April 24, 2017
IS ATHEROSCLEROSIS A CHOLESTEROL OR AN IMMUNE DISEASE?
Mihai G. NeteaNijmegen, Netherlands
Mihai Netea is Professor, Department of Internal Medicine, Nijmegen University Medical Center, Radboud University Nijmegen, The Netherlands. Mihai Netea was born and studied medicine in Cluj-Napoca, Romania. He completed his PhD at the Radboud University Nijmegen, The Netherlands, on studies investigating the cytokine network in sepsis. After working as a post-doc at the University of Colorado, he returned to Nijmegen where he finished his clinical training as an infectious diseases specialist, and where he currently heads the division of Experimental Medicine, Department of Internal Medicine, Nijmegen University Nijmegen Medical Center. His main research interests are sepsis and immunoparalysis, pattern recognition of fungal pathogens, primary immunodeficiencies in innate immune system, and the study of the memory traits of innate immunity. His laboratory has been a key contributor to the elucidation of mechanisms responsible for inflammasome activation in various cells types Professor Netea is the recipient of numerous awards, including the Radboud Science Award (2011), European Society for Clinical Investigation Award for Translational Research (2103) and the NWO Spinoza Prize (2016).
Innate immune response drives atherosclerosis
Atherosclerosis is characterized by persistent inflammation in the arterial wall. Monocyte-derived macrophages, the most abundant immune cells in atherosclerotic plaques, are the key effector cell of the innate immune response. Macrophages express receptors that recognize a broad range of molecular patterns foreign to the mammalian organism but commonly found on pathogens. Activation of these receptors stimulates the release of cytokines that regulate processes involved in the initiation and progression of atherosclerosis.
Research indicates that this innate immune response is not static. Indeed, there is accumulating evidence for innate immune memory, which can enhance the proinflammatory state in the long-term and result in increased production of proatherogenic cytokines. Thus, ‘trained immunity’, involving epigenetic reprogramming of monocytes due to persistent inflammatory stimulation, may exacerbate vascular wall inflammation and drive accelerated atherosclerosis, especially in the concomitant presence of other risk factors. For example, in the setting of diabetes, hyperglycemia may induce long-term activation of monocytes and macrophages and therefore exacerbate plaque development and cardiovascular complications. Understanding of the underlying molecular mechanisms may offer future potential for novel therapeutic approaches for the prevention of atherosclerosis and its associated cardiovascular complications.
Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, O’Neill LA, Xavier RJ. Trained immunity: A program of innate immune memory in health and disease. Science 2016;352:aaf1098.
Netea MG, van de Veerdonk FL, van der Meer JW, Dinarello CA, Joosten LA. Inflammasome-independent regulation of IL-1-family cytokines. Annu Rev Immunol 2015;33:49-77.
van Diepen JA, Thiem K, Stienstra R, Riksen NP, Tack CJ, Netea MG. Diabetes propels the risk for cardiovascular disease: sweet monocytes becoming aggressive? Cell Mol Life Sci 2016 [Epub ahead of print]
Chris J. PackardGlasgow, United Kingdom
Chris Packard is the Research and Development Director of NHS Greater Glasgow & Clyde, Scotland, UK. He holds an Honorary Professorship of Vascular Biochemistry at the University of Glasgow, and is also a Consultant Clinical Scientist for NHS Greater Glasgow & Clyde Biochemistry and founding Chairman of NEXXUS. Professor Packard received the Scottish Enterprise Special Recognition Award for his contribution to the Life Sciences industry in Scotland in February 2014 and was appointed Commander of the Order of the British Empire (CBE) in June 2014.
His research has focused on two key aspects: lipoprotein metabolism and how it is affected by diets and drugs, and large scale clinical trials of lipid lowering agents. Key contributions include evaluation of the role of the low-density lipoprotein (LDL) receptor in vivo, the discovery of metabolic channelling in the apolipoprotein B lipoprotein delipidation cascade, and the formulation of models to explain the generation of small, dense LDL. More recently his field of research has widened to include investigations of emerging risk factors, and the consequences of social deprivation on health and wellbeing.
Lowering LDL-C for cardiovascular disease
A causal relationship between low-density lipoprotein cholesterol (LDL-C) plasma levels and the risk of coronary atherosclerosis is now established. Indeed, the Cholesterol Treatment Trialists’ Collaboration showed reduction in the risk of major cardiovascular events by about one fifth per mmol/L LDL-C reduction (1). Long term follow-up from major statin trials indicate a potential lifetime benefit from LDL-lowering therapy. In the West of Scotland Coronary Prevention Study, a primary prevention trial, 20-year follow-up indicated a legacy effect associated with 5 years’ treatment with a statin, resulting in improved survival and reduction in major cardiovascular disease events (2); however, such findings were not consistently shown across all major statin trials. This may relate to the extent of disease at baseline; lowering LDL-C levels earlier rather than later in the atherosclerotic disease process may delay the development of atherosclerosis, resulting in improved clinical benefit over the trajectory of the disease.
The plethora of evidence demonstrating the relationship between LDL-C lowering and improved cardiovascular outcomes has been a key driver for the development of novel treatments that lower LDL‑C levels substantially beyond the effects observed with statins. The first of the PCSK9 inhibitor outcomes trials are expected in early 2017. If the magnitude of clinical benefit from these treatments is consistent with the regression line for LDL-C lowering observed with statins (and ezetimibe) even in patients with low LDL-C levels at baseline, this will reinforce the critical importance of lowering LDL-C to reduce absolute cardiovascular risk.
- Baigent C, Keech A, Kearney PM et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78.
- Ford I, Murray H, McCowan C, Packard CJ. Long-term safety and efficacy of lowering low-density lipoprotein cholesterol with statin therapy: 20-year follow-up of West of Scotland Coronary Prevention Study. Circulation 2016;133:1073-80.
Packard CJ, Ford I. Long-term follow-up of lipid-lowering trials. Curr Opin Lipidol 2015;26:572-9.
Packard CJ, Weintraub WS, Laufs U. New metrics needed to visualize the long-term impact of early LDL-C lowering on the cardiovascular disease trajectory. Vascul Pharmacol 2015;71:37-9.
Laufs U, Descamps OS, Catapano AL, Packard CJ. Understanding IMPROVE-IT and the cardinal role of LDL-C lowering in CVD prevention. Eur Heart J 2014;35:1996-2000.
Targeting inflammation in atherosclerosis, speaker to be confirmed
Inflammation plays a key role in all stages of the atherothrombotic process. Improved understanding of the underlying systemic process during both early stages of atherogenesis and the late stages of plaque rupture, clinical trial evidence that patients with elevated inflammatory biomarkers such as high-sensitivity C-reactive protein have increased cardiovascular risk, as well as recent research implicating interleukin-1 (IL-1) and interleukin-6 (IL-6) pathways in atherogenesis, support the inflammatory hypothesis of atherothrombosis. However, whether targeted inhibition of inflammation, as an adjunct to risk factor modification, will reduce cardiovascular events is uncertain. Moreover, the lack of effect of salsalate on progression of noncalcified coronary plaque volume in overweight and obese patients on statin therapy in the Targeting Inflammation Using Salsalate in Cardiovascular Disease (TINSAL-CVD) trial (1), is inconclusive, given the absence of progression of noncalcified plaque volume in the placebo group. Moreover, the influence of the underlying mechanism of inhibition, as well as the stage of atherothrombotic disease, also merit consideration.
To comprehensively address this question, two major outcomes studies are ongoing. CANTOS is testing whether canakinumab, a human monoclonal antibody with high specificity for IL-1β, can reduce recurrent vascular events in individuals with previous myocardial infarction (MI) and elevated hsCRP levels. The second trial, CIRT, is testing whether low-dose methotrexate, a generic anti-inflammatory drug widely used to treat rheumatoid arthritis, can safely reduce recurrent vascular events in individuals with type 2 diabetes or metabolic syndrome and history of MI or multivessel coronary artery disease. Together these trials, involving 17,000 patients, will help to define the role of inhibition of inflammation in cardiovascular clinical practice.
- Hauser TH, Salastekar N, Schaefer EJ et al. Effect of targeting inflammation with salsalate: the TINSAL-CVD randomized clinical trial on progression of coronary plaque in overweight and obese patients using statins. JAMA Cardiol 2016;1:413-23.
Ridker PM. Informative neutral studies matter-Why the Targeting Inflammation with Salsalate in Cardiovascular Disease (TINSAL-CVD) Trial deserves our attention. JAMA Cardiol 2016;1:423-4.
Ridker PM. Residual inflammatory risk: addressing the obverse side of the atherosclerosis prevention coin. Eur Heart J 2016;37:1720-2.
Ridker PM. From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving upstream to identify novel targets for atheroprotection. Circ Res 2016;118:145-56.
Everett BM, Pradhan AD, Solomon DH, Paynter N, Macfadyen J, Zaharris E, Gupta M, Clearfield M, Libby P, Hasan AA, Glynn RJ, Ridker PM. Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis. Am Heart J 2013;166:199-207.
Kathryn MooreNew York, USA
Kathryn Moore is the Jean and David Blechman Professor of Cardiology, and Professor of Cell Biology at New York University School of Medicine. Her research focuses on the mechanisms of metabolic dysfunction and chronic inflammation in atherosclerosis and obesity, with an emphasis on understanding maladaptive macrophage-driven inflammatory responses. She has been the recipient of numerous awards including the Claflin Distinguished Scholar Award, the Ellison Foundation New Scholar in Aging Award, and the American Heart Association’s Jeffrey Hoeg Arteriosclerosis Award for Basic Science and Clinical Research. Dr. Moore is a member of the editorial board of Arteriosclerosis, Thrombosis and Vascular Biology.
Role of non-coding RNA for cholesterol homeostasis and atherogenesis
There is accumulating evidence that non-coding RNAs play a key role in atherosclerosis. The best characterized to date are microRNAs (miRNAs), small, ~22 nucleotide sequences, which influence gene expression at the post-transcriptional level. miRNAs have been shown to modulate endothelial cell, vascular smooth cell, and macrophage functions, as well as lipoprotein metabolism. Notably, miR-33, located within the genes coding for sterol regulatory element-binding protein-2 (SREBP-2), a transcription factor known to regulate cholesterol levels, is an important regulator of cellular cholesterol efflux, fatty acid beta oxidation, as well as high-density lipoprotein metabolism.
Recent research has also identified the involvement of long non-coding RNAs in regulation of gene expression in a number of molecular contexts. One such long non-coding RNA, linc-OSBPL6, has received attention given that it appears to act as a binding hub for both miR-27b and miR-33a/b, and thus, indirectly, influences expression of their target genes. Overexpression of this long non-coding RNA increases cholesterol efflux, while RNA-silencing reduced cholesterol efflux from hepatocytes and macrophages.
These findings focus attention on noncoding RNAs as critical regulators of signalling pathways influencing lipid homeostasis, and thus the balance of atherosclerotic plaque progression and regression. Such understanding may offer future therapeutic potential.
Feinberg MW; Moore KJ. MicroRNA Regulation of atherosclerosis. Circ Res 2016;118:703-20.
Ouimet M, Ediriweera HN, Gundra UM, Sheedy FJ, Ramkhelawon B, Hutchison SB, Rinehold K, van Solingen C, Fullerton MD, Cecchini K, Rayner KJ, Steinberg GR, Zamore PD, Fisher EA, Loke P, Moore KJ. MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis. J Clin Invest 2015;125:4334-48.
Ouimet M, Hennessy EJ, van Solingen C, Koelwyn GJ, Hussein MA, Ramkhelawon B, Rayner KJ, Temel RE, Perisic L, Hedin U, Maegdefessel L, Garabedian MJ, Holdt LM, Teupser D, Moore KJ. miRNA targeting of Oxysterol-Binding Protein-Like 6 regulates cholesterol trafficking and efflux. Arterioscler Thromb Vasc Biol 2016;36:942-51.
April 25, 2017
THE BIOLOGY OF TRIGLYCERIDES REVISITED
Robert Farese, JrBoston, USA
Dr. Robert Farese, Jr., studied chemistry at the University of Florida and medicine at Vanderbilt University. He then completed a residency and chief residency in internal medicine at the University of Colorado. In 1989, Dr. Farese moved to the University of California San Francisco to train in endocrinology and metabolism and did his postdoctoral research training with Dr. Stephen Young at the Gladstone Institutes, where he became an expert in gene targeting in murine embryonic stem cells and studied lipoprotein and cholesterol metabolism. In 1994, Dr. Farese established his laboratory at the Gladstone and UCSF where he studied neutral lipid metabolism, focusing on the pathways of lipid synthesis and storage. His laboratory cloned many of the important enzymes of neutral lipid synthesis, including the DGAT enzymes, which mediate triglyceride (TG) synthesis. Excessive accumulation of TGs underlies obesity, diabetes, fatty liver, and other metabolic diseases. Dr. Farese and co-workers discovered the DGAT enzymes and defined their molecular functions in lipid biochemistry, physiology, identified human disease mutations, and laid the groundwork for development of DGAT inhibitors.
In 2005, Dr. Farese took a sabbatical with Dr. Peter Walther, where he began working with Dr. Tobias Walther on the cell biology of lipid droplets. They collaborated closely for many years and established a joint laboratory at Harvard in 2014. They have focused on unraveling the molecular mechanisms of LD formation, protein targeting to LDs, and the role that LDs play in disease.
In 2007, Dr. Farese co-founded the Consortium for Frontotemporal Dementia (FTD) Research (CFR), a UCSF-based, multi-investigator collaborative effort whose goal is to find cures for FTD by studying progranulin biology. Dr. Farese and co-workers have generated murine and iPS models for progranulin-deficient FTD, and he co-directs the Basic Research for the CFR.
Dr. Farese has received numerous honors, among them election to the American Society for Clinical Investigation and the Association of American Physicians, a “Freedom to Discover Award” from Bristol-Myers Squibb, and the Avanti Lipid research award.
Balancing the fat: lipid droplets and human disease
The most efficient way that cells store energy is in the form of fat, particularly triacylglycerols, which are packaged into lipid droplets, compact cytosolic organelles that also store precursors for membrane and hormone synthesis. When energy is in short supply, lipids are mobilized. Thus, lipid droplets are dynamic, either growing or shrinking in cells to maintain lipid levels and meet metabolic demands. Yet despite being discovered over a century ago, the mechanisms that underlie lipid droplet formation and response to metabolic demands have yet to be fully elucidated. Studies into these lipid storage mechanisms using mouse models of obesity and metabolic disease may offer important insights into lifestyle-related diseases, such as obesity, hepatic steatosis and liver disease, and cardiovascular disease.
Balancing fat storage in the lipid droplet is therefore critical for health. Recent research has provided insights into the molecular processes underlying lipid storage, notably identification of key proteins and genes involved in the regulation of lipid storage. For example, key surfactant proteins at the surface of the lipid droplet have been shown to have an important structural role, in packaging lipid in smaller units, protecting lipid droplets against endogenous lipases, and facilitating triglyceride formation. In addition, lipid droplets may integrate lipid metabolism, inflammatory mediator production, membrane trafficking, and intracellular signaling, in response to supply and demand for lipid. Improved understanding of these mechanisms may offer future therapeutic potential, especially in the management of metabolic disease.
Kory N, Farese RV Jr, Walther TC. Targeting fat: mechanisms of protein localization to lipid droplets. Trends Cell Biol 2016;26:535-46.
Wang H, Becuwe M, Housden BE, Chitraju C, Porras AJ, Graham MM, Liu XN, Thiam AR, Savage DB, Agarwal AK, Garg A, Olarte MJ, Lin Q, Fröhlich F, Hannibal-Bach HK, Upadhyayula S, Perrimon N, Kirchhausen T, Ejsing CS, Walther TC, Farese RV. Seipin is required for converting nascent to mature lipid droplets. Elife 2016; doi: 10.7554/eLife.16582.
Kory N, Thiam AR, Farese RV Jr, Walther TC. Protein crowding is a determinant of lipid droplet protein composition. Dev Cell 2015;34:351-63.
Gary F LewisToronto, Canada
Dr. Gary Lewis completed his medical training in 1982 at the University of Witwatersrand in South Africa, followed by specialty training in Internal Medicine and then Endocrinology at the University of Chicago. He joined the staff of the Toronto General Hospital in 1990, was appointed Head of the Division of Endocrinology at University Health Network and Mount Sinai Hospitals in 2001, Director of the University of Toronto Division of Endocrinology and Metabolism in 2008 and Director of the Banting and Best Diabetes Centre, U of T, in 2011. He is a Full Professor in the Departments of Medicine and Physiology, University of Toronto and he holds the Sun Life Financial Chair in Diabetes and the Drucker Family Chair in Diabetes Research. Dr. Lewis’ research focuses on elucidating the mechanisms of blood fat abnormalities in diabetes and prediabetic states.
Regulation of lipid mobilization and lipoprotein secretion by the intestine
Individuals with type 2 diabetes typically exhibit a dyslipidaemia characterized by high plasma triglyceride levels, carried mainly in triglyceride-rich lipoproteins (TRLs) such as chylomicrons and very low-density lipoproteins, decreased high-density lipoprotein cholesterol levels and qualitative changes in lipoproteins, as well as an abnormal postprandial lipid response. Both impaired clearance of TRLs from the circulation, as well as increased production of both hepatic and intestinal TRLs underpin the development of this dyslipidaemia.
Recent evidence indicates that the incretin hormones glucagon-like protein-1 (GLP-1) and a glucagon-like protein-2 (GLP-2) also affect intestinal lipid uptake and lipoprotein secretion via effects on multiple target organs. GLP-1 been shown to directly influence triglyceride homeostasis by inhibiting intestinal lipoprotein production, thus lowering plasma triglycerides. In contrast, GLP-2 promotes the release of chylomicrons into the circulation, thereby increasing plasma triglycerides. The net effect of these opposing actions has yet to be fully elucidated. There is also emerging evidence to implicate central regulation of triglyceride homeostasis. Thus, hypothalamic glucose-sensing mechanisms have been shown to regulate liver, but not intestinal, very low-density lipoprotein-triglyceride production. Further understanding of the regulation of triglyceride homeostasis by the gut-liver-brain axis may offer future therapeutic potential for the management of dyslipidaemia and prevention of atherosclerosis.
Xiao C, Dash S, Morgantini C, Hegele RA, Lewis GF. Pharmacological targeting of the atherogenic dyslipidemia complex: the next frontier in CVD prevention beyond lowering LDL cholesterol. Diabetes 2016;65:1767-78.
Lewis GF, Xiao C, Hegele RA. Hypertriglyceridemia in the genomic era: a new paradigm. Endocr Rev 2015;36:131-47.
Xiao C, Dash S, Morgantini C, Adeli K, Lewis GF. Gut peptides are novel regulators of intestinal lipoprotein secretion: experimental and pharmacological manipulation of lipoprotein metabolism. Diabetes 2015;64:2310-8.
Marja-Riitta TaskinenHelsinki, Finland
Marja-Riitta Taskinen is Emerita Professor of Medicine at the Cardiovascular Research Group, Heart and Lung Centre, at Helsinki University Central Hospital. Her research team, which focuses on lipoprotein kinetics in health and lipid disorders and the genetics of familial dyslipidemias, is a member of the Research Program Unit, Diabetes & Obesity Research program at the University of Helsinki. Professor Taskinen is the recipient of numerous awards including the Claude Bernard Award (2002), Edwin Bierman Award (2004), Novartis Award (2006), the Grand Award of the Finnish Foundation for Cardiovascular Research (2011), and the Pohjola and Suomi Mutual Medical Award of the Finnish Medical Foundation (2012). She has been a key player in the European Atherosclerosis Society (President, 2006-2008), International Atherosclerosis Society, European Association for the Study of Diabetes, and the International Diabetes Federation.
Hepatic lipid and lipoprotein metabolism
Triglyceride-rich very low-density lipoprotein 1 (VLDL1) particles are responsible for carrying most of the circulating triglycerides. The balance between synthesis of VLDL1-triglyceride in the liver and intestine, and subsequent removal by lipoprotein lipase (LPL) is a key determinant of circulating levels of plasma triglycerides. In individuals with abdominal obesity and dyslipidemia, VLDL1-triglyceride clearance predominates over increased secretion of VLDL1 particles.
Regulation of LPL is a key factor influencing triglyceride turnover. Post-transcriptionally, this is controlled by both liver-derived apolipoproteins, as well as angiopoietin-like proteins, specifically the products of the ANGPTL3, ANGPTL4 and ANGPTL8 genes. LPL is activated by apolipoprotein (apo)C-II and inhibited by apoC-III. ApoC III inhibits TRL remnant uptake by hepatic lipoprotein receptors, and hepatic assembly and secretion of VLDL apoC-III, and therefore plays a critical role in the development of hypertriglyceridaemia. ANGPTL3 and ANGPTL4 impair triglyceride clearance by inhibiting LPL. ANGPTL3 is expressed in the liver and regulated by the liver X receptor, whereas expression of ANGPTL4 is more widespread and controlled by the peroxisome proliferator-activated receptor (PPAR) family and fatty acids. But even before regulation by these proteins, LPL secretion and delivery is also influenced by other intermediaries, such as the products of LMF1 and GPIHBP1 genes. Further insights into the regulation of triglyceride turnover may offer future therapeutic potential.
Vergès B, Adiels M, Boren J, Barrett PH, Watts GF, Chan D, Duvillard L, Söderlund S, Matikainen N, Kahri J, Lundbom N, Lundbom J, Hakkarainen A, Aho S, Simoneau-Robin I, Taskinen MR. ApoA-II HDL catabolism and its relationships with the kinetics of ApoA-I HDL and of VLDL1, in abdominal obesity. J Clin Endocrinol Metab 2016;101:1398-406.
Borén J, Watts GF, Adiels M, Söderlund S, Chan DC, Hakkarainen A, Lundbom N, Matikainen N, Kahri J, Vergès B, Barrett PH, Taskinen MR. Kinetic and related determinants of plasma triglyceride concentration in abdominal obesity: multicenter tracer kinetic study. Arterioscler Thromb Vasc Biol 2015;35:2218-24.
Taskinen MR, Borén J. New insights into the pathophysiology of dyslipidemia in type 2 diabetes. Atherosclerosis 2015;239:483-95.
Robert A HegeleLondon, Ontario, Canada
Robert Hegele is an endocrinologist who cares for more than 2000 patients in his lipid clinic at University Hospital, London, Canada. He is Distinguished University Professor of Medicine and Biochemistry, Western University, and Director of the Lipid Genetics Clinic and the London Regional Genomics Centre at Robarts Research Institute. He holds the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Chair in Human Genetics and the Martha Blackburn Chair in Cardiovascular Research. He was first in Canada or North America to use 5 medications that are now routinely available to treat dyslipidemia and diabetes. Together or in collaboration, his lab has discovered the molecular genetic basis of more than 20 different human diseases. His research is focused on understanding the genetic basis of atherosclerosis, dyslipidaemia and type 2 diabetes and he has published more than 600 papers and has contributed to recent national and international clinical practice guidelines for lipids, blood pressure and diabetes. He has trained many physicians, medical students and graduate students.
Demystifying the management of hypercholesterolaemia
Hypercholesterolaemia is one of the major causes of atherosclerosis. Based on the totality of evidence from mechanistic, genetic, observational and intervention studies it is now clear that low-density lipoprotein cholesterol (LDL) is causal for atherosclerotic cardiovascular disease (ASCVD). Treatment relies on both lifestyle and pharmacotherapy.
Statins are indisputably the mainstay of LDL cholesterol lowering for prevention of ASCVD. However, recognition of variability in pharmacogenetics responsiveness, tolerability issues and improved mechanistic understanding of cholesterol homeostasis, underlines the need for alternative/additional approaches. Beyond conventional non-statin therapies (such as ezetimibe or bile acid sequestrants), the last decade has seen the emergence of a number of novel agents for management of hypercholesterolaemia, including severe inherited forms of dyslipidaemia. These include the microsomal transfer protein inhibitor lomitapide, the apolipoprotein B antisense oligonucleotides (mipomersen), as well as monoclonal antibody therapy to PCSK9. As a consequence, there has been new focus on identifying the underlying mutations, not only to provide a predictor of the failure of standard (statin) therapy, but also potential response to novel therapies. Such advances bring precision medicine within the domain of routine clinical practice.
Hegele RA. Multidimensional regulation of lipoprotein lipase: impact on biochemical and cardiovascular phenotypes. J Lipid Res 2016 Jul 13. pii: jlr.C070946. [Epub ahead of print]
Mancini GB, Baker S, Bergeron J, Fitchett D, Frohlich J, Genest J, Gupta M, Hegele RA, Ng D, Pearson GJ, Pope J, Tashakkor AY. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Consensus Working Group Update. Can J Cardiol 2016;32(7 Suppl):S35-65.
Hegele RA, Gidding SS, Ginsberg HN, McPherson R, Raal FJ, Rader DJ, Robinson JG, Welty FK. Nonstatin low-density lipoprotein-lowering therapy and cardiovascular risk reduction-Statement From ATVB Council. Arterioscler Thromb Vasc Biol 2015;35:2269-80.
April 26, 2017
CARDIOMETABOLIC RISK FACTORS BEYOND LIPIDS
Sarah LewingtonOxford, United Kingdom
Sarah Lewington is Associate Professor, MRC Population Health Research Unit, Director of Graduate Studies, Nuffield Department of Population Health, and Research Fellow, Green Templeton College, Oxford UK. Professor Lewington’s main research interest is in major risk factors for premature adult mortality, with a particular focus on tobacco, alcohol, blood pressure and obesity, and she is the Oxford-based principal investigator for studies conducted in Russia, Cuba and India. She leads a team of epidemiologists, statisticians and statistical programmers that forms the CTSU’s Population Studies Group and is the MRC Programme Leader Track, Statistical Epidemiology. Sarah is also a Scientific Director for the MSc in Global Health Science, with responsibility for the planning, development, delivery and management of all aspects of the fully revised MSc degree course.
Large-scale epidemiology assessment of the main determinants of cardiovascular disease
Cardiovascular disease is a leading cause of death and disability worldwide. While observational epidemiologic studies can provide useful insights into associations between biomarkers and cardiovascular disease, it is only with large-scale epidemiology assessment involving the use of meta-analysis that such associations can be conclusively established. Although not without limitations, meta-analysis of observational studies, especially individual subject data, has provided robust evidence to support the causal relevance of several major risk factors including smoking, adiposity, blood pressure, blood cholesterol, and diabetes mellitus to cardiovascular disease. This information has been critical for defining health policy targeting behavior, as well as use of pharmacotherapy, which has contributed to dramatic declines in cardiovascular disease mortality in developed regions over the last half of the 20th century. Recent insights from the Global Burden of Disease 2010 Study has, however, shown that the decline in mortality rates for both ischaemic heart disease and stroke between 1990 and 2010 in developed countries is not matched by that in developing regions, thus highlighting the need for further efforts to reduce cardiovascular disease globally.
Despite these advances, the established major risk factors may explain only part of cardiovascular disease risk, thus highlighting the need for further research to detect “novel” or “emerging” risk or biomarkers for cardiovascular disease. Large-scale epidemiology assessment will play a key role here in identifying whether such novel biomarkers are truly causal for cardiovascular risk.
Herrington W, Lacey B, Sherliker P, Armitage J, Lewington S. Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease. Circ Res 2016;118:535-46.
Global BMI Mortality Collaboration, Di Angelantonio E, Bhupathiraju ShN, Wormser D, Gao P, Kaptoge S, Berrington de Gonzalez A, Cairns BJ, Huxley R, Jackson ChL, Joshy G, Lewington S, Manson JE, Murphy N, Patel AV, Samet JM, Woodward M, Zheng W, Zhou M, Bansal N, Barricarte A, Carter B, Cerhan JR, Smith GD, Fang X, Franco OH, Green J, Halsey J, Hildebrand JS, Jung KJ, Korda RJ, McLerran DF, Moore SC, O’Keeffe LM, Paige E, Ramond A, Reeves GK, Rolland B, Sacerdote C, Sattar N, Sofianopoulou E, Stevens J, Thun M, Ueshima H, Yang L, Yun YD, Willeit P, Banks E, Beral V, Chen Zh, Gapstur SM, Gunter MJ, Hartge P, Jee SH, Lam TH, Peto R, Potter JD, Willett WC, Thompson SG, Danesh J, Hu FB. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet 2016;388:776-86.
Lewington S, Lacey B, Clarke R, Guo Y, Kong XL, Yang L, Chen Y, Bian Z, Chen J, Meng J, Xiong Y, He T, Pang Z, Zhang S, Collins R, Peto R, Li L, Chen Z; China Kadoorie Biobank Consortium. The burden of hypertension and associated risk for cardiovascular mortality in China. JAMA Intern Med 2016;176:524-32.
Qi SunBoston, USA
Qi Sun is Assistant Professor in the Department of Nutrition, Harvard T.H. Chan School of Public Health and Assistant Professor of Medicine at Brigham and Women’s Hospital and Harvard Medical School, Boston, USA. Dr. Sun’s primary research interests are focused on identifying biomedical risk factors, including dietary biomarkers, in relation to type 2 diabetes, obesity, and cardiovascular disease. His research is primarily based on a few large-scale cohort studies including the Nurses’ Health Study I and II and the Health Professionals Follow-up Study. In addition, Dr. Sun is interested in the role of environmental pollutants, especially those from dietary sources, in the aetiology of obesity and type 2 diabetes.
Diet and cardiometabolic health
Cardiometabolic disease is an important cause of morbidity and mortality worldwide, fueled by escalating rates of obesity and type 2 diabetes. Diet is a key modifiable lifestyle factor that can be targeted to reduce disease-risk profiles, and is therefore fundamental to lifestyle approaches to prevent cardiometabolic disease. Diet involves multidimensional exposure, given that it is a combination of different foods and nutrients, and thus quantitative and qualitative components of the diet, such as fat, warrant consideration.
Such thinking has prompted a shift towards consideration of overall dietary patterns, such as the Mediterranean diet, rather than focusing on individual nutrients and/or foods. Indeed, pivotal studies such as PREDIMED, show that the Mediterranean diet favourably impacts cardiometabolic risk factors and reduces cardiovascular events. Consideration of diet quality has now been incorporated into recent guidelines, notably the 2016 Joint ESC/EAS Guidelines for Management of Dyslipidaemia, and the 2016 Joint Task Force Guidelines for Prevention of Cardiovascular Disease. These also allow for adaptations to take account of personal and cultural food preferences.
Yet the reduction in risk of cardiometabolic disease with improvement in overall diet quality is only partly explained by changes in body weight, implying the contribution of other factors. Ongoing research has highlighted the relevance of interactions between diet and an individual’s genetic make-up (nutrigenetics) to both the initiation and progression of cardiometabolic disease. Worldwide collaborative efforts have identified common genetic variants associated with type 2 diabetes, as well as contributed to understanding of gene-environment interactions that may modify the cardiovascular risk phenotype. Additionally, experimental studies indicate that exercise and dietary intervention may play a key role in improving insulin resistance by alleviating oxidative stress. Such approaches provide new potential to addressing the major global challenge of cardiometabolic disease.
Ley SH, Pan A, Li Y, Manson JE, Willett WC, Sun Q, Hu FB. Changes in overall diet quality and subsequent type 2 diabetes risk: Three U.S. prospective cohorts. Diabetes Care 2016. pii: dc160574. [Epub ahead of print]
Ley SH, Ardisson Korat AV, Sun Q, Tobias DK, Zhang C, Qi L, Willett WC, Manson JE, Hu FB. Contribution of the Nurses’ Health Studies to uncovering risk factors for type 2 diabetes: diet, lifestyle, biomarkers, and genetics. Am J Public Health 2016;106:1624-30.
Yu E, Rimm E, Qi L, Rexrode K, Albert CM, Sun Q, Willett WC, Hu FB, Manson JE. Diet, lifestyle, biomarkers, genetic factors, and risk of cardiovascular disease in the Nurses’ Health Studies. Am J Public Health 2016;106:1616-23.
Fredrik BäckhedGothenburg, Sweden
Professor Fredrik Bäckhed combines clinical oriented research with gnotobiotic mouse models to address the role of the normal gut microbiota in metabolic diseases. Fredrik Bäckhed holds a PhD from the Karolinska Institute, and performed postdoctoral training at Washington University, St Louis where he identified the gut microbiota as an environmental factor that regulates adiposity and obesity. Dr Bäckhed is professor at University of Gothenburg and Director of the Wallenberg Laboratory (www.wlab.gu.se) for cardiovascular research. He is also Professor at Copenhagen University and has been guest Professor at University of Oslo. His research aims to identify novel therapeutic and diagnostic targets for the metabolic syndrome by focusing on the role of the gut microbiota. His team uses an interdisciplinary research approach to delineate the mechanisms by which the gut microbiota modulates host physiology and metabolism. Professor Bäckhed has co-authored more than 80 papers in international peer-reviewed journals, including Nature, Science, Cell and Proceedings of National Academy of Sciences.
Microbiome and cardiometabolic disease
New therapeutic targets are critical to combat the pandemic of obesity. The microbiome, which plays a key role in modulating host physiology and metabolism, has become a focus for research, given that it lies at the intersection of diet and metabolic health. Translational animal models and studies in humans have identified mechanisms that link the gut microbiota with obesity and thus cardiometabolic disease. Such studies have shown the relevance of dietary factors and macronutrients, which act as substrates for many microbially produced metabolites, such as short-chain fatty acids and bile acids, in modulating host metabolism. Changes in the gut ecology influence the inflammatory and metabolic properties of the gut microbiota and hence host physiology, and thus impact metabolic risk.
Despite accumulating evidence for a link between the gut microbiome and cardiometabolic health, few studies have validated causality in humans and the underlying mechanisms are yet to be fully elucidated. Greater understanding of alterations in the gut microbiota in combination with dietary patterns, as well as identification of novel signaling pathways, may provide insights into how the gut microbiota contributes to cardiometabolic disease progression. Indeed, recent findings have implicated a link between reduced levels of butyrate-producing bacteria and possible causality for type 2 diabetes, whereas the reverse has been found for levels of Lactobacillus species. Ultimately, the aim is to exploit such findings to enable the development of novel diagnostic and therapeutic targets directed to the microbiome for prevention of cardiometabolic disease.
Sonnenburg JL, Bäckhed F. Diet-microbiota interactions as moderators of human metabolism. Nature 2016; 535:56-64.
Schroeder BO, Bäckhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med 2016;22:1079-89.
Greiner TU, Bäckhed F. Microbial regulation of GLP-1 and L-cell biology. Mol Metab 2016;5:753-8.
Patrick SchrauwenMaastricht, Netherlands
Patrick Schrauwen, PhD is Professor of Metabolic aspects of Type 2 Diabetes Mellitus at the Maastricht University Medical Center (MUMC). The lab of Professor Schrauwen performs human translational research on insulin resistance, lipotoxicity, mitochondrial dysfunction and brown adipose tissue with special emphasis on type 2 diabetes mellitus. Professor Schrauwen was awarded the ‘Silver Medal Award’ from the Nutrition Society’ in 2006, the ‘Rising Star Award’ from the European Association for the Study of Diabetes (EASD) in 2008 and the Minkowski Award of the EASD in 2016. He received the prestigious Corona-Gallina Award for excellence in diabetes research in 2013. Professor Schrauwen has published over 200 publications, and is in the editorial boards of ‘Scientific Reports’ and ‘Diabetologia’. His main fields of interest include insulin resistance, lipotoxicity and mitochondrial dysfunction, with a special emphasis on type 2 diabetes.
Importance of physical activity in metabolic and cardiovascular health and the influence of obesity and diabetes
Accumulating evidence suggests that physical inactivity may be as important a factor as being overweight for the development of insulin resistance, type 2 diabetes and potentially fatty liver disease. Physical activity can improve several metabolic risk factors associated with cardiovascular disease. Skeletal muscle plays an important role in maintaining whole body energy and substrate metabolism and is responsible for ~80% of postprandial glucose uptake in humans. Exercise training has been shown to have beneficial effects on skeletal muscle metabolism, and there is also emerging evidence to suggest a benefit on liver metabolism, most likely by reducing hepatic fat availability and synthesis, and increasing hepatic triacylglycerol oxidation. Research efforts have therefore focused on understanding the underlying mechanisms influencing metabolic homeostasis. Studies have shown that physical exercise can promote selective induction of angiopoietin-like 4 (ANGPTL4) in non-exercising muscle and reduce local fatty acid uptake, while at the same time directing fatty acids to the active skeletal muscle, thus implying a key role for ANGPTL4 in regulation of lipid homeostasis during exercise.
Exercise also has a favourable impact on both the number and function/efficiency of mitochrondria. Exercise training has been shown to promote mitochondrial function and insulin sensitivity, which may underlie its role in the prevention and treatment of type 2 diabetes. Ongoing research has led to the emergence of novel targets for boosting mitochondrial function, many of which appear to be regulated by factors such as nutrition, ambient temperature and circadian rhythms. Carnitine acetyltransferase, a mitochondrial matrix enzyme, has attracted attention as a potential therapeutic target, given evidence suggesting a role in regulation of total body glucose tolerance and glucose oxidation. Studies have implicated carnitine insufficiency and reduced carnitine acetyltransferase activity as reversible components of the metabolic syndrome. Such insights may provide a basis for nonpharmacological strategies for prevention of type 2 diabetes.
Brouwers B, Hesselink MK, Schrauwen P, Schrauwen-Hinderling VB. Effects of exercise training on intrahepatic lipid content in humans. Diabetologia 2016;59:2068-79.
Combatting type 2 diabetes by turning up the heat. Schrauwen P, van Marken Lichtenbelt WD. Diabetologia 2016;59:2269-79.
Hansen J, Timmers S, Moonen-Kornips E, Duez H, Staels B, Hesselink MK, Schrauwen P. Synchronized human skeletal myotubes of lean, obese and type 2 diabetic patients maintain circadian oscillation of clock genes. Sci Rep 2016;6:35047.