Plenary programme

The Global Burden of Disease Study, established over two decades ago, estimates disability and death from a multitude of causes worldwide. The study has clearly shown that cardiovascular disease (CVD) is a major contributor to the escalating 21^st century pandemic of non-communicable chronic disease, responsible for nearly two-thirds of all global deaths. Indeed, much of the continuing burden from CVD has shifted to low- and middle-income countries, due to sociodemographic transition in these regions. However, it is also recognised that with the ongoing global epidemics of obesity and type 2 diabetes, CVD mortality rates have plateaued and are no longer declining for high-income regions.  These trends underline the importance of increased investment in prevention and treatment of CVD for all regions of the world.

Integration of data relating to incidence, prevalence, and mortality has established poor diet, physical inactivity, tobacco use and excessive alcohol use as key contributors to CVD, via their association with hypertension, hyperglycaemia, hypercholesterolaemia and type 2 diabetes mellitus. In addition, the Global Burden of Disease Study has been instrumental in identifying other risk factors that are precursors of CVD.  

The Global Burden of Disease study provides a novel platform for tracking changes in CVD epidemiology linked to demographic and socioeconomic change. Findings from the study will be critical to improving health systems to reduce or eliminate disparities in CVD prevention across the globe. 

Key references

Thomas H, Diamond J, Vieco A, Chaudhuri S, Shinnar E, Cromer S, Perel P, Mensah GA, Narula J, Johnson CO, Roth GA, Moran AE. Global Atlas of Cardiovascular Disease 2000-2016: the path to prevention and control. Glob Heart 2018;13:143-63.

Murphy A, Johnson CO, Roth GA, Forouzanfar MH, Naghavi M, Ng M, Pogosova N, Vos T, Murray CJL, Moran AE. Ischaemic heart disease in the former Soviet Union 1990-2015 according to the Global Burden of Disease 2015 Study. Heart 2018;104:58-66.

Prabhakaran D, Singh K, Roth GA, Banerjee A, Pagidipati NJ, Huffman MD.  Cardiovascular diseases in India compared with the United States. J Am Coll Cardiol 2018;72:79-95.

Advances in genomic research, biobank resources and computational methodologies offer the tantalising prospect of personalised genomic medicine to facilitate more appropriate medical interventions to reduce the burden of disease. Recent efforts have been directed to investigating the clinical utility of polygenic risk profiling to identify groups of individuals who could benefit from the knowledge of their likely susceptibility to disease.

The polygenic risk score is based on the premise that multiple gene variants with weak associations with disease risk collectively may enhance disease predictive value in the population. Information from the increasing number of biobanks has been instrumental in the development of very large longitudinal cohorts that are needed to verify and test polygenic risk scores. Translation to the clinic, however, poses several challenges. Consideration of the contribution of the genetic component to the underlying mechanisms of the disease is critical, as are appropriate selection of variants for use in the risk score and their weighting. Importantly, the disparity in precision between those of European descent and other ethnicities, a direct consequence of Eurocentric biases in genome-wide association studies, highlights an urgent need for greater diversity in genetic studies. Integration of the use of polygenic risk profiling with other tools and metrics for disease diagnosis and prognosis is also critical.

Key references

Benn M, Tybjærg-Hansen A, Nordestgaard BG. Low LDL cholesterol by PCSK9 variation reduces cardiovascular mortality. J Am Coll Cardiol 2019;73:3102-14.

Marott SCW, Nordestgaard BG, Tybjærg-Hansen A, Benn M. Causal associations in type 2 diabetes development.  J Clin Endocrinol Metab 2019;104:1313-24.

Rasmussen KL, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Plasma levels of apolipoprotein E, APOE genotype, and all-cause and cause-specific mortality in 105 949 individuals from a white general population cohort. Eur Heart J 2019. doi: 10.1093/eurheartj/ehz402.

Much of the focus in cardiovascular disease (CVD) prevention has been on the major established risk factors. It is increasingly recognised, however, that environmental factors pose additional risks with health implications. For example, in Europe, current estimates suggest that environmental factors are responsible for up to 20% of the disease burden, with CVD the largest component of this burden.

Air and noise pollution are environmental health risks with a wide-ranging impact on CVD. A wealth of epidemiologic studies has linked exposure to air pollutants including particulate matter, nitrogen oxides, and carbon monoxide to subclinical CVD and clinical cardiovascular outcomes, with the greatest impact in individuals already at risk. While the underlying mechanisms require further elucidation, pathways implicated include inflammation, oxidative stress, and vascular (endothelial) dysfunction, which can facilitate the development of hypertension, diabetes, and atherosclerosis.

Public policies are essential to protect health and, ultimately, to reduce the burden of CVD. Good evidence supports better urban and transport planning to promote physical activity and reduce levels of air and noise pollution. Moreover, a switch to clean, renewable energy sources has been estimated to more than halve the attributable CVD mortality rate in Europe by over 50%.

Key references

Meier-Girard D, Delgado-Eckert E, Schaffner E, Schindler C, Künzli N, Adam M, Pichot V, Kronenberg F, Imboden M, Frey U, Probst-Hensch N. Association of long-term exposure to traffic-related PM10 with heart rate variability and heart rate dynamics in healthy subjects. Environ Int 2019;125:107-16.

Vienneau D, Héritier H, Foraster M, Eze IC, Schaffner E, Thiesse L, Rudzik F, Habermacher M, Köpfli M, Pieren R, Brink M, Cajochen C, Wunderli JM, Probst-Hensch N, Röösli M; SNC study group. Façades, floors and maps – Influence of exposure measurement error on the association between transportation noise and myocardial infarction. Environ Int 2019;123:399-406.

Thiesse L, Rudzik F, Spiegel K, Leproult R, Pieren R, Wunderli JM, Foraster M, Héritier H, Eze IC, Meyer M, Vienneau D, Brink M, Probst-Hensch N, Röösli M, Cajochen C. Adverse impact of nocturnal transportation noise on glucose regulation in healthy young adults: Effect of different noise scenarios. Environ Int 2018;121(Pt 1):1011-23.

Cellular senescence is a process in which cells cease dividing and undergo distinctive phenotypic alterations, including profound chromatin and secretome changes. Senescent cells may only represent 1–5% of the cells in a tissue, but due to their aggressive nature they have a very profound effect on neighbouring cells. Historically, this process has been viewed as an irreversible cell-cycle arrest mechanism that acts to protect against cancer. However, recent insights indicate that, unlike a static endpoint, senescence represents a series of progressive and phenotypically diverse cellular states acquired after the initial growth arrest. Resistance of senescent cells to both extrinsic and intrinsic pro-apoptotic stimuli implies complex regulation of apoptosis. Indeed, this is a highly dynamic, multi-step process, involving morphological changes, chromatin remodelling, and metabolic reprogramming, as well as secretion of a complex mix of mostly proinflammatory factors termed the senescence-associated secretory phenotype. Epigenetic and genetic changes are important in driving these changes. Thus, these findings extend the role of cellular senescence to complex biological processes such as tissue repair, ageing and age-related disorders.

A deeper understanding of the molecular mechanisms underlying the multi-step progression of senescence and the development and function of acute versus chronic senescent cells offers nascent therapeutic potential. Given the heterogeneity of senescent cell phenotypes, characterisation of senescent cells in vivo using single-cell transcriptome and proteome profiling of tissues will be fundamental to this process. Novel senolytic therapies offer possibilities in future regenerative medicine and age-related pathologies.

Key references

van Deursen JM. Senolytic therapies for healthy longevity. Science 2019;364:636-7.

Childs B, van Deursen J. Inhibition of ‘jumping genes’ promotes healthy ageing. Nature 2019;566:46-8.

Childs BG, Li H, van Deursen JM. Senescent cells: a therapeutic target for cardiovascular disease. J Clin Invest 2018;128:1217-28.

Lipoprotein(a) [Lp(a)] has been considered a cardiovascular risk factor for many years. In the last decade, there has been accumulating and substantial evidence from epidemiologic and Mendelian randomization studies, as well as genome-wide association studies, to support a likely causal role for elevated Lp(a) levels in cardiovascular disease. Until recently, however, the main obstacle to confirmation of causality has been the lack of treatments that specifically lower Lp(a) for testing in large-scale cardiovascular outcomes studies.

A new frontier in Lp(a) research has emerged with antisense-oligonucleotide therapy, which targets Lp(a) production at the level of mRNA translation. Antisense oligonucleotides targeting apolipoprotein(a) have shown promise in early trials. Subsequent development led to an antisense oligonucleotide containing an N-acetyl-galactosamine (GalNac3)−conjugated molecule, which was shown to be highly and selectively taken up by hepatocytes. These properties allowed the use of lower doses and longer dose intervals for this agent compared with other antisense oligonucleotides. In early clinical trials, treatment with this novel therapy was associated with dose dependent reduction in plasma Lp(a) of up to 90% or more in some patients. These advances provide the opportunity to finally test whether pharmacologically lowering elevated Lp(a) levels reduces the risk of cardiovascular events against a background of current best evidence-based therapy.

Key references

Hegele RA, Tsimikas S. Lipid-lowering agents. Circ Res 2019;124:386-404.

Tsimikas S, Gordts PLSM, Nora C, Yeang C, Witztum JL. Statin therapy increases lipoprotein(a) levels. Eur Heart J 2019. pii: ehz310.

Tsimikas S. In search of patients with elevated Lp(a): Seek and ye shall find. J Am Coll Cardiol 2019;73:1040-2.

Willeit P, Ridker PM, Nestel PJ, Simes J, Tonkin AM, Pedersen TR, Schwartz GG, Olsson AG, Colhoun HM, Kronenberg F, Drechsler C, Wanner C, Mora S, Lesogor A, Tsimikas S. Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet 2018;392;1311-20.

Atherosclerosis is well recognised as a chronic inflammatory disease of the arterial wall, responsible for most ischaemic cardiovascular events. Moreover, inflammation may account for a substantial proportion of the residual risk for cardiovascular disease that persists in high risk patients on current therapies. Both innate and adaptive immune responses are involved in all stages of atherosclerosis. If adaptive immune responses occur early during the disease process, then despite reduction in risk factors such as low-density lipoprotein (LDL) cholesterol, there may be sustained production of pathogenic effectors.

T cell and B cell responses play prominent roles in atherosclerotic lesion development and inflammation. T cells are found within coronary atherosclerotic plaques at many stages of disease progression. Indeed, various functional T cell subsets have been associated with cardiovascular disease, whereas levels of regulatory T cells, which dampen immune responses in many ways, are reduced. B cells control cellular immune responses through cell-cell contact, antigen presentation, and cytokine production, and thereby participate in systemic and local immune responses in atherosclerotic arteries. To date, both proatherogenic and antiatherogenic properties have been assigned to B cells, depending on subsets and how they are functionally targeted.

Deciphering the role of specific subtypes of immune cells in atherosclerotic plaque development offers the potential for novel and specific therapeutic strategies to limit progression of atherosclerosis and reduce residual cardiovascular risk.

Key references

Zhao TX, Mallat Z. Targeting the immune system in atherosclerosis: JACC State-of-the-Art Review. J Am Coll Cardiol 2019;73:1691-706.

Sage AP, Tsiantoulas D, Binder CJ, Mallat Z. The role of B cells in atherosclerosis. Nat Rev Cardiol 2019;16:180-96.

Zhao TX, Kostapanos M, Griffiths C, Arbon EL, Hubsch A, Kaloyirou F, Helmy J, Hoole SP, Rudd JHF, Wood G, Burling K, Bond S, Cheriyan J, Mallat Z. Low-dose interleukin-2 in patients with stable ischaemic heart disease and acute coronary syndromes (LILACS): protocol and study rationale for a randomised, double-blind, placebo-controlled, phase I/II clinical trial. BMJ Open 2018;8(9):e022452.

Individuals with type 2 diabetes are at greater risk for cardiovascular disease and associated mortality than those without diabetes. Previous clinical studies had consistently showed that improving glycaemic control in patients with type 2 diabetes had minimal effect, or at best, only a modest effect in reducing the risk of cardiovascular events. However, the growing armamentarium of glucose-lowering therapies has yielded new insights. Clinical trials with the glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown a favourable benefit-risk balance in mitigating cardiovascular risk in high-risk patients with type 2 diabetes. Both empagliflozin and liraglutide also showed reduction in all-cause mortality in diabetic patients with cardiovascular disease. These benefits were independent of the glucose-lowering effects of these agents and improvement in traditional cardiovascular risk factors. European guidelines on diabetes, pre-diabetes and cardiovascular disease now recommend GLP‑1 receptor agonists and SGLT2 inhibitors as first-line treatments in type 2 diabetes patients with established cardiovascular disease or at high/very high risk of cardiovascular disease.

These recommendations herald a new paradigm for the management of patients with type 2 diabetes to improve cardiovascular outcome. With the increasing prevalence of obesity and diabetes globally, the advent of pharmacotherapies with proven efficacy in reducing cardiovascular outcomes makes it imperative to understand the underlying mechanisms for these cardiovascular benefits, to inform clinicians for the best approach for combination glucose-lowering therapy in patients with type 2 diabetes.

Key references

Del Prato S. Heterogeneity of diabetes: heralding the era of precision medicine. Lancet Diabetes Endocrinol 2019;7:659-66.

Del Prato S. Rational combination therapy for type 2 diabetes. Lancet Diabetes Endocrinol 2019;7:328-9.

Hernandez AF, Green JB, Janmohamed S, D’Agostino RB Sr, Granger CB, Jones NP, Leiter LA, Rosenberg AE, Sigmon KN, Somerville MC, Thorpe KM, McMurray JJV, Del Prato S; Harmony Outcomes committees and investigators. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 2018;392:1519-29.

The gut microbiota act collectively as an integrated organ, regulating multiple biological functions that can modulate cardiovascular risk factors and the pathogenic mechanisms of this process. These activities are mediated by various metabolites that can act locally in the gut, as well as travel systemically to affect host physiology. Changes in the composition of the gut microbiota are identified as contributing factors in the development of atherosclerosis and cardiometabolic disease. In particular, three main classes of gut microorganism-dependent metabolites have been linked to cardiovascular health – trimethylamine N-oxide (TMAO), short chain fatty acids and secondary bile acids. If these pathways are dysregulated, there is the potential for exacerbation of risk for cardiovascular disease.

Perhaps the most compelling evidence for the role of the gut bacterial metabolites in cardiometabolic diseases is provided by TMAO. At the molecular level, TMAO has been shown to activate inflammatory gene expression, increase uptake of modified low-density lipoprotein by macrophages, and predispose to increased aggregation and thrombosis. In population-based and intervention studies, increased plasma levels of TMAO were associated with risk of type 2 diabetes mellitus, cardiovascular disease and incident thrombosis. 

Short chain fatty acids produced by the gut microbiota are critical in multiple regulatory roles in energy homeostasis, insulin sensitivity, and glucose and lipid metabolism. Studies consistently show that these metabolites are associated with a reduced risk of cardiovascular and metabolic diseases. The secondary bile acids, deoxycholic acid and lithocholic acid, are the main ligands for TGR5, a G protein-coupled receptor, implicated in weight maintenance and glucose metabolism.

Further understanding of the gut microbe pathways involved in the biosynthesis of cardiovascular-related metabolites, in particular characterisation of their cellular receptors and signalling pathways, may offer potential therapeutic application for managing cardiac health and preventing cardiovascular disease.

Key references

Li XS, Obeid S, Wang Z, Hazen BJ, Li L, Wu Y, Hurd AG, Gu X, Pratt A, Levison BS, Chung YM, Nissen SE, Tang WHW, Mach F, Räber L, Nanchen D, Matter CM, Lüscher TF, Hazen SL. Trimethyllysine, a trimethylamine N-oxide precursor, provides near- and long-term prognostic value in patients presenting with acute coronary syndromes. Eur Heart J 2019;40:2700-9.

Tang WHW, Bäckhed F, Landmesser U, Hazen SL. Intestinal microbiota in cardiovascular health and disease: JACC State-of-the-Art Review. J Am Coll Cardiol 2019;73:2089-105.

McMillan A, Hazen SL. Gut microbiota involvement in ventricular remodeling post-myocardial infarction. Circulation 2019;139:660-2.

Koeth RA, Lam-Galvez BR, Kirsop J, Wang Z, Levison BS, Gu X, Copeland MF, Bartlett D, Cody DB, Dai HJ, Culley MK, Li XS, Fu X, Wu Y, Li L, DiDonato JA, Tang WHW, Garcia-Garcia JC, Hazen SL. l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans. J Clin Invest 2019;129:373-87.