Progress in Molecular Cardiovascular Medicine: Lipidomics .../media/Non-Clinical/Files-PDFs... · Progress in Molecular Cardiovascular Medicine: Lipidomics, Proteomics & MicroRNAs.

Progress in Molecular Cardiovascular Medicine:Lipidomics, Proteomics & MicroRNAs

Manuel MAYR, MD, PhDBHF Professor of Cardiovascular Proteomics

King’s College London, UKIcahn School of Medicine at Mount Sinai, NY

From Genes to Gene Products

Lipidomics

High-density Lipoprotein

Low-density Lipoprotein

Most Events in Patient at Intermediate Risk

Courtesy of Prof. Steve Humphries (UCL)

High-density Lipoprotein

Low-density Lipoprotein

Most Events in Patient at Intermediate Risk

Routine lipid parameters have not changed over the last 50 years.

Courtesy of Prof. Steve Humphries (UCL)

Bruneck Study on Cardiovascular Disease

Stegemann et al, Circulation 2014Brown & Hazen, Circulation 2014

Lipidomics and Cardiovascular Risk

Proteomics

HDLApoA1

LDLApoB

Most Events in Patient at Intermediate Risk

Courtesy of Prof. Steve Humphries (UCL)

HDLApoA1

LDLApoB

Courtesy of Prof. Steve Humphries (UCL)

Most Events in Patient at Intermediate Risk

No direct comparison of the different apolipoproteins thus far.

Pechlaner et al. JACC 2017

Towards a Less Imprecise Medicine

HDL

Pechlaner et al. JACC 2017

Towards a Less Imprecise Medicine

HDL

ApoB

Pechlaner et al. JACC 2017

Towards a Less Imprecise Medicine

HDL

LDLApoB

Pechlaner et al. JACC 2017

Towards a Less Imprecise Medicine

HDL

LDLApoB

VLDL

Pechlaner et al. JACC 2017

Towards a Less Imprecise Medicine

HDLApoA1LDL

ApoB

Pechlaner et al. JACC 2017

Cardiovascular Risk Beyond LDL Cholesterol?

Pechlaner et al. JACC 2017

Pechlaner et al. JACC 2017

+30%

Pechlaner et al. JACC 2017

+30%

+31%

+38%+40%

HDLApoA1LDL

ApoB

VLDLApoBApoC2ApoC3ApoE

Very Low-Density Lipoprotein

Pechlaner et al. JACC 2017

Cardiovascular Risk Beyond LDL Cholesterol?

Function of ApoC2 and ApoC3

Function of ApoC2 and ApoC3

NEJM 2014

NEJM 2014

Faster Triglyceride Clearance

NEJM 2014

NEJM 2014

HDLApoA1LDL

ApoB

VLDLApoBApoC2ApoC3ApoE

Very Low-Density Lipoprotein

Pechlaner et al. JACC 2017

Cardiovascular Risk Beyond LDL Cholesterol?

Antisense Therapy Targeting ApoC3

NEJM 2014IONIS 1 (n=3)

NEJM 2015IONIS 2 (treated n=11, placebo n=6)

Management of Very High Triglycerides

ApoE

ApoD

ApoC-III

ApoC-II

ApoC-1

ApoB-100

Pechlaner et al. JACC 2017

Effect of ApoC3 Antisense

ApoE

ApoD

ApoC-III

ApoC-II

ApoC-1

ApoB-100

Pechlaner et al. JACC 2017

-70%

Effect of ApoC3 Antisense

ApoE

ApoD

ApoC-III

ApoC-II

ApoC-1

ApoB-100

Pechlaner et al. JACC 2017

-40%

-40%

-70%

Effect of ApoC3 Antisense

MicroRNAs: Small Non-coding RNAs

VLDL

ApoB100

VLDL Biogenesis

miR-122 ASO

LPL

LDL

CholesterolSynthesis

HMGCRmiR-122

ASOFA oxidationFatty acid synthesis

Plasma TG

Cholesterol synthesismiR-122

ASO Plasma cholesterol

miR-122KO

MTP VLDL secretion

FA Oxidation FA Synthesis

MTP

miR-122 KO

MicroRNA-122 & Lipid Metabolism

Willeit et al. Eu Heart J 2017

MicroRNA-122 in Circulation

Willeit et al, Diabetes 2017

Willeit et al, Diabetes 2017

MicroRNA-122 & Apolipoproteins

Willeit et al, Diabetes 2017

MicroRNA-122 & Apolipoproteins

Willeit et al, Diabetes 2017

MicroRNA-122 & Apolipoproteins

Willeit et al, Diabetes 2017

MicroRNA-122: Risk of Metabolic Syndrome

Willeit et al, Diabetes 2017

Willeit et al, Diabetes 2017

MicroRNA-122: Risk of Metabolic Syndrome

Willeit et al, Diabetes 2017

Conclusions•Currently, we just monitor lipid classes (total cholesterol, totaltriglycerides) as well as HDL and LDL cholesterol. The focus is on“quantity” rather than “molecular composition”.

Conclusions

•Currently, we just monitor lipid classes (total cholesterol, totaltriglycerides) as well as HDL and LDL cholesterol. The focus is on“quantity” rather than “molecular composition”.

•The strong associations of certain triglyceride species and VLDL-associated apolipoproteins with incident CVD in the generalcommunity provide support to the concept of targeting triglyceride-rich lipoproteins to further reduce risk of CVD in the statin era.

Conclusions

Conclusions•Currently, we just monitor lipid classes (total cholesterol, totaltriglycerides) as well as HDL and LDL cholesterol. The focus is on“quantity” rather than “molecular composition”.

•The strong associations of certain triglyceride species and VLDL-associated apolipoproteins with incident CVD in the generalcommunity provide support to the concept of targeting triglyceride-rich lipoproteins to further reduce risk of CVD in the statin era.

•Circulating levels of liver-derived miRNA-122 positively correlate toVLDL-associated apolipoproteins and are a strong predictor ofmetabolic syndrome.

Conclusions

Innsbruck:Dr. Raimund PechlanerDr. Peter WilleitProf. Johann WilleitProf. Stefan Kiechl

King’s College London:Dr. Xiaoke YinDr. Konstantinos TheofilatosDr. Ursula MayrDr. Gonca SunaDr Temo BarwariMs. Ferheen BaigMr. Marc LynchMr. Sean Burnap

UCSD:Prof. Sam TsimikasProf. Joe Witztum

Acknowledgements