Plenary Programme

Cardiovascular disease (CVD) is among the leading causes of morbidity and premature mortality worldwide. Although age-standardized mortality from CVD has decreased in many regions of the world, the absolute number of deaths continues to increase.  INTERHEART, a case-control study involving 52 countries worldwide, demonstrated that nine risk factors – abnormal lipids, smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, consumption of fruits, vegetables, and alcohol, and regular physical activity – accounted for >90% of the population attributable risk for myocardial infarction (MI). Among these, dyslipidaemia (defined as the ratio of apolipoproteins B/AI) was the single most important risk factor for first MI. Yet the persistence of variation in CVD risk factors indicates that there are additional factors that apply to ‘populations.’ In other words, the environment also influences the risk of CVD. However, there are issues in analysis of the impact of different environmental factors, given the possibility of confounding with multiple highly correlated factors.

Interpretation of epidemiological data also requires caution. For example, both blood pressure and low-density lipoprotein cholesterol (LDL-C) show continuous graded associations with cardiovascular risk in observational studies. In randomized controlled trials, LDL-C lowering reduces CVD risk with the absolute benefit achieved dependent on baseline LDL-C level and the absolute magnitude of LDL-C reduction. Indeed, recent analysis from the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) showed no lower threshold for the relationship between absolute LDL-C reduction and absolute reduction in CVD events. In contrast, trial data suggested that there is lower threshold for benefit from blood pressure lowering. In primary prevention trials, reduction in blood pressure only reduced CVD risk in patients with established hypertension and not in those with normal blood pressure levels. Thus, it may be inappropriate to interpret the associated disease burden solely from observational data. In respect of dietary effects, findings from the Prospective Urban Rural Epidemiology (PURE) study has provided new insights into the relationship between different nutrients and CVD events and mortality. Importantly, however, while there has been much progress in understanding global CVD epidemiology, there remain gaps in evidence, especially in middle- and low-income countries.

Key references

Joseph P, Leong D, McKee M, Anand SS, Schwalm JD, Teo K, Mente A, Yusuf S. Reducing the global burden of cardiovascular disease, Part 1: the epidemiology and risk Factors. Circ Res 2017;121:677-94.

Miller V, Mente A, Dehghan M, Rangarajan S, Zhang X, Swaminathan S, Dagenais G, Gupta R, Mohan V, Lear S, Bangdiwala SI, Schutte AE, Wentzel-Viljoen E, Avezum A, Altuntas Y, Yusoff K, Ismail N, Peer N, Chifamba J, Diaz R, Rahman O, Mohammadifard N, Lana F, Zatonska K, Wielgosz A, Yusufali A, Iqbal R, Lopez-Jaramillo P, Khatib R, Rosengren A, Kutty VR, Li W, Liu J, Liu X, Yin L, Teo K, Anand S, Yusuf S; Prospective Urban Rural Epidemiology (PURE) study investigators. Fruit, vegetable, and legume intake, and cardiovascular disease and deaths in 18 countries (PURE): a prospective cohort study. Lancet 2017; doi: 10.1016/S0140-6736(17)32253-5. [Epub ahead of print]

Mente A, Dehghan M, Rangarajan S, McQueen M, Dagenais G, Wielgosz A, Lear S, Li W, Chen H, Yi S, Wang Y, Diaz R, Avezum A, Lopez-Jaramillo P, Seron P, Kumar R, Gupta R, Mohan V, Swaminathan S, Kutty R, Zatonska K, Iqbal R, Yusuf R, Mohammadifard N, Khatib R, Nasir NM, Ismail N, Oguz A, Rosengren A, Yusufali A, Wentzel-Viljoen E, Puoane T, Chifamba J, Teo K, Anand SS, Yusuf S; Prospective Urban Rural Epidemiology (PURE) study investigators. Association of dietary nutrients with blood lipids and blood pressure in 18 countries: a cross-sectional analysis from the PURE study. Lancet Diabetes Endocrinol 2017;5:774-87.

There is indisputable evidence that low-density lipoprotein cholesterol (LDL-C) is causal for the development and progression of atherosclerotic cardiovascular disease. Consequently, LDL-C is established as the primary target of lipid-directed therapies for the prevention of cardiovascular events. Current European guidelines recommend an LDL-C goal of less than 1.8 mmol/L (70 mg/dl) or at least 50% reduction if the baseline LDL-C is between 1.8 and 3.5 mmol/L (70-135 mg/dL) in patients at very high cardiovascular risk.

The Cholesterol Treatment Trialists’ Collaboration established the relationship between baseline LDL-C level, absolute change in LDL-C and absolute cardiovascular benefit with statin therapy.  Yet, with the advent of PCSK9 monoclonal antibody therapy, LDL-C levels well below LDL-C levels seen with statin therapy are attainable. The first of the outcomes studies with these novel agents have shown that substantial LDL-C lowering against a background of intensive statin treatment reduced major adverse cardiovascular events. Furthermore, subsequent analyses of these data showed that there did not appear a lower LDL-C threshold for cardiovascular benefit. Thus, the evolving evidence base highlights a need for a rethink of LDL-C goals, especially in patients at very high risk of recurrent events or with rapidly progressive atherosclerotic cardiovascular disease.

Key references

Landmesser U, Chapman MJ, Stock JK, Amarenco P, Belch JJF, Borén J, Farnier M, Ference BA, Gielen S, Graham I, Grobbee DE, Hovingh GK, Lüscher TF, Piepoli MF, Ray KK, Stroes ES, Wiklund O, Windecker S, Zamorano JL, Pinto F, Tokgözoğlu L, Bax JJ, Catapano AL. 2017 Update of ESC/EAS Task Force on Practical Clinical Guidance for PCSK9 inhibition in patients with ASCVD or in familial hypercholesterolaemia. Eur Heart J 2017; (in press).

Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, Hegele RA, Krauss RM, Raal FJ, Schunkert H, Watts GF, Borén J, Fazio S, Horton JD, Masana L, Nicholls SJ, Nordestgaard BG, van de Sluis B, Taskinen MR, Tokgözoglu L, Landmesser U, Laufs U, Wiklund O, Stock JK, Chapman MJ, Catapano AL. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-72.

Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, Hoes AW, Jennings CS, Landmesser U, Pedersen TR, Reiner Ž, Riccardi G, Taskinen MR, Tokgozoglu L, Verschuren WM, Vlachopoulos C, Wood DA, Zamorano JL. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J 2016;37:2999-3058.

Current risk stratification tools have their limitations, especially in younger asymptomatic individuals. While detection of subclinical atherosclerosis improves risk prediction, factors associated with the early stages and progression of atherosclerosis are poorly defined. Thus, from a population perspective, identifying associations between cardiovascular risk factors (both established and newly-identified) and the presence and quantification of atherosclerotic disease in its earliest phases, as well as its progression, may offer potential for improved risk stratification, thus enabling therapeutic intervention to be targeted more efficiently.

Advances in imaging techniques that allow the detection of arterial lesions before the development of irreversible damage have now made this proposal feasible. Application of both conventional and novel imaging approaches to population studies such as the PESA (Progression of Early Subclinical Atherosclerosis) study, offers the opportunity to identify new imaging and biological factors associated with the presence and progression of atherosclerosis. This will improve the detection of individuals who have already begun to develop the disease but who do not fall into the established risk categories and are asymptomatic. Such an approach is also consistent with the concept of personalized medicine, allowing cardiovascular prevention strategies to be targeted to those individuals most at risk of clinical disease. When applied on a population level, inclusion of factors associated with subclinical atherosclerotic disease will improve cardiovascular risk management, and undoubtedly provide clinical and socioeconomic benefits at a time when healthcare budgets are increasingly under scrutiny.

Key references

Greenland P, Fuster V. Cardiovascular risk factor control for all. JAMA 2017;318:130-1.

Fuster V. Changing demographics: a new approach to global health care due to the aging population. J Am Coll Cardiol 2017;69:3002-5.

López-Melgar B, Fernández-Friera L, Oliva B, García-Ruiz JM, Peñalvo JL, Gómez-Talavera S, Sánchez-González J, Mendiguren JM, Ibáñez B, Fernández-Ortiz A, Sanz J, Fuster V. Subclinical atherosclerosis burden by 3D ultrasound in mid-life: the PESA Study. J Am Coll Cardiol 2017;70:301-13.

Xing L, Higuma T, Wang Z, Aguirre AD, Mizuno K, Takano M, Dauerman HL, Park SJ, Jang Y, Kim CJ, Kim SJ, Choi SY, Itoh T, Uemura S, Lowe H, Walters DL, Barlis P, Lee S, Lerman A, Toma C, Tan JWC, Yamamoto E, Bryniarski K, Dai J, Zanchin T, Zhang S, Yu B, Lee H, Fujimoto J, Fuster V, Jang IK. Clinical significance of lipid-rich plaque detected by optical coherence tomography: a 4-year follow-up study. J Am Coll Cardiol 2017;69:2502-13.

Over the past 30 years, an extensive body of experimental and clinical research supports a link between psychosocial stress and the development of cardiovascular disease (CVD). Both acute and chronic psychosocial stress has been shown to trigger cardiovascular dysfunction. Furthermore, there is evidence that susceptibility to such stressors may differ between the sexes. Notably, psychosocial stress is strongly predictive of incident CVD in young women in the general population, and recent research has linked stress with adverse outcome in young women with coronary heart disease.  This increased susceptibility may in part be due to a higher burden of psychosocial risk factors in women than in men; studies have reported that stress-related mental disorders such as depression and post-traumatic stress disorder are more prevalent in women than in men.

The mechanisms that underlie this vulnerability to stress-related cardiovascular risk require further elucidation. It has been suggested that effects on the central and autonomic nervous systems may lead to an imbalance between sympathetic and parasympathetic nervous system activation, potentially resulting in oxidative stress and inflammatory signalling that may accelerate metabolic and vascular dysfunction. Indeed, even a slight increase in psychosocial stress has been linked with increases in systemic oxidative stress and inflammation, irrespective of concomitant cardiovascular risk factors. Additionally, changes in the central and autonomic nervous systems that are involved in the regulation of blood pressure and heart rate may be implicated in the link between post-traumatic stress disorder and increased risk for coronary heart disease.

Key references

Vaccarino V, Wilmot K, Al Mheid I, Ramadan R, Pimple P, Shah AJ, Garcia EV, Nye J, Ward L, Hammadah M, Kutner M, Long Q, Bremner JD, Esteves F, Raggi P, Quyyumi AA. Sex differences in Mental Stress-Induced Myocardial Ischemia in patients with coronary heart disease. J Am Heart Assoc 2016;5:doi: 10.1161/JAHA.116.003630.

Hammadah M, Alkhoder A, Al Mheid I, Wilmot K, Isakadze N, Abdulhadi N, Chou D, Obideen M, O’Neal WT, Sullivan S, Tahhan AS, Kelli HM, Ramadan R, Pimple P, Sandesara P, Shah AJ, Ward L, Ko YA, Sun Y, Uphoff I, Pearce B, Garcia EV, Kutner M, Bremner JD, Esteves F, Sheps DS, Raggi P, Vaccarino V, Quyyumi AA. Hemodynamic, catecholamine, vasomotor and vascular responses: Determinants of myocardial ischemia during mental stress. Int J Cardiol 2017;243:47-53.

Al Mheid I, Held E, Uphoff I, Martin GS, Dunbar S, Bidulescu A, Gibbons G, Jones DP, Vaccarino V, Quyyumi AA. Depressive symptoms and subclinical vascular disease: the role of regular physical activity. J Am Coll Cardiol 2016;67:232-234.

Patel RS, Ghasemzadeh N, Eapen DJ, Sher S, Arshad S, Ko YA, Veledar E, Samady H, Zafari AM, Sperling L, Vaccarino V, Jones DP, Quyyumi AA. Novel biomarker of oxidative stress is associated with risk of death in patients with coronary artery disease. Circulation 2016;133:361-9.

Inflammation plays a key role in all stages of the atherothrombotic process, and it has long been recognized that subclinical inflammation is a predictor of future cardiovascular events. Vascular biology research has also provided important insights into the inflammatory pathways mediating atherothrombosis, and identified potential targets for therapeutic intervention. Thus, accumulating evidence has provided a rationale for testing whether drugs that primarily target inflammation can reduce cardiovascular events. In particular, one mediator – interleukin-1β (IL-1β), a proinflammatory cytokine that has multiple roles in the atherothrombotic process –attracted interest as a focus for therapeutic intervention.

In 2017, there was the first evidence from a prospective outcomes study that targeting inflammation reduced cardiovascular events in high risk patients. The agent tested in this trial was canakinumab, a high affinity monoclonal antibody that specifically targets IL-1β. The trial was very much ‘proof-of-concept’ in that the trial population was well treated with intensive statin therapy with low-density lipoprotein cholesterol (LDL-C) levels at baseline lower than those observed in the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial. CANTOS showed a significant reduction in the primary ‘hard outcomes’ endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death, with evidence of a dose-response for canakinumab, and greater clinical benefit in patients with higher levels of inflammation. Incidentally, canakinumab had effects beyond reduction in cardiovascular outcomes, specifically a reduction in cancer mortality, which is consistent with mechanistic and observational findings linking inflammation and cancer.

CANTOS has therefore provided the foundation for a new era for anti-inflammatory therapies for atherothrombosis. It is, however, recognized that not all patients will present with this inflammatory profile. From the clinician’s perspective, such insights offer the possibility of personalizing the management of high risk patients in accordance with their risk factor profile, thus enabling judicious and appropriate use of healthcare resources.

Key references

Libby P. Interleukin-1 beta as a target for atherosclerosis therapy: biological basis of CANTOS and beyond. J Am Coll Cardiol 2017;70:2278-89.

Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-31.

Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ; CANTOS Trial Group. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 2017;390:1833-42.

Libby P, Nahrendorf M, Swirski FK. Leukocytes link local and systemic inflammation in ischemic cardiovascular disease: an expanded “Cardiovascular Continuum”. J Am Coll Cardiol 2016;67:1091-103.

Atherosclerosis is a chronic inflammatory disease that occurs over a prolonged period and culminates in obstructive coronary artery disease. In contrast, neoatherosclerosis, the development of atherosclerotic changes within the neointimal tissue that forms inside the stented segment of a coronary artery, is differentiated by rapid onset. Evidence from pathologic and clinical imaging studies shows that neoatherosclerosis occurs earlier with drug-eluting stents (as early as 4 months) than bare metal stents.

Histologically, neoatherosclerosis is characterized by infiltration of macrophage-derived foam cells within the neointima, with or without necrotic core formation and/or calcification. Calcification is typically microcalcifications combined with apoptotic foam cells or calcification of persistent fibrin in peristrut regions. This progresses to more advanced lesions of fibroatheroma. Histopathology studies have shown that most neoatherosclerotic plaques are confined to the area of the stent.

The precise mechanism(s) of accelerated in-stent neoatherosclerosis have not been fully elucidated although absent or abnormal endothelial functional integrity has been implicated. In the case of drug-eluting stents, it is thought that nonspecific antiproliferative effects of these agents may act both at vascular smooth muscle cells and endothelial cells, leading to dysfunctional endothelial coverage of the stented segment, reduced expression of antithrombotic molecules, platelet deposition, and increased subendothelial permeability to low-density lipoproteins. Low wall shear stress also contributes to activation of endothelial cells, and promotion of monocyte binding and transformation to macrophage-derived foam cells.  In the case of bare-metal stents, the formation of lipid pools within the neointima, vascular smooth muscle apoptosis and proteoglycan deposition, precedes the development of a necrotic core. Ultimately, it is likely that the development of neoatherosclerosis in both settings is likely to be multifactorial.

Key references

Kolodgie FD, Yahagi K, Mori H, Romero ME, Trout HH Rd, Finn AV, Virmani R. High-risk carotid plaque: lessons learned from histopathology. Semin Vasc Surg 2017;30:31-43.

Virmani R, Torii S, Mori H, Finn AV. The stress of plaque prognostication. JACC Cardiovasc Imaging 2017. doi: 10.1016/j.jcmg.2016.12.033. [Epub ahead of print]

Finn AV, Virmani R. Biodegradable polymer drug-eluting stents: non-inferiority waiting for superiority? Lancet 2016;388:2567-8.

RNA editing is a post‐transcriptional process which alters the nucleotide sequence of an RNA molecule relative to the corresponding gene sequence in the primary RNA transcript. As a result, functionally distinct proteins can be produced from a single gene. All types of cellular RNA (messenger, transfer and ribosomal) may undergo editing, as well as intron, noncoding and viral sequences. RNA‐editing systems are mechanistically diverse and biochemically distinct, implying separate evolutionary origins. Understanding of RNA editing has developed with the availability of next generation sequencing technology, which allows for in-depth definition of an RNA editome at nucleotide level of resolution.

In humans, adenosine-to-inosine RNA editing represents the most important class of RNA editing. Using RNA-sequencing and advanced molecular biology techniques, a previously unrecognized role of RNA editing in human atherosclerotic vascular disease has been identified. Specifically, adenosine-to-inosine RNA editing of the extracellular matrix degradation enzyme cathepsin S, an enzyme with a well-established role in the development and prognosis of cardiovascular disease, led to modification of the RNA-protein interaction controlling cathepsin S mRNA stability and expression in inflammatory vascular diseases. For the future, genome-wide investigations are needed to better understand the determinants and the functional consequences of RNA editing.

Key references

Stellos K, Gatsiou A, Stamatelopoulos K, Perisic Matic L, John D, Lunella FF, Jaé N, Rossbach O Amrhein C, Sigala F, Boon RA, Fürtig B, Manavski Y, You X, Uchida S, Keller T, Boeckel JN, Franco-Cereceda A, Maegdefessel L, Chen W, Schwalbe H, Bindereif A, Eriksson P, Hedin U, Zeiher AM, Dimmeler S. Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation. Nat Med 2016;22:1140-50.

Poller W, Dimmeler S, Heymans S, Zeller T, Haas J, Karakas M, Leistner DM, Jakob P, Nakagawa S, Blankenberg S, Engelhardt S, Thum T, Weber C, Meder B, Hajjar R, Landmesser U. Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives. Eur Heart J 2017. doi: 10.1093/eurheartj/ehx165. [Epub ahead of print]

Keller T, Boeckel JN, Groß S, Klotsche J, Palapies L, Leistner D, Pieper L, Stalla GK, Lehnert H, Silber S, Pittrow D, Maerz W, Dörr M, Wittchen HU, Baumeister SE, Völker U, Felix SB, Dimmeler S, Zeiher AM. Improved risk stratification in prevention by use of a panel of selected circulating microRNAs. Sci Rep 2017;7:4511.

Chronic unresolved inflammation plays a key role in the development of advanced atherosclerosis. Under normal physiologic conditions, efferocytosis is fundamental to resolution of the inflammatory response by activating macrophages and other phagocytes to recognize, engulf, and degrade apoptotic cells, thereby dampening inflammation. Specialized pro-resolving mediators, which include fatty acid-derived ligands and proteins, such as annexin A1, are actively involved in driving this process. When efferocytosis is defective, however, apoptotic cells resist uptake by phagocytes, and in advanced plaques this can precipitate clinical events such as myocardial infarction, sudden cardiac death, or stroke.  While understanding of the mechanisms that drive the imbalance between pro-inflammatory and pro-resolving mediators is still far from complete, this concept offers new therapeutic potential.

Identification of these specialized pro-resolving mediators, and recognition that they do not evoke unwanted side effects, such as immunosuppression, has prompted investigation of innovative approaches in atherosclerosis and other inflammatory conditions. The field of ‘resolution pharmacology’ aims to develop agonists at pro-resolving targets.  For example, in experimental models of atherosclerosis, mimetics to these specialized pro-resolving mediators have been shown to attenuate atherosclerotic plaque formation in diet- and inflammation-induced atherogenesis, attenuate atherosclerosis on top of statin therapy, as well as increase plaque stability in human carotid atherosclerotic plaques. These findings have paved the way for clinical trials investigating the potential of these agents in improving the cardiovascular benefits of lipid-lowering therapy.

Key references

Doran AC, Ozcan L, Cai B, Zheng Z, Fredman G, Rymond CC, Dorweiler B, Sluimer JC, Hsieh J, Kuriakose G, Tall AR, Tabas I. CAMKIIγ suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis. J Clin Invest 2017; doi: 10.1172/JCI94735. [Epub ahead of print]

Wang Y, Subramanian M, Yurdagul A Jr, Barbosa-Lorenzi VC, Cai B, de Juan-Sanz J, Ryan TA, Nomura M, Maxfield FR, Tabas I. Mitochondrial fission promotes the continued clearance of apoptotic cells by macrophages. Cell 2017;171:331-345.e22.

Cai B, Thorp EB, Doran AC, Sansbury BE, Daemen MJ, Dorweiler B, Spite M, Fredman G, Tabas I. MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis.  J Clin Invest 2017;127:564-68.

Fredman G, Tabas I. Boosting inflammation resolution in atherosclerosis: the next frontier for therapy. Am J Pathol 2017;187:1211-21.

The concept of the ‘vulnerable plaque’ has undergone evolution in recent years. While previous studies defined the vulnerability of atherosclerotic plaques by histological appearance, i.e., those with a thin fibrous cap, high lipid content, and neovascularization, intravascular imaging studies questioned this, as few of these plaques ruptured and even fewer led to clinical events. Advances in imaging have been used in an attempt to define high-risk plaque features, albeit with limited success. Indeed, a key limitation of these approaches is failure to take account of the atherosclerotic disease burden as a potential confounder. Added to this, information from biobanking has shown a shift in atherosclerotic plaque characteristics that associate with a thrombotic event, reflecting changing treatment and risk factor management, including the widespread use of statins.

These findings have highlighted the need for new approaches to define determinants of plaque vulnerability that do not rely on imaging or histopathological measures. One focus of investigation has been the vascular extracellular matrix (ECM), given its role in the structural organization and integrity of the artery wall, and that degradation and pathological remodelling of the ECM leads to the development and progression of the atherosclerotic plaque. Additionally, investigation of the mechanisms driving the individual’s response to thrombogenic triggers (both internal and external) is needed. Indeed, studies have highlighted the need to take account of the complex interplay between intrinsic and extrinsic factors affecting plaque stability, which could offer markers of advanced atherosclerosis progression. Ultimately, the integration of lesion characteristics with risk factors may provide the most value in accurate individual risk prediction of acute coronary events. 

Key references

Langley SR, Willeit K, Didangelos A, Matic LP, Skroblin P, Barallobre-Barreiro J, Lengquist M, Rungger G, Kapustin A, Kedenko L, Molenaar C, Lu R, Barwari T, Suna G, Yin X, Iglseder B, Paulweber B, Willeit P, Shalhoub J, Pasterkamp G, Davies AH, Monaco C, Hedin U, Shanahan CM, Willeit J, Kiechl S, Mayr M. Extracellular matrix proteomics identifies molecular signature of symptomatic carotid plaques. J Clin Invest 2017;127:1546-60.

Pasterkamp G, den Ruijter HM, Libby P. Temporal shifts in clinical presentation and underlying mechanisms of atherosclerotic disease. Nat Rev Cardiol 2017;14:21-9.

Libby P, Pasterkamp G. Requiem for the ‘vulnerable plaque’. Eur Heart J 2015;36:2984-7.

Atherogenic dyslipidaemia is characterized by elevated plasma concentrations of both fasting and postprandial triglyceride-rich lipoproteins (TRLs), small dense low-density lipoprotein (LDL) and low plasma concentration of high-density lipoprotein (HDL) cholesterol. This dyslipidaemia is a major driver of cardiovascular risk in individuals who are obese and/or have type 2 diabetes. The different components of diabetic dyslipidemia are not isolated abnormalities but closely linked to each other metabolically.

Elevated circulating TRLs, which reflect an imbalance between the synthesis and removal of the largest of the TRLs, very low-density lipoproteins (VLDL₁), are pivotal to the development of atherogenic dyslipidaemia. Two key metabolic defects contribute: hepatic overproduction and delayed clearance of VLDL1. Increased deposition of fat in the liver (steatosis) and visceral adiposity are linked with increased secretion of VLDL1, whereas increased levels of apolipoprotein C-III (apoC-III), which regulates the metabolism of TRLs via direct effects on lipoprotein lipase and indirect mechanisms, such as promoting secretion of TRLs, is implicated in the reduced clearance of TRLs. Of the two defects, kinetic studies have shown that the increase in apoC-III is a more important contributor to plasma triglycerides. Together with evidence from studies showing a link between higher apoCIII levels in VLDL and LDL and increased cardiovascular risk, as well as recent genetic insights, these findings reinforce the relevance of apoC-III as a proatherogenic apolipoprotein.

Understanding the metabolic defects in hepatic and lipoprotein metabolism that underpin the development of atherogenic dyslipidaemia in abdominal obesity offers the opportunity for the development of novel therapeutic approaches, notably those targeting apoC-III. Ultimately these strategies may result in improvements in the prevention, diagnosis and management of atherogenic dyslipidaemia.

Key references

Taskinen MR, Söderlund S, Bogl LH, Hakkarainen A, Matikainen N, Pietiläinen KH, Räsänen S, Lundbom N, Björnson E, Eliasson B, Mancina RM, Romeo S, Alméras N, Pepa GD, Vetrani C, Prinster A, Annuzzi G, Rivellese A, Després JP, Borén J. Adverse effects of fructose on cardiometabolic risk factors and hepatic lipid metabolism in subjects with abdominal obesity. J Intern Med 2017;282:187-201.

Björnson E, Adiels M, Taskinen MR, Borén J. Kinetics of plasma triglycerides in abdominal obesity. Curr Opin Lipidol 2017;28:11-18.

Taskinen MR, Borén J. Why is apolipoprotein CIII emerging as a novel therapeutic target to reduce the burden of cardiovascular disease? Curr Atheroscler Rep 2016;18:59.

Genome wide association studies involving genetic data from very large numbers of individuals has been instrumental in identifying many genetic variants with small effects on lipoprotein levels. Individually, these variants explain a very small fraction of the variation in complex traits and thus have limited predictive capacity for disease risk. Combining the small effects of these multiple variants into a single genetic risk score, however, provides a useful tool for examining the cumulative predictive ability of genetic variation at known genetic loci on cardiovascular disease (CVD) outcomes and related phenotypes.  

The use of genetic data in this way offers a number of advantages. First, genetic risk scores could be used to predict risk for CVD outcomes and subclinical phenotypes in clinical and other high-risk populations, and could help to identify those individuals who respond best to established preventive pharmacotherapeutic strategies. For example, a polygenic risk score not only defines individuals with a higher burden of atherosclerosis, but can also identify those likely to derive the greatest benefit when treated with statin therapy.1,2 Such data allows the possibility of tailoring treatment according to the individual’s risk to optimize response.

Second, genetic risk scores may have potential in evaluating gene-by-environment interaction, of particular relevance in obesity, type 2 diabetes, and lipid research. Genetic risk scores also have application as instrumental variables in Mendelian randomization studies. This approach has been valuable in recent studies evaluating the benefits of therapeutic approaches, as for example those targeting PCSK9 or CETP. Finally, the extension of Mendelian randomization techniques to other data types, such as epigenetic and metabolomic data, may be a promising area of future research. Ultimately, these approaches provide the key to personalization of preventive approaches in CVD.  

1. Mega JL, Stitziel NO, Smith JG et al. Lancet 2015;385:2264-71.

2. Natarajan P, Young R, Stitziel NO et al. Circulation 2017;135:2091-101.

Key references

Ference BA, Kastelein JJP, Ginsberg HN, Chapman MJ, Nicholls SJ, Ray KK, Packard CJ, Laufs U, Brook RD, Oliver-Williams C, Butterworth AS, Danesh J, Smith GD, Catapano AL, Sabatine MS. Association of genetic variants related to CETP inhibitors and statins with lipoprotein levels and cardiovascular risk. JAMA 2017;318:947-56.

Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, Hegele RA, Krauss RM, Raal FJ, Schunkert H, Watts GF, Borén J, Fazio S, Horton JD, Masana L, Nicholls SJ, Nordestgaard BG, van de Sluis B, Taskinen MR, Tokgözoglu L, Landmesser U, Laufs U, Wiklund O, Stock JK, Chapman MJ, Catapano AL. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-72.

Ference BA, Robinson JG, Brook RD, Catapano AL, Chapman MJ, Neff DR, Voros S, Giugliano RP, Davey Smith G, Fazio S, Sabatine MS. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med 2016;375:2144-53.

Atherothrombosis, characterized by atherosclerotic lesion disruption with superimposed thrombus formation, is the major cause of acute coronary syndromes and the leading cause of mortality in the industrialized world. Subendothelial retention of cholesterol-containing plasma lipoproteins, together with flow-mediated inflammatory changes in endothelial cells, trigger the process of atherogenesis. In individual lesions, vascular endothelial disruption may provoke platelet adhesion activation, and aggregation, resulting in thrombotic complications. Neutrophils, early mediators of the innate immune defense, play a key role in amplifying intravascular coagulation. Coronary artery revascularization strategies, together with pharmacological therapies targeting molecular and cellular components involved in the pathophysiology of atherothrombosis, are mandatory to prevent cardiovascular complications during and after revascularization and therefore improve clinical outcomes.

Stent thrombosis, however, is a serious complication of coronary stenting. With the widespread use of drug eluting stents, there is evidence of an excess of late stent thrombosis. While the triggering mechanisms are not yet fully understood, delayed healing of the coronary artery segment as evident by persistent late platelet accumulation and aberrant activation of the coagulation cascade are thought to play a role. Recent findings have also suggested that both immunothrombosis-related pathways and allergic reactions may also contribute to the development of late stent thrombosis. Consequently, immune cells could represent an important target for the prevention of stent thrombosis and associated complications in the future.

Key references

Adriaenssens T, Joner M, Godschalk TC, Malik N, Alfonso F, Xhepa E, De Cock D, Komukai K, Tada T, Cuesta J, Sirbu V, Feldman LJ, Neumann FJ, Goodall AH, Heestermans T, Buysschaert I, Hlinomaz O, Belmans A, Desmet W, Ten Berg JM, Gershlick AH, Massberg S, Kastrati A, Guagliumi G, Byrne RA; Prevention of Late Stent Thrombosis by an Interdisciplinary Global European Effort (PRESTIGE) Investigators. Optical coherence tomography findings in patients with coronary stent thrombosis: a report of the PRESTIGE Consortium (Prevention of Late Stent Thrombosis by an Interdisciplinary Global European Effort). Circulation 2017;136:1007-21.

Uderhardt S, Ackermann JA, Fillep T, Hammond VJ, Willeit J, Santer P, Mayr M, Biburger M, Miller M, Zellner KR, Stark K, Zarbock A, Rossaint J, Schubert I, Mielenz D, Dietel B, Raaz-Schrauder D, Ay C, Gremmel T, Thaler J, Heim C, Herrmann M, Collins PW, Schabbauer G, Mackman N, Voehringer D, Nadler JL, Lee JJ, Massberg S, Rauh M, Kiechl S, Schett G, O’Donnell VB, Krönke G. Enzymatic lipid oxidation by eosinophils propagates coagulation, hemostasis, and thrombotic disease. J Exp Med 2017;214:2121-38.

Bamberg F, Hetterich H, Rospleszcz S, Lorbeer R, Auweter SD, Schlett CL, Schafnitzel A, Bayerl C, Schindler A, Saam T, Müller-Peltzer K, Sommer W, Zitzelsberger T, Machann J, Ingrisch M, Selder S, Rathmann W, Heier M, Linkohr B, Meisinger C, Weber C, Ertl-Wagner B, Massberg S, Reiser MF, Peters A. Subclinical disease burden as assessed by whole-body MRI in subjects with prediabetes, subjects with diabetes, and normal control subjects from the general population: the KORA-MRI Study. Diabetes 2017;66:158-69.

Antisense inhibition offers a promising approach to the management of dyslipidaemia. It functions at the cellular level by interfering with RNA function, often leading to degradation of specifically targeted abnormal gene products implicated in the disease process. Antisense oligonucleotides are short single strands of DNA, consisting of sequences that are complementary to the target RNA; stability and efficient delivery are prerequisites for the suitability of this therapy. The development of second generation antisense oligonucleotides, aided by advances in liposomal formulas, nanoparticles and oligonucleotide conjugates offers targeted delivery with improved cellular uptake and distribution. Such advances in antisense inhibition technology have led to novel approaches to address unmet clinical needs in the management of hypertriglyceridaemia or elevated lipoprotein(a) levels, with antisense oligonucleotides targeting APOC3 or apolipoprotein(a) messenger RNA, respectively.

Beyond these developments, antisense strategies have now expanded to encompass the inclusion of small interfering RNAs (siRNAs). Not only do siRNAs offer advantages in terms of efficiency and specificity but also improvements in stability, delivery, and duration of action. Evidence to date also suggests a reduced propensity for off-target effects, suggesting new therapeutic potential for this approach.

Key references

Graham MJ, Lee RG, Brandt TA, Tai LJ, Fu W, Peralta R, Yu R, Hurh E, Paz E, McEvoy BW, Baker BF, Pham NC, Digenio A, Hughes SG, Geary RS, Witztum JL, Crooke RM, Tsimikas S. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med 2017;377:222-32.

Viney NJ, van Capelleveen JC, Geary RS, Xia S, Tami JA, Yu RZ, Marcovina SM, Hughes SG, Graham MJ, Crooke RM, Crooke ST, Witztum JL, Stroes ES, Tsimikas S. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 2016;388:2239-53.

van Capelleveen JC, Bernelot Moens SJ, Yang X, Kastelein JJP, Wareham NJ, Zwinderman AH, Stroes ESG, Witztum JL, Hovingh GK, Khaw KT, Boekholdt SM, Tsimikas S. Apolipoprotein C-III levels and incident coronary artery disease risk: the EPIC-Norfolk Prospective Population Study. Arterioscler Thromb Vasc Biol 2017;37:1206-12.

Vulnerable plaques are defined as nonobstructive atherosclerotic lesions that are prone to rupture, resulting in acute coronary syndromes. The common feature of vulnerable plaques is lipid accumulation, either as a lipid core or lipid pools, covered by a thin fibrous cap. While intravascular ultrasound (IVUS) allows the visualization of plaque morphology, it is unable to accurately differentiate specific plaque components, and thus is inappropriate for identification of the vulnerable plaque.

Imaging technologies that are able to quantify lipid accumulation in the plaque may offer therapeutic potential. One such approach is the use of near-infrared spectroscopy (NIRS) combined with IVUS, which can be used to evaluate the lipid core burden, a clinical correlate of the vulnerable plaque. This approach therefore offers the possibility of identifying vulnerable plaques so that they can be treated before the onset of clinical events. Studies have shown that NIRS has a high specificity for differentiating ST-segment myocardial infarction culprit plaques from nonculprit plaques. In addition, information about the composition of a plaque and the extent of the lipid core, together with structural information from IVUS, provides true vessel characterization, which can be used in risk stratification of patients for treatment, as well as optimization of coronary interventions. NIRS-IVUS may also have application in clinical development as a surrogate end-point for future acute coronary syndromes.  

Key references

Szummer K, Wallentin L, Lindhagen L, Alfredsson J, Erlinge D, Held C, James S, Kellerth T, Lindahl B, Ravn-Fischer A, Rydberg E, Yndigegn T, Jernberg T. Improved outcomes in patients with ST-elevation myocardial infarction during the last 20 years are related to implementation of evidence-based treatments: experiences from the SWEDEHEART registry 1995-2014. Eur Heart J 2017;38:3056-65.

Erlinge D, Omerovic E, Fröbert O, Linder R, Danielewicz M, Hamid M, Swahn E, Henareh L, Wagner H, Hårdhammar P, Sjögren I, Stewart J, Grimfjärd P, Jensen J, Aasa M, Robertsson L, Lindroos P, Haupt J, Wikström H, Ulvenstam A, Bhiladvala P, Lindvall B, Lundin A, Tödt T, Ioanes D, Råmunddal T, Kellerth T, Zagozdzon L, Götberg M, Andersson J, Angerås O, Östlund O, Lagerqvist B, Held C, Wallentin L, Scherstén F, Eriksson P, Koul S, James S. Bivalirudin versus heparin monotherapy in myocardial infarction. N Engl J Med 2017;377:1132-42.

Madder RD, Puri R, Muller JE, Harnek J, Götberg M, VanOosterhout S, Chi M, Wohns D, McNamara R, Wolski K, Madden S, Sidharta S, Andrews J, Nicholls SJ, Erlinge D. Confirmation of the intracoronary near-infrared spectroscopy threshold of lipid-rich plaques that underlie ST-segment-elevation myocardial infarction. Arterioscler Thromb Vasc Biol 2016;36:1010-5.