Plenary programme

Artificial Intelligence assisted diagnostics of atherosclerotic vascular disease

Artificial intelligence (AI) has the potential to transform the diagnosis and management of atherosclerotic cardiovascular disease (ASCVD), with imaging one key area where it is likely to impact markedly. In part this has been enabled by improvement in the quality and precision of imaging approaches, as well as wider access. With expanding imaging capabilities, AI offers a solution to the need for operational efficiency and focus on precision medicine.

One area where AI offers promise is in coronary computed tomography (CT) technology. Application of AI provides opportunities to improve the process of image acquisition, interpretation, and decision-making, as well as enhance the reproducibility of technical protocols. Two distinct approaches have been investigated: classical machine learning approaches using clinical and/or pre-computed image features, and deep learning.  Integration of anatomical, functional, and biological information relating to the coronary circulation aids risk stratification of patients, so that preventive therapeutic strategies can be targeted more specifically to those individuals likely to benefit most, a key aim underpinning personalised medicine. Before AI can be adopted into routine practice, however, several challenges need to be addressed, in particular, defining how best to apply this technology to address outcome needs for patients. As a tool to improve the application of precision medicine, AI solutions in cardiac imaging will undoubtedly impact the entire healthcare system.

References

Antonopoulos AS, Angelopoulos A, Papanikolaou P, Simantiris S, Oikonomou EK, Vamvakaris K, Koumpoura A, Farmaki M, Trivella M, Vlachopoulos C, Tsioufis K, Antoniades C, Tousoulis D. Biomarkers of vascular inflammation for cardiovascular risk pPrognostication: a meta-analysis. JACC Cardiovasc Imaging 2021:S1936-878X(21)00698-7.

Antoniades C, Oikonomou EK. Artificial intelligence in cardiovascular imaging-principles, expectations, and limitations. Eur Heart J 2021;doi: 10.1093/eurheartj/ehab678.

Kotanidis CP, Antoniades C. Perivascular fat imaging by computed tomography (CT): a virtual guide. Br J Pharmacol 2021;178(21):4270-4290.

Nonpharmacologic approaches to promote population cardiovascular health

Worldwide, cardiovascular disease (CVD) is the leading cause of death and contributes to an escalating burden of disease, aligned with trends in population growth and aging. The shift in the burden of disease, from mortality to morbidity, and its impact on cost has significant implications for public health policy. While advances in pharmacological approaches to preventive management have shown value, health economics underline the need to focus on promoting ideal cardiovascular health and healthy aging with feasible and affordable nonpharmacological strategies.

Reducing exposure to established modifiable cardiovascular risk factors is key to population health preventive strategies, supported by insights from major epidemiologic studies such as the Prospective Urban Rural Epidemiology (PURE) Study. A heart healthy diet, limiting saturated and trans fats and increasing fibre, regular physical activity, smoking cessation, and maintaining a healthy weight comprise the foundation for CVD risk reduction. Consideration of the overall dietary profile is more important as individual nutrient food groups cannot be viewed in isolation. Even when risk factors such as cholesterol are controlled with pharmacological therapy, adoption of lifestyle changes contributes to improved outcome and well-being.

Population health policies should focus on risk factors that have the greatest impact in preventing CVD and death globally, with additional emphasis on risk factors of greatest importance in specific groups of countries. This low-cost high-value approach to population‐wide prevention offers the potential to substantially impact the global CVD burden, especially among lower- and middle-income countries.

References

Iqbal R, Dehghan M, Mente A, Rangarajan S, Wielgosz A, Avezum A, Seron P, AlHabib KF, Lopez-Jaramillo P, Swaminathan S, Mohammadifard N, Zatońska K, Bo H, Varma RP, Rahman O, Yusufali A, Lu Y, Ismail N, Rosengren A, Imeryuz N, Yeates K, Chifamba J, Dans A, Kumar R, Xiaoyun L, Tsolekile L, Khatib R, Diaz R, Teo K, Yusuf S. Associations of unprocessed and processed meat intake with mortality and cardiovascular disease in 21 countries [Prospective Urban Rural Epidemiology (PURE) Study]: a prospective cohort study. Am J Clin Nutr 2021;114:1049-1058.

Naito R, Leong DP, Bangdiwala SI, McKee M, Subramanian SV, Rangarajan S, Islam S, Avezum A, Yeates KE, Lear SA, Gupta R, Yusufali A, Dans AL, Szuba A, Alhabib KF, Kaur M, Rahman O, Seron P, Diaz R, Puoane T, Liu W, Zhu Y, Sheng Y, Lopez-Jaramillo P, Chifamba J, Rosnah I, Karsidag K, Kelishadi R, Rosengren A, Khatib R, K R LIA, Azam SI, Teo K, Yusuf S. Impact of social isolation on mortality and morbidity in 20 high-income, middle-income and low-income countries in five continents. BMJ Glob Health 2021;6(3):e004124.

Mohan D, Mente A, Dehghan M, Rangarajan S, O’Donnell M, Hu W, Dagenais G, Wielgosz A, Lear S, Wei L, Diaz R, Avezum A, Lopez-Jaramillo P, Lanas F, Swaminathan S, Kaur M, Vijayakumar K, Mohan V, Gupta R, Szuba A, Iqbal R, Yusuf R, Mohammadifard N, Khatib R, Yusoff K, Gulec S, Rosengren A, Yusufali A, Wentzel-Viljoen E, Chifamba J, Dans A, Alhabib KF, Yeates K, Teo K, Gerstein HC, Yusuf S; PURE, ONTARGET, TRANSCEND, and ORIGIN investigators. Associations of fish consumption with risk of cardiovascular disease and mortality among individuals with or without vascular disease from 58 countries. JAMA Intern Med 2021;181:631-649.

Jenkins DJA, Dehghan M, Mente A, Bangdiwala SI, Rangarajan S, Srichaikul K, Mohan V, Avezum A, Díaz R, Rosengren A, Lanas F, Lopez-Jaramillo P, Li W, Oguz A, Khatib R, Poirier P, Mohammadifard N, Pepe A, Alhabib KF, Chifamba J, Yusufali AH, Iqbal R, Yeates K, Yusoff K, Ismail N, Teo K, Swaminathan S, Liu X, Zatońska K, Yusuf R, Yusuf S; PURE Study Investigators. Glycemic index, glycemic load, and cardiovascular disease and mMortality. N Engl J Med 2021;384:1312-1322.

Swaminathan S, Dehghan M, Raj JM, Thomas T, Rangarajan S, Jenkins D, Mony P, Mohan V, Lear SA, Avezum A, Lopez-Jaramillo P, Rosengren A, Lanas F, AlHabib KF, Dans A, Keskinler MV, Puoane T, Soman B, Wei L, Zatonska K, Diaz R, Ismail N, Chifamba J, Kelishadi R, Yusufali A, Khatib R, Xiaoyun L, Bo H, Iqbal R, Yusuf R, Yeates K, Teo K, Yusuf S. Associations of cereal grains intake with cardiovascular disease and mortality across 21 countries in Prospective Urban and Rural Epidemiology study: prospective cohort study. BMJ 2021;372:m4948.

Should we target inflammation?

Systemic vascular inflammation plays a central role in all stages of atherosclerosis, from initiation to the progression and destabilization of atheroma, and consequent development of acute coronary syndromes. Although understanding of the underlying biology of inflammation has increased, translation into effective therapies has proved challenging. The CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) provided proof of the concept that targeting IL (interleukin)-1β, an major cytokine involved in activation of proinflammatory signalling pathways, reduced cardiovascular events in high-risk patients with established atherosclerotic disease. Subsequent to CANTOS, clinical trials have confirmed the benefits of another anti-inflammatory therapy, colchicine in patients with a recent myocardial infarction or with chronic coronary syndromes. However, not all trials have been positive. In CIRT (Cardiovascular Inflammation Reduction Trial), treatment with low-dose methotrexate, a widely used therapy for inflammatory conditions, was not associated with fewer cardiovascular events than placebo due to lack of effect on levels of interleukin-1β, interleukin-6, or C-reactive protein.

Taken together these findings imply considering both the relevance of the patient population – targeting treatment to patients with sufficiently elevated inflammation  – and the diversity of inflammatory pathways involved in atherosclerosis. Thus, while residual inflammatory risk is increasingly recognised as a viable therapeutic target, identifying which inflammatory pathways are preferable targets for intervention requires clarification. Moreover, despite evidence for the clinical utility of high-sensitivity C-reactive protein, it may not be the ideal target for anti-inflammatory therapies.

Recent insights suggest that targeting the NLRP3 inflammasome pathway, which plays a central role in atherosclerosis and the pathogenesis of heart disease, may offer therapeutic potential. Animal models have demonstrated protective effects from NLRP3 inflammasome inhibition, and early clinical data for selective inhibitors of the NLRP3 inflammasome supported this as a feasible and effective strategy. Realizing the promise of targeting inflammation will likely require more individualized approaches targeting different contributors to residual inflammatory risk.

References

Ridker PM, Devalaraja M, Baeres FMM, Engelmann MDM, Hovingh GK, Ivkovic M, Lo L, Kling D, Pergola P, Raj D, Libby P, Davidson M; RESCUE Investigators. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 2021;397:2060-2069.

Ridker PM, Rane M. Interleukin-6 signaling and anti-interleukin-6 therapeutics in cardiovascular disease. Circ Res 2021;128:1728-1746.

Adamstein NH, MacFadyen JG, Rose LM, Glynn RJ, Dey AK, Libby P, Tabas IA, Mehta NN, Ridker PM. The neutrophil-lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials. Eur Heart J 2021;42:896-903.

Targeting non-coding RNAs

Non-coding RNAs do not encode proteins but are instead involved in the regulation of complex biological processes, including cellular lipid metabolism. Accumulating evidence indicates that these non-coding RNAs are functionally active in major regulatory gene expression networks at epigenetic, transcriptional, and even post-transcriptional levels.

Non-coding RNAs, can be classified as either small non-coding RNAs such as microRNAs or long non-coding RNAs, with >200 nucleotides. Over the last decade, research focused on microRNAs which have been shown to act mainly in post-transcriptional control.  Specific microRNAs were identified as potent regulators of cholesterol homeostasis through their ability to repress the expression of genes in the integrated pathways of cholesterol and fatty acid biosynthesis, reverse cholesterol transport, and lipid storage. Increasingly, however, attention has been directed to long-coding RNAs, given associations with atherosclerosis and cardiovascular disease, and aided by high-throughput sequencing technologies. Recent studies in primates identified a novel long-coding RNA (CHROME, (Cholesterol Homeostasis Regulator of MiRNA Expression) involved in the maintenance of cholesterol homeostasis, via upregulation of cholesterol efflux and high-density lipoprotein biogenesis. Moreover, CHROME also inhibited specific miRNAs , implying a coordinated and flexible mechanism to counter post-transcriptional repression of the cholesterol efflux pathway.

Elucidation of the functional significance of non-coding RNAs remains a major challenge. Despite this, emerging evidence suggests a role in modulating gene expression at multiple levels of regulatory pathways involved in cellular and systemic cholesterol homeostasis, which may offer future therapeutic potential.

References

van Solingen C, Moore KJ. Two birds, one stone: NFATc3 controls dual actions of miR-204 in foam cell formation. Eur Heart J 2021;doi: 10.1093/eurheartj/ehab640

Afonso MS, Sharma M, Schlegel M, van Solingen C, Koelwyn GJ, Shanley LC, Beckett L, Peled D, Rahman K, Giannarelli C, Li H, Brown EJ, Khodadadi-Jamayran A, Fisher EA, Moore KJ. miR-33 silencing reprograms the immune cell landscape in atherosclerotic plaques. Circ Res 2021;128:1122-1138.

Sansbury BE, Corr EM, van Solingen C, Koelwyn GJ, Shanley LC, Beckett L, Peled D, Lafaille JJ, Spite M, Loke P, Fisher EA, Moore KJ. Regulatory T cells license macrophage pro-resolving functions during atherosclerosis regression. Circ Res 2020;127:335-353.

ApoB – friend and foe

Cholesterol-rich apolipoprotein (apo) B-containing lipoproteins, of which low-density lipoprotein (LDL) is the archetypal representative, play a fundamental role in the genesis and promotion of atherosclerosis. Mechanistic and genetic studies suggest that assessment of the atherogenic particle subpopulations (LDL and very-low-density lipoprotein [VLDL]) rather than their lipid content may be a better predictor of cardiovascular risk. Alternatively, with accumulating evidence that apoB is integral to lipoproteins exerting their causal effect on risk for cardiovascular disease, measurement of apoB may be preferable.

While LDL cholesterol is conventionally used as a predictor of cardiovascular risk, its use is not without issues, especially when calculated measures of LDL cholesterol are used. In individuals with diabetes or metabolic syndrome, LDL cholesterol levels may not reflect the atherogenicity of the abnormal lipid profile associated with elevated triglyceride-rich lipoproteins. In these patients, apoB is a more accurate measure of risk rather than the concentration of cholesterol contained in lipoproteins. Evidence from epidemiologic studies also supports apoB as a better predictor of cardiovascular risk and response to treatment than measurement of LDL cholesterol. These findings make a case for considering apoB as a priority lipid target in prevention of cardiometabolic disease.

Although improvement in standardization and accessibility is needed, the totality of evidence supports apoB for both risk assessment and as a treatment target in routine clinical practice.

Key references

Zanoni P, Panteloglou G, Othman A, Haas JT, Meier R, Rimbert A, Futema M, Abou-Khalil Y, Nørrelykke SF, Rzepiela A, Stoma S, Stebler M, Dijk FV, Wijers M, Wolters JC, Dalila N, Huijkman N, Smit M, Gallo A, Carreau V, Philippi A, Rabès JP, Boileau C, Visentin M, Vonghia L, Weyler J, Francque S, Verrijken A, Verhaegen A, Van Gaal LF, van der Graaf A, van Rosmalen BV, Robert J, Velagapudi S, Yalcinkaya M, Keel M, Radosavljevic S, Geier A, Tybjærg-Hansen A, Varret M, Rohrer L, Humphries SE, Staels B, van de Sluis B, Kuivenhoven JA, Von Eckardstein A. Posttranscriptional regulation of the human LDL receptor by the U2-spliceosome. Circ Res 2021;doi: 10.1161/CIRCRESAHA.120.318141.

Loaiza N, Hartgers ML, Reeskamp LF, Balder JW, Rimbert A, Bazioti V, Wolters JC, Winkelmeijer M, Jansen HPG, Dallinga-Thie GM, Volta A, Huijkman N, Smit M, Kloosterhuis N, Koster M, Svendsen AF, van de Sluis B, Hovingh GK, Grefhorst A, Kuivenhoven JA. Taking one step back in familial hypercholesterolemia: STAP1 does not alter plasma LDL (Low-Density Lipoprotein) cholesterol in mice and humans. Arterioscler Thromb Vasc Biol 2020;40:973-985.

Rimbert A, Dalila N, Wolters JC, Huijkman N, Smit M, Kloosterhuis N, Riemsma M, van der Veen Y, Singla A, van Dijk F; Biobank-Based Integrative Omics Studies Consortium, Frikke-Schmidt R, Burstein E, Tybjærg-Hansen A, van de Sluis B, Kuivenhoven JA. A common variant in CCDC93 protects against myocardial infarction and cardiovascular mortality by regulating endosomal trafficking of low-density lipoprotein receptor. Eur Heart J 2020;41:1040-1053.

Emerging therapies for dyslipidemia

Low-density lipoprotein cholesterol (LDL-C) is undoubtedly the priority target for lipid lowering therapy to prevent atherosclerotic cardiovascular disease (ASCVD). However, despite maximally tolerated LDL-C lowering, including PCSK9-directed therapies, residual cardiovascular risk persists. Advances in human genetics enabling the identification of rare genetic variants with strong effects on ASCVD risk not only accelerated the development of therapies for severe dyslipidaemia, but also led to identification of novel pathways involved in the metabolism of other atherogenic lipoproteins, most notably triglyceride rich lipoproteins. These insights were critical to the application of a Mendelian randomization design to establish elevated plasma levels of these lipoproteins, as well as lipoprotein(a) [Lp(a)], as independent causal risk factors for ASCVD and thus potential contributors to residual risk. Understanding the underlying genetic and cell machinery has also provided impetus in treating rare dyslipidaemias.

The development of novel antisense therapies, including oligonucleotides and short interfering RNA-based strategies, addresses several unmet medical needs in lipidology. Among these treatments, those targeting apolipoprotein C-III or angiopoietin-like protein 3 have demonstrated substantial lowering of plasma triglycerides in the setting of moderate to severe hypertriglyceridaemia.

Despite the potential efficacy of these new therapies in ASCVD prevention, cost is likely to be prove a major obstacle to their clinical use. Affordability and access are therefore the key challenges facing the next generation of lipid-lowering agents in the era of precision medicine.

Key references

Ginsberg HN, Packard CJ, Chapman MJ, Borén J, Aguilar-Salinas CA, Averna M, Ference BA, Gaudet D, Hegele RA, Kersten S, Lewis GF, Lichtenstein AH, Moulin P, Nordestgaard BG, Remaley AT, Staels B, Stroes ESG, Taskinen MR, Tokgözoğlu LS, Tybjaerg-Hansen A, Stock JK, Catapano AL. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. Eur Heart J 2021; doi: 10.1093/eurheartj/ehab551.

Ahmad Z, Pordy R, Rader DJ, Gaudet D, Ali S, Gonzaga-Jauregui C, Ponda MP, Shumel B, Banerjee P, Dunbar RL. Inhibition of Angiopoietin-Like Protein 3 with evinacumab in subjects with high and severe hypertriglyceridemia. J Am Coll Cardiol 2021;78:193-195.

Gouni-Berthold I, Alexander VJ, Yang Q, Hurh E, Steinhagen-Thiessen E, Moriarty PM, Hughes SG, Gaudet D, Hegele RA, O’Dea LSL, Stroes ESG, Tsimikas S, Witztum JL; COMPASS study group. Efficacy and safety of volanesorsen in patients with multifactorial chylomicronaemia (COMPASS): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol 2021;9:264-275.

Lp(a): The next frontier

Following decades of debate, lipoprotein(a) [Lp(a)] is now recognised as a causal risk factor for atherosclerotic cardiovascular disease and aortic valvular stenosis, supported by evidence from genetic, epidemiological and mechanistic studies. Until recently, however, final proof of causality has proved elusive as the available lipid lowering therapies either have minimal effect on Lp(a) or effects on multiple lipoproteins. The emergence of novel antisense treatments that specifically inhibit the synthesis of apolipoprotein(a) offers the key to addressing this enigma.

Advances in antisense oligonucleotide development, notably conjugation with N-acetylgalactosamine to direct the therapy specifically to hepatocytes, has resulted in improved affinity and selectivity. In phase 2 trials, this agent reduced Lp(a) levels by up to 80%, providing a basis for further development to investigate the impact of Lp(a) lowering on cardiovascular events. The major outcomes study Lp(a)HORIZON (Assessing the Impact of Lipoprotein(a) Lowering With TQJ230 on Major Cardiovascular Events in Patients With CVD) with the apolipoprotein (a) antisense oligonucleotide pelacarsen is testing the Lp(a) hypothesis in secondary prevention patients with elevated Lp(a) levels and optimally managed of low-density lipoprotein cholesterol levels. This trial will be pivotal to bridging the final frontier: Is Lp(a)-associated risk abolished by potent Lp(a) lowering? If proven, the results of Lp(a)HORIZON will be crucial for the development of paradigms aiming to improve awareness, diagnosis, and management of elevated Lp(a).

Key references

Tsimikas S, Moriarty PM, Stroes ES. Emerging RNA therapeutics to lower blood levels of Lp(a): JACC Focus Seminar 2/4. J Am Coll Cardiol 2021;77:1576-1589.

DeFilippis AP, Trainor PJ, Thanassoulis G, Brumback LC, Post WS, Tsai MY, Tsimikas S. Atherothrombotic factors and atherosclerotic cardiovascular events: the multi-ethnic study of atherosclerosis. Eur Heart J 2021: doi: 10.1093/eurheartj/ehab600.

Karwatowska-Prokopczuk E, Clouet-Foraison N, Xia S, Viney NJ, Witztum JL, Marcovina SM, Tsimikas S. Prevalence and influence of LPA gene variants and isoform size on the Lp(a)-lowering effect of pelacarsen. Atherosclerosis 2021;324:102-108.

Trigylcerides: From systemic to cellular metabolism

Whether elevated triglycerides, a surrogate for triglyceride [TG]-rich lipoproteins and their remnants, are associated with risk for cardiovascular disease, has engendered much debate over the decades. Current thinking, largely driven by insights from genetic studies, supports this association although definitive proof is still lacking from major outcomes studies. In addition, the underlying mechanisms of the atherogenicity of TG-rich lipoproteins merit further study. Given that lipoprotein lipase (LpL) plays a central role in TG metabolism, and those genes that modulate its activity correlate with the risk of cardiovascular disease events, research has focused on LpL biology to address this latter question.

ElucidatIon of the structure of the LpL active protein and its interaction with other post-translational regulators has been an important step. Studies showing that LpL is active as a monomer challenged thinking that LpL inhibitors like angiopoietin-like 4 (ANGPTL4) and stabilizers like lipid maturation factor 1 (LMF1) act by disrupting or maintaining LpL in dimer form. These insights prompted interest in developing targets to block LpL to reduce circulating TG levels.

Involvement of LpL in the intravascular hydrolysis of TG-rich lipoproteins on the surface of capillary endothelial cells has driven research into the multiple pathways that mediate endothelial transit of lipids into tissues. There is evidence to suggest a role for receptor-mediated processes in the movement of lipoproteins into the sub-endothelial space. In addition, studies have identified factors that may influence endothelial barrier integrity and thus delivery of lipids.

Taken together, it is evident that improved understanding of TG regulation at the cellular level may offer new therapeutic potential for the management of elevated TG to reduce residual risk.

Key references

Goldberg IJ, Cabodevilla AG, Samovski D, Cifarelli V, Basu D, Abumrad NA. Lipolytic enzymes and free fatty acids at the endothelial interface. Atherosclerosis 2021;329:1-8.

Cabodevilla AG, Tang S, Lee S, Mullick AE, Aleman JO, Hussain MM, Sessa WC, Abumrad NA, Goldberg IJ. Eruptive xanthoma model reveals endothelial cells internalize and metabolize chylomicrons, leading to extravascular triglyceride accumulation. J Clin Invest 2021;131:e145800.

Abumrad NA, Cabodevilla AG, Samovski D, Pietka T, Basu D, Goldberg IJ. Endothelial cell receptors in tissue lipid uptake and metabolism. Circ Res 2021;128:433-450.

Deep phenotyping of disease

Systems approaches encompassing genomics, lipidomics and metabolomics have advanced understanding of the biology of atherosclerosis. Application of deep phenotyping of gene transcriptional and regulatory effects of lipid associated loci, together with ‘cloud’ computing power and ‘big data’, have also identified novel targets with therapeutic potential.

A key focus is inflammation, given its involvement at all stages of atherosclerosis, and evidence that anti-inflammatory interventions reduce the risk of adverse cardiovascular events in patients with recent acute myocardial infarction. Until recently, research has targeted systemic inflammation; however, the emergence of single-cell technologies offers the capability for multi-dimensional profiling of human atherosclerotic plaques, providing insights into novel immune alterations in the plaque microenvironment that are associated with the clinical manifestations of atherosclerosis, as well as key cell-cell signalling networks contributing to progression of atherosclerosis. Single-cell omics can therefore have value in identifying precise interventions that restore the function of immune cellular and molecular networks acting within the circulation and in atherosclerotic lesions in the same patient, with the ultimate goal of reducing both systemic and plaque inflammation.

For the future, the integration of single-cell omics studies in humans with relevant functional experimental models will provide a framework for the development of personalised immunotherapies targeting specific groups of patients who will derive most benefit.

Key references

Hill CA, Fernandez DM, Giannarelli C. Single cell analyses to understand the immune continuum in atherosclerosis. Atherosclerosis 2021;330:85-94.

Afonso MS, Sharma M, Schlegel M, van Solingen C, Koelwyn GJ, Shanley LC, Beckett L, Peled D, Rahman K, Giannarelli C, Li H, Brown EJ, Khodadadi-Jamkaran A, Fisher EA, Moore KJ. miR-33 silencing reprograms the immune cell landscape in atherosclerotic plaques. Circ Res 2021;128:1122-1138.

Fernandez DM, Giannarelli C. Mapping transplant arteriosclerosis cell-by-cell: a path to new immune insights. Circ Res 2020;127:994-996.

Imaging and biomarkers: Targeting the right patient for the right treatment

Personalised medicine, in which medical therapy is tailored to specific patient characteristics, is now a clinical reality. Imaging and biomarkers are two of the tools that can help in precisely defining disease mechanisms so that treatments are targeted to patients likely to benefit most.

Imaging already has a pivotal role in diagnosis and risk stratification in atherosclerotic cardiovascular disease (ASCVD) prevention. Multimodal cardiovascular imaging can identify vulnerable plaque and may anticipate the beneficial effect of pharmacological agents on clinical endpoints and patients’ potential responsiveness to these agents. Leveraging artificial intelligence and machine learning provides objective assessment of the potential clinical benefit to the individual, and thus aids transition to personalised delivery of precision cardiovascular medicine.

Identification and validation of novel biomarkers also provide opportunities for personalising therapy, moving beyond the use of a single marker such as apolipoprotein B/LDL-C to simultaneously target other drivers of atherosclerotic risk. For example, mechanistic studies have shown an interplay between inflammatory processes within the arterial wall or systemic circulation and the cholesterol pathway, linked by activation of the NLRP3 inflammasome. Prevailing evidence suggests that targeting the NLRP3 inflammasome pathway may help to refine phenotypic screening, improve risk stratification, and guide treatment eligibility. Combining multiple markers into a multiplex panel could further improve the application of personalised approaches to ASCVD prevention.

Taken together, integrating information from ‘omics’ technologies with traditional risk factors and imaging data, using artificial intelligence approaches will aid the implementation of specific treatment strategies for precision cardiovascular medicine.

Key references

Sujana C, Salomaa V, Kee F, Costanzo S, Söderberg S, Jordan J, Jousilahti P, Neville C, Iacoviello L, Oskarsson V, Westermann D, Koenig W, Kuulasmaa K, Reinikainen J, Blankenberg S, Zeller T, Herder C, Mansmann U, Peters A, Thorand B; BiomarCaRE Consortium. Natriuretic peptides and risk of type 2 diabetes: results from the biomarkers for cardiovascular risk assessment in Europe (BiomarCaRE) Consortium. Diabetes Care 2021;44:2527-2535.

Batra G, Ghukasyan Lakic T, Lindbäck J, Held C, White HD, Stewart RAH, Koenig W, Cannon CP, Budaj A, Hagström E, Siegbahn A, Wallentin L; STABILITY Investigators. Interleukin 6 and cardiovascular outcomes in patients with chronic kidney disease and chronic coronary syndrome. JAMA Cardiol 2021:e213079.

Wallentin L, Eriksson N, Olszowka M, Grammer TB, Hagström E, Held C, Kleber ME, Koenig W, März W, Stewart RAH, White HD, Åberg M, Siegbahn A. Plasma proteins associated with cardiovascular death in patients with chronic coronary heart disease: A retrospective study. PLoS Med 2021;18(1):e1003513.

Implementing genetics scores in clinical practice

Genetic risk scores offer great potential in the delivery of precision cardiovascular medicine, across primary and early secondary prevention settings, with the opportunity to intervene earlier to inform treatment choices and reduce the likelihood of clinical disease. Integration of genetic risk scores within clinical practice also has wider impact, in optimising healthcare resource use to individuals most likely to be benefit from specific interventions.

While widely applied in research studies, the clinical utility of genetic risk scores has yet to be established. There are also important challenges to their implementation. Key amongst these is the need for further validation to ensure accuracy and reliability, barriers to implementation and to the interpretation of information, education of healthcare personnel, and reimbursement issues. There are also ethical issues relating to how such information is used and the paucity of representation from different ethnicities. These challenges underline the need for further validation within each population ancestry group; definition of the added clinical value from the use of the score; consideration of benefits versus harms in research studies; and assessment of relevant social, ethical and legal issues that may impact reimbursement and health policy. Successful implementation will most likely be in personalising preventive measures and informing treatment choice.

Key references

Patel AP, Wang M, Kartoun U, Ng K, Khera AV. Quantifying and understanding the higher risk of atherosclerotic cardiovascular disease among South Asian individuals: results from the UK Biobank Prospective Cohort Study. Circulation 2021;144:410-422.

Kim MS, Kim WJ, Khera AV, Kim JY, Yon DK, Lee SW, Shin JI, Won HH. Association between adiposity and cardiovascular outcomes: an umbrella review and meta-analysis of observational and Mendelian randomization studies. Eur Heart J 2021;42:3388-3403.

Hindy G, Aragam KG, Ng K, Chaffin M, Lotta LA, Baras A; Regeneron Genetics Center, Drake I, Orho-Melander M, Melander O, Kathiresan S, Khera AV. Genome-wide polygenic score, clinical risk factors, and long-term trajectories of coronary artery disease. Arterioscler Thromb Vasc Biol 2020;40:2738-2746.

Vascular response in atherosclerosis: From epigenetics to bone marrow

Epigenetic control is one of the most fundamental regulatory systems within the cell. Although different cells contain the same genetic material, they have different epigenomic signatures, which may be heritable or temporary, caused by dynamic responses to the environment thereby providing a link between phenotypic profile and disease risk. Epigenetic modifications, such as DNA methylation and post-translational histone processing, have emerged as important regulators of key signalling pathways that alter monocyte/macrophage phenotypes in response to environmental stimuli, and thus important factors in the pathogenesis of atherosclerosis. In contrast to adaptive immune responses, epigenetic reprogramming of transcriptional pathways mediates trained immunity, involving enhanced responsiveness to subsequent triggers. This process is likely to confer detrimental outcomes in the context of chronic inflammatory diseases, such as atherosclerosis.

Atherosclerotic plaque formation is a dynamic multi-cellular process in which the activity of the different cell types involved is essentially determined by the regulation of different genes. Epigenetic factors modulate vascular smooth muscle cell phenotype to either promote or prevent arterial remodelling. These insights have led to suggestions that atherosclerosis is an epigenetic disorder rather than a ‘lipid’, ‘metabolic’, and ‘inflammatory’ disorder. The ongoing challenge is to understand how the mechanisms of epigenetic regulation, including those mediated by intragenic epigenetic modifications and long coding RNAs, promote vascular disease. Finally, the reversibility of epigenetic modifications may suggest future potential for identifying novel therapeutic targets for atherosclerosis.

Key references

Budden CF, Gearing LJ, Kaiser R, Standke L, Hertzog PJ, Latz E. Inflammasome-induced extracellular vesicles harbour distinct RNA signatures and alter bystander macrophage responses. J Extracell Vesicles 2021;10(10):e12127.

Latz E. The inflammasome: from bench to bedside. Nat Rev Immunol 2021;21:622-623.

Divangahi M, Aaby P, Khader SA, Barreiro LB, Bekkering S, Chavakis T, van Crevel R, Curtis N, DiNardo AR, Dominguez-Andres J, Duivenvoorden R, Fanucchi S, Fayad Z, Fuchs E, Hamon M, Jeffrey KL, Khan N, Joosten LAB, Kaufmann E, Latz E, Matarese G, van der Meer JWM, Mhlanga M, Moorlag SJCFM, Mulder WJM, Naik S, Novakovic B, O’Neill L, Ochando J, Ozato K, Riksen NP, Sauerwein R, Sherwood ER, Schlitzer A, Schultze JL, Sieweke MH, Benn CS, Stunnenberg H, Sun J, van de Veerdonk FL, Weis S, Williams DL, Xavier R, Netea MG. Trained immunity, tolerance, priming and differentiation: distinct immunological processes. Nat Immunol 2021;22:2-6