Report || Plenary 3 – Changing landscape in atherosclerotic vascular disease – a brave new world

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Plenary 3 focused on the future for cardiovascular disease prevention, ranging from systems biology and AI, personalised medicine for older patients, to the future for lipid lowering pharmacotherapeutics.

Implementing systems biology to personalise medicine

Professor Johan Björkegren (Icahn School of Medicine at Mount Sinai, New York, USA) overviewed the role of systems biology in personalisation of cardiovascular medicine. A key focus is cardiometabolic disease, given its multidimensional phenotype. Although there is extensive information about the role of energy balance (i.e. lipids/glucose), understanding the interconnecting roles of other molecular trafficking, such as endocrine factors, is limited. A broader framework using systems biology offers potential.

Studies using the STARNET (Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task) cohort, involving nearly 1200 coronary artery disease subjects and over 300 controls, has shown coherent coexpression networks for cardiometabolic risk loci (1). Cross-tissue networks imply a communicative role for endocrine signalling factor, such as leptin and interleukin-6, although so far little is known about the underlying mechanisms. Professor Björkegren concluded that systems biology offers a mechanistic framework for coronary artery disease and cardiometabolic disease, with potential for personalised diagnostics and identification of novel targets.

AI in CVD and beyond

Dr. Jörg Menche (CeMM Research Center for Molecular Medicine in Vienna, Austria) used an innovative format to discuss the promise of network science. Systems biology and -omics provide a map of molecular interactions, defined by location, as well as functional and disease association networks, which translate to biological relatedness. The use of a virtual reality network platform enables researchers to dive into molecular networks. Application of artificial intelligence will drive innovation in cardiovascular medicine and improved clinical management in the future.

Personalised medicine in the elderly – how to avoid overtreatment

Personalised medicine also offers the potential for better care of older patients, as discussed by Professor Bischoff-Ferrari (University Hospital and University of Zurich, Switzerland). This is increasingly relevant as populations age and the burden of age-related chronic disease increases. Multimorbidity and polypharmacy have numerous negative impacts, including nonadherence, overtreatment and increasing negative health outcomes, such as unplanned hospitalisations, all of which are costly for society.

Personalised prevention to extend healthy life expectancy aims to slow biological aging and reduce age-related chronic disease risk. Turning back the clock for biological age, with several small changes personalised to the individual, such as increasing physical activity, adopting a Mediterranean-style diet and incorporating vitamin D, will have major impact on the burden of age-related chronic disease and frailty.

Looking to the future for lipid lowering pharmacotherapeutics

Finally, discussion focused on New Therapeutic Approaches, as discussed by Professor John JP Kastelein (Academic Medical Center, University of Amsterdam, the Netherlands). 2020 represents a crossroad for LDL cholesterol, moving from targets to elimination, with the availability of highly efficacious LDL-lowering combination therapy. However, it is not just ‘lower is better’ but also ‘earlier is better’, with familial hypercholesterolaemia a prime example (2). Aggressively lowering LDL cholesterol beyond current goals has shown no threshold in terms of reduction of major adverse cardiovascular events (MACE) and is safe (3).

New modalities such as siRNA, mRNA and monoclonal antibody approaches offer improved dosing strategies. For example, the siRNA inclisiran allows for twice-yearly injection with durable reduction in LDL cholesterol of more than 50% over time, which will undoubtedly benefit adherence (4). There are also new targets; these include lipoprotein(a) – as discussed by Professor Tsimikas in Plenary 1 – , apolipoprotein CIII, targeting clearance of remnants (5) with the potential for significant MACE reduction over and above the effects of LDL cholesterol reduction, and ANGPTL3. Therapies targeting ANGPTL3 reduce both triglycerides and cholesterol, and as shown by the ANGPTL3 monoclonal antibody evinacumab, are remarkably effective in lowering LDL cholesterol in homozygous FH, thereby reducing the need for lipoprotein apheresis.

The last decade has seen major innovation in LDL cholesterol lowering. Sights are now set on the next major clinical problem, the nonalcoholic fatty liver disease, metabolic syndrome, insulin resistance and dyslipidaemia axis.

References

  1. Zeng L, et al. Contribution of gene regulatory networks to heritability of coronary artery disease. J Am Coll Cardiol 2019;73:2946-2957.
  2. Wiegman A, et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J 2015;36:2425-2437.
  3. Giugliano RP, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet 2017;390:1962-1971.
  4. Ray KK, et al; ORION-10 and ORION-11 Investigators. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med 2020;382:1507-19.
  5. Gaudet DA, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med 2015;373:438-447.