathero

Libby: is the distinction between plaque rupture and erosion impt?

Small provocative study: ACS with erosion may not require stent but just intense antiplatelet

academic.oup.com/eurheartj/arti…

Gerard Pasterkamp, Utrecht:

Large atherosclerosis plaque biobank

Underlying pathology of plaque changing over time.

#KSathero

Pasterkamp: Describes a toolkit to analyze pathological slides of atherosclerosis

Uses Cellprofiler; cc @DrAnneCarpenter

journals.plos.org/plosone/articl…

Philippe Boucher, Strasbourg.

40-50% foam cells from vascular smooth cells, not macrophages

LRP1 activates wnt5a;

wnt5a protects against chol accumulation.

ncbi.nlm.nih.gov/m/pubmed/26792…

#KSathero

Summer Khetarpal, @PennMedicine

dissection on how a missense variant in APOC3 (A43T):
1. Leads to loss of protein function
2. Mutant apoc3 cleared much faster than wild-type
3. Mutant binds less well to TRLs
4. Unbound apoc3 cleared by kidney

nature.com/articles/nm.43…

Khetarpal:

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

nature.com/articles/nm.43…

Kiran Musunuru, @PennMedicine

Therapeutic genomic editing to ‘cure’ atherosclerotic cardiovascular disease.

Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing.

#KSathero

ncbi.nlm.nih.gov/m/pubmed/24916…

Musunuru, @PennMedicine

For therapeutic genome editing, need to look at cells with human genome.

Targeting human PCSK9 in chimeric liver-humanized mice

ncbi.nlm.nih.gov/m/pubmed/26941…

#KSathero

, @PennMedicine

in vivo base editing of murine Pcsk9
in vivo base editing of murine Angptl3

ncbi.nlm.nih.gov/pubmed/28751571

Dan Rader, @PennMedicine, Functionalizing HDL
LCAT gain-of-function mutation
V114M, African-American specific, rare
12mg/dl higher HDL
GoF in vitro & in vivo
unknown relationship to CAD
he's looking at variant protein for gene therapy rare disease - LCAT deficiency
#KSAthero

Rader, @PennMedicine
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)

Rader, @PennMedicine
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

Rader, @PennMedicine
CSL112 formulation - extract ApoAI from plasma donated by humans, complex w/ phospholipids; infusion post ACS
Trial n=17,400
So far, in Phase 2, safe & alter surrogate - cholesterol efflux capacity
Will this translate into CVOT?
@CMichaelGibson leading CVOT

Do you think improving plasma cholesterol efflux capacity by infusing ApoAI will improve atherosclerotic cardiovascular disease outcomes?

@CSLBehring has bet big on this hypothesis.

J. Mark Brown, @ClevelandClinic
Selective small molecule inhibition of gut microbial enzymes for the treatment of cardiometabolic disorders
Talking about role of FMO3 (enzyme that generates TMAO) in reverse cholesterol transport
uknowledge.uky.edu/cgi/viewconten…
#KSathero

Brown, @ClevelandClinic
TMAO pathway. Dietary choline, converted by bacterial enzyme TMA lyase to generate TMA. Absorbed thru gut. In blood, TMA to TMAO by FMO3. TMAO hypothesized to be proatherogenic.

Describing development of TMA lyase inhibitors
cell.com/cell/abstract/…

Joerg Heeren, UMC Hamburg-Eppendorf
Protective role of brown adipose in atherosclerosis development

In mice, brown adipose tissue activity controls triglyceride clearance

ncbi.nlm.nih.gov/pubmed/21258337

J. Heeren
Brown adipose tissue activation improves hyperlipidemia and protects from atherosclerosis in mice
Model dependent:
Protective in APOE*3-Leiden.CETP mice but not in Apoe(-/-) or Ldlr(-/-) mice
#KSAthero
ncbi.nlm.nih.gov/pubmed/25754609

J. Heeren
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

L. Michael, @LillyPad, co-organizer @KeystoneSymp athero
anti-diabetic agents & cardiovascular outcomes
Reviewing hx approaches to reduce CV outcomes in T2D pts
FDA/EMA guidance 2008/2012: new anti-diabetic meds need to show that they do *NOT* worsen CV outcomes
#KSAthero

L. Michael, @LillyPad
Anti-diabetic agents that have been/are being studied for CVOT:
DPP4i
SGLT2i
GLP1RA
oral GLP1RA
insulin
TZD

L. Michael, @LillyPad
DPP4i, improve glucose, no change in CV outcomes

L. Michael, @LillyPad

GLP1 analogues - lower glucose, improve CV outcomes
Example: LEADER trial

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes | NEJM nejm.org/doi/full/10.10…

L. Michael, @LillyPad

SGLT2 inhibitors - lower glucose, improve CV outcomes
Example: EMPA-REG trial

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes | NEJM nejm.org/doi/full/10.10…

Terrific review of the GLP1 axis here by @DanielJDrucker

The Cardiovascular Biology of Glucagon-like Peptide-1 cell.com/cell-metabolis…

, @Columbia
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

Adipose-specific TRIB1 KO:
higher plasma adiponectin levels
no difference in insulin sensitivity
plasma TG down (but liver-specific KO had increased TG)

Brian Parks, U. Wisconsin
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

#KSAthero

Beautiful study by Brian Parks
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
#KSAthero

Ziad Mallat, @UniCambridge

Immune modulation in atherosclerosis

sensing of necrotic cells by DNGR-1 plays a role in the inflammatory response of atherosclerosis

ncbi.nlm.nih.gov/m/pubmed/28607…

#KSathero

Ziad Mallat

B cell depletion with rituximab in acute STEMI!

Doing proof of concept studies for this hypothesis

#KSAthero

Jan Nilsson, @lunduniversity

Posits that with pervasive statin Rx, new mechanisms leading to plaque instability and clinical events

Mechanisms such as cell death and matrix repair

Studying biomarkers of apoptosis.

ncbi.nlm.nih.gov/m/pubmed/29208…

#KSAthero

J. Nilsson

ApoB peptide based vaccines reduce athero mice.
Talking about 15y, why no trials?

Challenges:
Lack robust effect of GMP grade formulations
Presumed tolerance difficult to monitor in clinic
Ph2 lack good surrogate measures
Little experience vaccine chronic diseases

Outside Millicent Rogers Museum, NM

Last but not least for tonight: Paul Ridker, @BrighamWomens

Can inflammation reduction, in absence of lipid lowering, reduce clinical cardiovascular outcomes?

#KSAthero

academic.oup.com/eurheartj/arti…

Ridker:

Chose IL1-beta antagonist (canakinumab) to test inflammation CVD hypothesis

CANTOS trial

Dose dependent decreases CRP 35-40%

Placebo event rate: 4.5% per y

150mg dose: 3.9% per y

HR 0.85 for MACE

nejm.org/doi/full/10.10…

Ridker:

With canakinumab Rx, remarkable reduction in incident lung cancer (non-small cell, largely)

thelancet.com/journals/lance…

#KSathero

Ridker

IL1beta antagonism ‘worked’

What didn’t work/in progress
Losmapimod
Low-dose colchicine
IL6receptor antagonists
NLRP3 inhibitor
Methotrexate
Darapladib

He suggests things that work primarily target IL1-beta pathway

#KSathero

Ridker took some friendly fire from Salim Yusuf on the methodologic appropriates of responder/non-responder (got to CRP<2 or not) analysis in a completed RCT

Basically, this is observational analysis with all its attendant limitations re causal inference.

Finis