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Progress in Molecular Cardiovascular Medicine: Lipidomics, Proteomics & MicroRNAs Manuel MAYR, MD, PhD BHF Professor of Cardiovascular Proteomics King’s College London, UK Icahn School of Medicine at Mount Sinai, NY
Transcript of Progress in Molecular Cardiovascular Medicine: Lipidomics .../media/Non-Clinical/Files-PDFs... ·...
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
