Monday 27 May
METABOLIC DYSFUNCTION IN CARDIOVASCULAR DISEASE
Klaus Ley, La Jolla, USA
Manipulating adaptive immunity to curb atherosclerosis
Atherosclerosis is a chronic inflammatory disease that is driven by subendothelial accumulation of low-density lipoprotein in the arterial wall. The retained lipoproteins provoke a series of maladaptive immune responses that in turn promote plaque progression and eventually rupture. Monocytes are important mediators of the inflammatory responses involved in atherosclerosis progression. Their differentiation to macrophages, and phenotypic characterization of these macrophages, can be modulated by microenvironmental signals within the artery wall, including oxidized lipids, Toll-like receptor ligands, hematopoietic growth factors, cytokines, and chemokines. Dynamic modulation of macrophage phenotypes affects atherosclerosis progression by modulating the inflammatory responses within the vessel wall. On this basis, therefore, macrophage phenotype modulation represents an attractive therapeutic target.
Atherosclerotic plaques contain T cells, most of which are CD4+ T cells in humans. A key step in the immune response is the activation of T cells by antigens. Peptide epitopes from apolipoprotein B (apoB) have been shown to act as atherosclerosis-related autoantigens, by binding to major histocompatibility complex class II molecules and inducing specific T cell responses. Recently, apoB peptide18 was identified as the first regulatory T cell epitope in human atherosclerosis. In animal models, vaccination with p18 prevented atherosclerosis. Other studies have focused on the role of myeloid epsins, a family of ubiquitin-binding endocytic adaptors, in the regulation of atherogenicity. These epsins appear to promote atherogenesis by facilitating proinflammatory macrophage recruitment and inhibiting efferocytosis. Therefore, manipulating the adaptive immune system by vaccination or immunomodulatory strategies may offer future therapeutic potential in preventing and treating atherosclerosis.
Wolf D, Ley K. Immunity and inflammation in atherosclerosis. Circ Res 2019;124:315-27.
Ley K, Hoffman HM, Kubes P, Cassatella MA, Zychlinsky A, Hedrick CC, Catz SD. Neutrophils: New insights and open questions. Sci Immunol 2018;3(30). pii: eaat4579.
Kimura T, Kobiyama K, Winkels H, Tse K, Miller J, Vassallo M, Wolf D, Ryden C, Orecchioni M, Dileepan T, Jenkins MK, James EA, Kwok WW, Hanna DB, Kaplan RC, Strickler HD, Durkin HG, Kassaye SG, Karim R, Tien PC, Landay AL, Gange SJ, Sidney J, Sette A, Ley K. Regulatory CD4+ T cells recognize major histocompatibility complex class II molecule-restricted peptide epitopes of apolipoprotein B. Circulation 2018;138:1130-43.
Helen Hobbs, Dallas, USA
Lipids, lipases and fatty liver disease
World-wide, the escalating prevalence of nonalcoholic fatty liver disease (NAFLD) poses a major challenge, with estimates suggesting that over one billion individuals are currently affected. Although obesity and insulin resistance are the most prevalent risk factors, genetic factors also play a role in determining both risk for and clinical manifestations of NAFLD.
Studies have shown that variants in a number of genes including PNPLA3 (palatin-like phospholipase domain-containing 3) and TM6SF2 (transmembrane 5 superfamily member 2) genes increase the heritability of NAFLD. One of the most important genetic risk factors is a missense mutation in PNPLA3 (PNPLA3-148M), which been shown to influence both hepatic fat accumulation and susceptibility for more severe liver damage. Experimental studies indicate that the mechanism(s) involved may include disruption of ubiquitylation and proteasomal degradation of PNPLA3, resulting in impaired mobilization of triglycerides from lipid droplets. Concomitant adiposity has been shown to amplify clinical manifestation of this variant on liver fat content and hepatic transaminases. Another variant in TM6SF2 (TM6SF2-167K) was associated with increased risk for hepatic fibrosis independent of age, obesity, diabetes, and PNPLA3 genotype.
Insights from genetic studies, together with improved understanding of the molecular basis of NAFLD, may provide a basis for the development of effective therapies so far lacking. Genetic screening in obese individuals may also help to identify those at highest risk of progression to more severe manifestations of NAFLD.
Mitsche MA, Hobbs HH, Cohen JC. Patatin-like phospholipase domain-containing protein 3 promotes transfer of essential fatty acids from triglycerides to phospholipids in hepatic lipid droplets. J Biol Chem 2018;293:6958-6968.
Banfi S, Gusarova V, Gromada J, Cohen JC, Hobbs HH. Increased thermogenesis by a noncanonical pathway in ANGPTL3/8-deficient mice. Proc Natl Acad Sci U S A 2018;115:E1249-58.
BasuRay S, Smagris E, Cohen JC, Hobbs HH. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology 2017;66:1111-24.
Peter Carmeliet, Leuven, Belgium
Angiogenesis Revisited: Role and (Therapeutic) Implications of Endothelial Metabolism
Endothelial cells are critical to the regulation of organ growth, regeneration and stem cell function and therefore play a key role in the pathophysiology of diseases such as atherosclerosis, diabetes and hypertension. Within the same organ, endothelial cells may have different origins, heterogeneous properties and functional specialization. Distinct gene expression patterns influence the function of endothelial cells including their angiogenic potential, together with the tissue environment and epigenetic factors.
Insights into endothelial metabolism have indicated the importance of glycolysis, a key metabolic pathway, in the regulation of endothelial cell function. Other pathways have also been implicated, including fatty acid oxidation and, more recently, glutamine/asparagine metabolism. Targeting endothelial cell metabolism and metabolic crosstalk may therefore offer a means of limiting oxidative stress and hyperglycaemia-induced endothelial dysfunction that underpin the development of diabetes-related vascular complications. However, as hyperglycaemia-induced endothelial cell dysfunction varies across different vascular beds, and diabetes preferentially affects endothelial cells in some but not in all vascular beds, further study is needed. Investigation of the consequences of over- or underexpression of a specific target in endothelial cells could ultimately provide future therapeutic potential.
Eelen G, Dubois C, Cantelmo A, Goveia J, Brüning U, DeRan M, Jarugumilli G, van Rijssel J, Saladino G, Comitani F, Zecchin A, Rocha S, Chen R, Huang H, Vandekeere S, Kalucka J, Lange C, Morales-Rodriguez F, Cruys B, Treps L, Ramer L, Vinckier S, Brepoels K, Wyns S, Souffreau J, Schoonjans L, Lamers WH, Wu Y, Haustraete J, Hofkens J, Liekens S, Cubbon R, Ghesquière B, Dewerchin M, Gervasio FL, Li X, van Buul JD, Wu X, Carmeliet P. Role of glutamine synthetase in angiogenesis beyond glutamine synthesis. Nature 2018;561:63-9.
Kalucka J, Bierhansl L, Conchinha NV, Missiaen R, Elia I, Brüning U, Scheinok S, Treps L, Cantelmo AR, Dubois C, de Zeeuw P, Goveia J, Zecchin A, Taverna F, Morales-Rodriguez F, Brajic A, Conradi LC, Schoors S, Harjes U, Vriens K, Pilz GA, Chen R, Cubbon R, Thienpont B, Cruys B, Wong BW, Ghesquière B, Dewerchin M, De Bock K, Sagaert X, Jessberger S, Jones EAV, Gallez B, Lambrechts D, Mazzone M, Eelen G, Li X, Fendt SM, Carmeliet P. Quiescent endothelial cells upregulate fatty acid β-oxidation for vasculoprotection via redox homeostasis. Cell Metab 2018; doi: 10.1016/j.cmet.2018.07.016. [Epub ahead of print]
Bruning U, Morales-Rodriguez F, Kalucka J, Goveia J, Taverna F, Queiroz KCS, Dubois C, Cantelmo AR, Chen R, Loroch S, Timmerman E, Caixeta V, Bloch K, Conradi LC, Treps L, Staes A, Gevaert K, Tee A, Dewerchin M, Semenkovich CF, Impens F, Schilling B, Verdin E, Swinnen JV, Meier JL, Kulkarni RA, Sickmann A, Ghesquière B, Schoonjans L, Li X, Mazzone M, Carmeliet P. Impairment of angiogenesis by fatty acid synthase inhibition involves mTOR malonylation. Cell Metab 2018; doi: 10.1016/j.cmet.2018.07.019. [Epub ahead of print]
Douglas R. Seals, Boulder, USA
Cardiovascular aging and mitochondia function
Mitochondrial dysfunction plays a critical role in cardiovascular aging, with crosstalk between the mitochondria and cellular signaling implicated in both cardiac and vascular effects. It is already well established that age-related changes in mitochondria function are integral to pathological alterations in the heart. Added to this, recent studies have also implicated age-related changes in the mitochondria that are associated with vascular pathophysiological changes.
Studies have shown that mitochondria-derived oxidative stress is an important mechanism underlying the development of arterial endothelial dysfunction, a precursor to the development of cardiovascular disease. There is evidence that an excess of mitochondria-derived reactive oxygen species promotes adverse structural changes, notably an increase in collagen production and elastin degradation. Additionally, studies in animal models indicate that modulation of mitochondria-derived reactive oxygen species contributes to large elastic artery stiffening. Beyond these effects, mitochondria-derived reactive oxygen species have also been implicated in exacerbating and sustaining arterial inflammation. This may further contribute to arterial stiffening via a number of mechanisms, including induction of gene expression patterns that modulate structural protein turnover, impairment of vascular endothelial function, increases in vascular smooth muscle cell tone, and exacerbation of the local proinflammatory environment in the vascular wall.
Thus, the emerging evidence suggests the possibility of novel approaches to preventing cardiovascular disease. A key consideration is whether intervention with mitochondria-targeted antioxidants earlier in life could decrease aortic stiffness, and potentially, the risk of associated cardiovascular complications. Indeed, initial clinical studies in healthy older subjects suggest that this approach offers promise for treating age-related vascular dysfunction.
Gioscia-Ryan RA, Battson ML, Cuevas LM, Eng JS, Murphy MP, Seals DR. Mitochondria-targeted antioxidant therapy with MitoQ ameliorates aortic stiffening in old mice. J Appl Physiol 2018;124:1194-202.
Rossman MJ, Santos-Parker JR, Steward CAC, Bispham NZ, Cuevas LM, Rosenberg HL, Woodward KA, Chonchol M, Gioscia-Ryan RA, Murphy MP, Seals DR. Chronic supplementation with a mitochondrial antioxidant (MitoQ) improves vascular function in healthy older adults. Hypertension 2018;71:1056-63.
LaRocca TJ, Martens CR, Seals DR. Nutrition and other lifestyle influences on arterial aging. Ageing Res Rev 2017;39:106-19.
Tuesday 28 May
PREVENTING CVD RISK: WHERE DO WE STAND?
Chris Packard, Glasgow, UK
Biomarkers predicting CVD
The morbidity and disability associated with nonfatal cardiovascular complications are major contributors to the societal burden of cardiovascular disease. With increasing financial pressures on healthcare systems, it is therefore critical to identify susceptible individuals so as to prevent new events. Much of the focus of previous guidelines for cardiovascular disease prevention has been on traditional modifiable risk factors; however, it is evident that these risk factors do not explain all risk, as there are individuals who have events who do not fit the traditional definition of “high risk”. Consequently, there has been a drive to identify and validate novel biomarkers that may be of relevance.
Investigation of this question has offered a diversity of biomarker candidates. One example is troponin I, a specific marker of myocardial injury and an independent predictor of cardiovascular mortality in patients with and without cardiovascular disease. Analyses from the West of Scotland Coronary Prevention Study also showed that serial troponin I measurement has therapeutic potential as a dynamic biomarker of cardiovascular disease risk. To date, however, there is no ‘one’ biomarker that can be recommended. Furthermore, while incorporation of multiple biomarkers in one multimodal marker can improve predictive ability, the costs entailed can limit the gains of this approach.
More recently, attention has also focused on the potential of small non-coding microRNAs (miR) as biomarkers of disease, given their regulatory roles in gene expression. For example, miR-30 has been suggested as one possibility given evidence of a positive association with total- and low-density lipoprotein cholesterol, implicating regulatory functions in lipid homeostasis. Studies also implicate miR‑30c-5p as a promoter of early atherosclerosis. These novel miR may therefore offer promise as non-invasive biomarkers in diagnosis and cardiovascular disease risk stratification, providing information complementary to traditional markers and established clinical variables. As with other potential biomarker candidates, however, there are a range of issues to consider, including changes in the utility of the biomarker in different clinical settings, the extent of intra-individual variability over time, as well as practical requirements. If validated, the use of such novel biomarkers, either alone or in combination, may offer opportunities for tailoring treatment to the individual, as well as monitoring efficacy, consistent with the concept of personalized cardiovascular disease medicine.
Annemans L, Packard CJ, Briggs A, Ray KK. ‘Highest risk-highest benefit’ strategy: a pragmatic, cost-effective approach to targeting use of PCSK9 inhibitor therapies. Eur Heart J 2018;39:2546-50.
Packard CJ, Young R, Ross K, Ford I, Ambegaonkar BM, Brudi P, McCowan C. Modelling total coronary heart disease burden and long-term benefit of cholesterol lowering in middle aged men with and without a history of cardiovascular disease. Eur Heart J Qual Care Clin Outcomes 2017;3:281-8.
Sodi R, Eastwood J, Caslake M, Packard CJ, Denby L. Relationship between circulating microRNA-30c with total- and LDL-cholesterol, their circulatory transportation and effect of statins. Clin Chim Acta 2017;466:13-19.
Heribert Schunkert, Munich, Germany
The genetic burden in CVD
Cardiovascular disease is multifactorial with a diversity of underlying causative factors. While clinical, biochemical, and imaging parameters have been used to stratify cardiovascular risk and, potentially, to tailor therapy, further insights into the pathophysiology of atherosclerosis is now needed to improve preventive strategies. Consideration of genetic susceptibility to cardiovascular disease suggests a way forward.
Methodological advances together with collaborative efforts have improved understanding of the heritability of coronary artery disease. There is now evidence that genetic susceptibility accounts for a proportion of the risk for coronary artery disease, as demonstrated in reproducible findings from genome-wide association studies (GWAS) in extremely large cohorts. GWAS have identified over 50 genetic variants associated with coronary artery disease and myocardial infarction; almost all of these loci are commonly found in European populations. While there are rare variants with a strong impact on disease risk, in the majority of cases, polygenic effects, i.e. the combined small effects of hundreds of thousands of variants are more typical.
Understanding of the biology and pathways which mediate the effects of these loci, and the interplay between multiple genes and non-genetic factors, such as lifestyle factors, lags behind. Improved elucidation of the translation of human genetics to functional biology is fundamental to the development of a simple, clinically meaningful genetic risk score which would provide complementary prognostic information, with the ultimate aim of providing personalized management of coronary artery disease risk and treatment strategies.
van der Laan SW, Siemelink MA, Haitjema S, Foroughi Asl H, Perisic L, Mokry M, van Setten J, Malik R, Dichgans M, Worrall BB; METASTROKE Collaboration of the International Stroke Genetics Consortium, Samani NJ, Schunkert H, Erdmann J, Hedin U, Paulsson-Berne G, Björkegrenn JLM, de Borst GJ, Asselbergs FW, den Ruijter FW, de Bakker PIW, Pasterkamp G. Genetic susceptibility loci for cardiovascular disease and their impact on atherosclerotic plaques. Circ Genom Precis Med 2018;11(9):e002115.
Vilne B, Schunkert H. Integrating genes affecting coronary artery disease in functional networks by multi-OMICs pproach. Front Cardiovasc Med 2018;5:89.
Li Y, Wang DW, Chen Y, Chen C, Guo J, Zhang S, Sun Z, Ding H, Yao Y, Zhou L, Xu K, Song C, Yang F, Zhao B, Yan H, Wang WJ, Wu C, Lu X, Yang X, Dong J, Zheng G, Tian S, Cui Y, Jin L, Liu G, Cui H, Wang S, Jiang F, Wang C, Erdmann J, Zeng L, Huang S, Zhong J, Ma Y, Chen W, Sun J, Lei W, Chen S, Rao S, Gu D, Schunkert H, Tian XL. Genome-wide association and functional studies identify SCML4 and THSD7A as novel susceptibility genes for coronary artery disease. Arterioscler Thromb Vasc Biol 2018;38:964-75.
Schunkert H. Genetics of CVD in 2017: Expanding the spectrum of CVD genetics. Nat Rev Cardiol 2018;15:77-8.
Wednesday 29 May
LOOKING TO THE FUTURE - NOVEL TREATMENT STRATEGIES
Matthias Nahrendorf, Boston, USA
The immune system: The next game-changer?
Development of atherogenesis involves a complex interplay between lipids, inflammatory stress and cellular immune responses. Circulating monocytes have been shown to have a pivotal role in plaque inflammation, infiltrating the plaque where they differentiate into macrophages, and further exacerbate the inflammatory environment. Recent studies have implicated that the ‘neural-hematopoietic’ inflammatory axis as a key driver of atherogenesis. Imaging approaches may hold the key to understanding vascular changes in the bone marrow during acute inflammation and help to identify novel therapeutic targets.
Monocytes and monocyte-derived macrophages also play a key role in the immune response to cardiac ischaemia associated with myocardial infarction (MI). In particular, pro-inflammatory monocytes dominate the early acute period after MI, with neutrophils the first immune cells present at the site of injury in response to danger-associated molecules released by necrotic tissue. Although neutrophils initially help to clear cellular debris, their inflammatory mediators can lead to tissue damage and further leucocyte recruitment. Monocytes and monocyte-derived macrophages release inflammatory cytokines, proteases, and reactive oxygen which together perpetuate inflammation. There is emerging evidence, however, that neutrophils may also have a protective role in MI, as the lack of neutrophil -derived mediators impacts the ability of cardiac macrophages to clear cellular debris, and promotes a reparative phenotype. Identification of novel targets that restrict the local inflammatory monocyte response and potentiate cardioprotective properties may offer therapeutic potential for immunomodulatory approaches to healing post-MI.
Vandoorne K, Rohde D, Kim HY, Courties G, Wojtkiewicz GR, Honold L, Hoyer FF, Frodermann V, Nayar R, Herisson FE, Jung Y, Désogère P, Vinegoni C, Caravan P, Weissleder R, Sosnovik DE, Lin CP, Swirski FK, Nahrendorf M. Imaging the vascular bone marrow niche during inflammatory stress. Circ Res 2018; doi: 10.1161/CIRCRESAHA.118.313302. [Epub ahead of print]
Honold L, Nahrendorf M. Resident and monocyte-derived macrophages in cardiovascular disease. Circ Res 2018; 122:113-27.
Hoogeveen RM, Nahrendorf M, Riksen NP, Netea MG, de Winther MPJ, Lutgens E, Nordestgaard B, Neidhart M, Stroes ESG, Catapano AL, Bekkering S. Monocyte and haematopoietic progenitor reprogramming as common mechanism underlying chronic inflammatory and cardiovascular diseases. Eur Heart J 2017 doi: 10.1093/eurheartj/ehx581. [Epub ahead of print]
Laszlo Nagy, Florida, USA
System-level analyses of inflammatory and repair macrophages reveal an integrated circuitry of lipid and epigenomic changes
Systems biology provides a holistic collaborative approach when investigating complex cellular processes, integrating data from many scientific areas to predict how these systems change over time and under varying conditions. A combination of high-throughput, multiplexed, quantitative methods with computational modelling and statistical approaches is required, especially relevant in the context of macrophage function, given the versatility, plasticity and multiple roles of macrophages in the innate immune system.
The rapid re-programming required for the plasticity of macrophage function depends on the changing microenvironment and metabolic processes. Understanding the transcriptional regulation of macrophage-specific responses to environmental cues has been aided by recent progress in genomics, both for transcriptional activation and, more recently, transcriptional repression. Mechanistic models that explain how transcription factors control macrophage activation and function provide an interpretative framework for the impact of genetic variability on macrophage-specific gene expression. Future systems analysis of the regulation of specific genes involved in macrophage activation in response to different stimuli is likely to represent the next frontier for this field.
Czimmerer Z, Daniel B, Horvath A, Rückerl D, Nagy G, Kiss M, Peloquin M, Budai MM, Cuaranta-Monroy I, Simandi Z, Steiner L, Nagy B Jr, Poliska S, Banko C, Bacso Z, Schulman IG, Sauer S, Deleuze JF, Allen JE, Benko S, Nagy L. The Transcription Factor STAT6 mediates direct repression of inflammatory enhancers and limits activation of alternatively polarized macrophages. Immunity 2018;48:75-90.
Czimmerer Z, Horvath A, Daniel B, Nagy G, Cuaranta-Monroy I, Kiss M, Kolostyak Z, Poliska S, Steiner L, Giannakis N, Varga T, Nagy L. Dynamic transcriptional control of macrophage miRNA signature via inflammation responsive enhancers revealed using a combination of next generation sequencing-based approaches. Biochim Biophys Acta 2018;1861:14-28.
Czimmerer Z, Nagy ZS, Nagy G, Horvath A, Silye-Cseh T, Kriston A, Jonas D, Sauer S, Steiner L, Daniel B, Deleuze JF, Nagy L. Extensive and functional overlap of the STAT6 and RXR cistromes in the active enhancer repertoire of human CD14+ monocyte derived differentiating macrophages. Mol Cell Endocrinol 2018;471:63-74.
Erik S. Stroes, Amsterdam, The Netherlands
New lipid drugs: Is LDL done, ready for new targets?
Much of the emphasis on novel treatments in atherosclerosis has been on apolipoprotein (apo)B-containing lipoproteins, especially in view of the indisputable causality of low-density lipoprotein (LDL) for atherosclerotic cardiovascular disease. Cardiovascular outcomes studies with proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibody therapy represent the pinnacle of this avenue, showing that lowering LDL cholesterol levels, beyond those attained on intensive statin therapy, reduced cardiovascular events in very high risk patients. Moreover, there was no evidence to suggest any threshold in LDL cholesterol lowering for associated clinical benefit.
Yet despite the availability of these highly efficacious LDL cholesterol lowering treatments, very high risk patients continue to experience cardiovascular events. This implies the need to address other targets that contribute to this residual cardiovascular risk. Lipoprotein(a) [Lp(a)] is a key contender, given evidence from epidemiologic and genetic studies for a causal role in atherosclerotic cardiovascular disease. Insights from cardiovascular outcomes studies with the PCSK9 inhibitors add further support, showing that patients with higher baseline Lp(a) levels gained greater cardiovascular benefit from PCSK9 inhibition.
Other lipid targets also merit attention. Recently, the REDUCE-It trial demonstrated reduction in cardiovascular events with high dose (4-g daily) of the omega-3 oil eicosapentaenoic acid in very high risk patients with elevated triglycerides. While the magnitude of benefit (25% relative risk reduction) implies the involvement of mechanisms beyond lipid-lowering, the study is pivotal in supporting the importance of targeting elevated triglycerides, a characteristic of the atherogenic dyslipidaemia associated with type 2 diabetes. Beyond lipids, findings from the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) provide proof of principle for targeting inflammatory risk to reduce cardiovascular events.
The search for other novel targets will undoubtedly continue. In the future, this will undoubtedly include the opportunity to ‘re-programme’ aberrant changes in the control of gene expression with epigenetic treatments for cardiovascular disease prevention.
O’Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E, Gouni-Berthold I, Im K, Lira Pineda A, Wasserman SM, Češka R, Ezhov MV, Jukema JW, Jensen HK, Tokgözoğlu SL, Mach F, Huber K, Sever PS, Keech AC, Pedersen TR, Sabatine MS. Lipoprotein(a), PCSK9 Inhibition, and cardiovascular risk. Circulation 2019;139:1483-92.
Stiekema LCA, Stroes ESG, Verweij SL, Kassahun H, Chen L, Wasserman SM, Sabatine MS, Mani V, Fayad ZA. Persistent arterial wall inflammation in patients with elevated lipoprotein(a) despite strong low-density lipoprotein cholesterol reduction by proprotein convertase subtilisin/kexin type 9 antibody treatment. Eur Heart J 2018 Dec 18. doi: 10.1093/eurheartj/ehy862. [Epub ahead of print]
Kastelein JJP, Stroes ESG. FISHing for the miracle of eicosapentaenoic acid. N Engl J Med 2019;380:89-90.
Nicorescu I, Dallinga GM, de Winther MPJ, Stroes ESG, Bahjat M. Potential epigenetic therapeutics for atherosclerosis treatment. Atherosclerosis 2019;281:189-97.
M. John Chapman, Paris, France
The HDL story: time to reconsider?
The relationship between HDL and cardiovascular disease has had a turbulent history. Evidence from observational studies of an inverse association between HDL cholesterol levels and coronary artery disease risk prompted the notion that increasing HDL levels therapeutically would reduce atherosclerosis. The results of a number of studies involving different therapeutic approaches have, however, been largely negative and led to the demise of the ‘HDL hypothesis’. In addition, recent epidemiologic data have shown that in some clinical settings very high HDL cholesterol levels may correlate with increased atherosclerotic risk.
The key message from these findings is that HDL cholesterol is not an appropriate measure for assessing the relationship between HDL and atherosclerotic cardiovascular disease. Instead, there has been a renewed focus on HDL functionality, including protective effects of HDL on lipid oxidation, endothelial cell functions/integrity, and anti-inflammatory/antiapoptotic effects. Increased understanding of HDL particle composition with ‘omics’ technologies has also underlined the oversimplification of previous thinking. There is now increasing evidence that modification of the structure and composition of HDL particles in numerous disease states including diabetes, auto-immune disease, and cardiovascular disease, results in functionally defective particles; these changes may also indirectly enhance low-density lipoprotein atherogenicity. Taken together, evidence suggests that improving HDL particle quality rather than HDL quantity may offer alternative therapeutic approaches in the future.
Rosenson RS, Brewer HB Jr, Barter PJ, Björkegren JLM, Chapman MJ, Gaudet D, Kim DS, Niesor E, Rye KA, Sacks FM, Tardif JC, Hegele RA. HDL and atherosclerotic cardiovascular disease: genetic insights into complex biology. Nat Rev Cardiol 2018;15:9-19.
Feng M, Rached F, Kontush A, Chapman MJ. Impact of lipoproteins on atherobiology: emerging insights. Cardiol Clin 2018;36:193-201.
Muñoz-Hernandez L, Ortiz-Bautista RJ, Brito-Córdova G, Lozano-Arvizu F, Saucedo S, Pérez-Méndez O, Zentella-Dehesa A, Dauteuille C, Lhomme M, Lesnik P, Chapman MJ, Kontush A, Aguilar Salinas CA. Cholesterol efflux capacity of large, small and total HDL particles is unaltered by atorvastatin in patients with type 2 diabetes. Atherosclerosis 2018;277:72-9.
Chapman MJ, Orsoni A, Robillard P, Therond P, Giral P. Duality of statin action on lipoprotein subpopulations in the mixed dyslipidemia of metabolic syndrome: Quantity vs quality over time and implication of CETP. J Clin Lipidol 2018;12:784-800.