Progress in Molecular Cardiovascular Medicine: Lipidomics .../media/Non-Clinical/Files-PDFs... ·...
Transcript of Progress in Molecular Cardiovascular Medicine: Lipidomics .../media/Non-Clinical/Files-PDFs... ·...
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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
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From Genes to Gene Products
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Lipidomics
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High-density Lipoprotein
Low-density Lipoprotein
Most Events in Patient at Intermediate Risk
Courtesy of Prof. Steve Humphries (UCL)
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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)
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Bruneck Study on Cardiovascular Disease
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Stegemann et al, Circulation 2014Brown & Hazen, Circulation 2014
Lipidomics and Cardiovascular Risk
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Proteomics
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HDLApoA1
LDLApoB
Most Events in Patient at Intermediate Risk
Courtesy of Prof. Steve Humphries (UCL)
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HDLApoA1
LDLApoB
Courtesy of Prof. Steve Humphries (UCL)
Most Events in Patient at Intermediate Risk
No direct comparison of the different apolipoproteins thus far.
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Pechlaner et al. JACC 2017
Towards a Less Imprecise Medicine
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HDL
Pechlaner et al. JACC 2017
Towards a Less Imprecise Medicine
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HDL
ApoB
Pechlaner et al. JACC 2017
Towards a Less Imprecise Medicine
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HDL
LDLApoB
Pechlaner et al. JACC 2017
Towards a Less Imprecise Medicine
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HDL
LDLApoB
VLDL
Pechlaner et al. JACC 2017
Towards a Less Imprecise Medicine
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HDLApoA1LDL
ApoB
Pechlaner et al. JACC 2017
Cardiovascular Risk Beyond LDL Cholesterol?
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Pechlaner et al. JACC 2017
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Pechlaner et al. JACC 2017
+30%
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Pechlaner et al. JACC 2017
+30%
+31%
+38%+40%
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HDLApoA1LDL
ApoB
VLDLApoBApoC2ApoC3ApoE
Very Low-Density Lipoprotein
Pechlaner et al. JACC 2017
Cardiovascular Risk Beyond LDL Cholesterol?
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Function of ApoC2 and ApoC3
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Function of ApoC2 and ApoC3
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NEJM 2014
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NEJM 2014
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Faster Triglyceride Clearance
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NEJM 2014
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NEJM 2014
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HDLApoA1LDL
ApoB
VLDLApoBApoC2ApoC3ApoE
Very Low-Density Lipoprotein
Pechlaner et al. JACC 2017
Cardiovascular Risk Beyond LDL Cholesterol?
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Antisense Therapy Targeting ApoC3
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NEJM 2014IONIS 1 (n=3)
NEJM 2015IONIS 2 (treated n=11, placebo n=6)
Management of Very High Triglycerides
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ApoE
ApoD
ApoC-III
ApoC-II
ApoC-1
ApoB-100
Pechlaner et al. JACC 2017
Effect of ApoC3 Antisense
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ApoE
ApoD
ApoC-III
ApoC-II
ApoC-1
ApoB-100
Pechlaner et al. JACC 2017
-70%
Effect of ApoC3 Antisense
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ApoE
ApoD
ApoC-III
ApoC-II
ApoC-1
ApoB-100
Pechlaner et al. JACC 2017
-40%
-40%
-70%
Effect of ApoC3 Antisense
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MicroRNAs: Small Non-coding RNAs
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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
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MicroRNA-122 in Circulation
Willeit et al, Diabetes 2017
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Willeit et al, Diabetes 2017
MicroRNA-122 & Apolipoproteins
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Willeit et al, Diabetes 2017
MicroRNA-122 & Apolipoproteins
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Willeit et al, Diabetes 2017
MicroRNA-122 & Apolipoproteins
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Willeit et al, Diabetes 2017
MicroRNA-122: Risk of Metabolic Syndrome
Willeit et al, Diabetes 2017
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Willeit et al, Diabetes 2017
MicroRNA-122: Risk of Metabolic Syndrome
Willeit et al, Diabetes 2017
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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
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•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
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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
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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