Report || Plenary 1: Nature and nurture – impact on traditional cardiovascular risk factors

This session is available on demand

The nature versus nurture debate in the context of cardiovascular risk is well recognised. However, it may be an oversimplification, given evidence that genetic, environmental and modifiable factors interact to impact risk. Monday’s Plenary Session covered key topics from this area.

Opening this Plenary, Dr Gregory A. Roth (University of Washington, USA) gave a global perspective of cardiovascular disease risk. The Global Burden of Disease (GBD) Study established in 1990 provides annual updates of the impact of risk factors on disease, with information on 354 diseases and 84 risk factors. The GBD is essential to the field as it provides metrics of population health to describe global patterns of disease. According to the GBD, the prevalence of cardiovascular disease is increasing, not just in the lowest sociodemographic index (SDI) countries, but also now in higher SDI countries, reflecting global increases in diabetes and obesity. Both high fasting glucose and high body mass index rank within the top five leading risk factors accounting for the largest proportion of disease burden (1). In Europe, Eastern European countries, together with the Russian Federation, have the highest rates for disability-adjusted life-years for ischaemic heart disease.

Clearly there is a need for concerted global action to address this increasing cardiometabolic risk. One such example is the NCD Global Action Plan, targeting alcohol intake, physical inactivity, smoking, diabetes, and obesity, aiming to reduce premature mortality by 25% by 2025 (2). Pharmacotherapeutic intervention also has a role in attainment of this goal, although delivery may vary according to the availability of resources in local areas. The development of the polypill is one approach to improve this in areas with limited resources (2). Tailoring global risk factors to the local context and health system capacity, together with sharing evidence, are fundamental to achieving best practice.

Polygenic risk scores – will they reach clinical practice?

Professor Anne Tybjærg-Hansen (Rigshospitalet, Copenhagen University Hospital, Denmark) overviewed why the use of polygenic risk scores are an attractive proposition in cardiovascular risk management. Representing the summation of the effects of many common variants associated with coronary artery disease not only provides a better estimate of disease prevalence but also improves risk prediction, given the interaction of genetic and lifestyle risk (3,4).

Polygenic risk scores may also aid in identification of individuals who benefit more from therapeutic intervention. For example, data from the ODYSSEY OUTCOMES study show that a high polygenic risk score for coronary artery disease is associated with an increased risk of major cardiovascular events. Such individuals gain a larger absolute benefit from PCSK9 inhibition in the setting of acute coronary syndrome (5). While polygenic risk scores will undoubtedly have a future role in clinical practice, there are still several outstanding issues, including how best to integrate these scores into overall risk estimation.

What is the environment doing to cardiovascular health?

Professor Nicole Probst-Hensch (Swiss Tropical and Public Health Institute, Basel, Switzerland) discussed why consideration of environmental risk factors is essential for improving cardiovascular health. Overall, the effects of air, water and soil pollution are responsible for 9 million deaths annually – 6.2% of global output – although this is likely to be an underestimate as it does not take account of interactive effects or co-morbidities.

The risk of air pollution to cardiovascular risk is now established, with good evidence for the causal short- and long-term effects of particulate matter on cardiovascular risk. In the LUDOK database long-term exposure to ambient ultrafine particles was associated with an increased risk for all incident cardiovascular disease, including myocardial infarction and heart failure (6). For lower middle-income countries, biomass fuel exposure is more of an issue, and as individuals move to an urban environment, may predispose to increased susceptibility to cardiovascular disease at an earlier age. Overall, 50% of deaths caused by particulate air pollution is due to cardiovascular disease, highlighting the urgent need for personalised measures to reduce exposure (7).

After air pollution, traffic noise is a key stressor. In Europe, traffic noise is responsible for more than one million healthy years of life lost and 61,000 disability adjusted life years lost annually due to ischaemic heart disease (8). Road traffic noise increases the incidence of obesity, depression, diabetes and vascular stiffness (9).  In particular, night-time noise increases levels of stress hormones and vascular oxidative stress, which may promote endothelial dysfunction and arterial hypertension.

With integration of the exposome within cardiovascular risk, there is a clear need to consider environmental risk factors in combination. This becomes more important given that by 2030 more than 80% of Europe’s population will live in a complex urban environment. The use of systems biology approaches to improve causal understanding, together with the EXPANSE project in over 55 million people in Europe, are key to addressing many outstanding issues relating to the exposome and its role in cardiometabolic disease, and critical to improving urban health and informing policy action.

Age, the unpreventable risk factor – targeting senescence

While age is generally regarded as the unmodifiable risk, does the study of senescence offer therapeutic potential? Professor Jan Van Deursen (The Mayo Clinic, Rochester, Minnesota, USA) overviewed mechanistic understanding of this process. Senescence is a highly dynamic, multi-step process, involving morphological changes, and metabolic reprogramming. Senescent cells accumulate during ageing, notably in advanced atherosclerotic lesions. Studies in a transgenic mouse model suggest that senescent cells play a key role in atheroma development and progression, promoting plaque instability in advanced lesions by enhancing metalloprotease production (10). These insights have led to the proposal that targeting senescence with selective senolytic agents, such as ABT which has been investigated in experimental models, may offer therapeutic potential for the management of atherosclerosis.

References

  1. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392:1789-1858.
  2. Webster R, et al. Fixed low-dose triple combination antihypertensive medication vs usual care for blood pressure control in patients with mild to moderate hypertension in Sri Lanka: a randomized clinical trial. JAMA 2018;320:560-579.
  3. Khera AV, et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet 2018;50:1219-1224.
  4. Khera AV, et al. Genetic risk, adherence to a healthy lifestyle, and coronary disease. N Engl J Med 2016;375:2349-2358.
  5. Damask A, et al. Patients with high genome-wide polygenic risk scores for coronary artery disease may receive greater clinical benefit from alirocumab treatment in the ODYSSEY OUTCOMES Trial. Circulation 2020;141:624-636.
  6. Downward GS, et al. Long-term exposure to ultrafine particles and incidence of cardiovascular and cerebrovascular disease in a prospective study of a Dutch cohort. Environ Health Perspect 2018;126(12):127007
  7. Al-Kindi SG, et al. Environmental determinants of cardiovascular disease: lessons learned from air pollution. Nat Rev Cardiol 2020;17:656-672.
  8. Eze IC, et al. Incidence of depression in relation to transportation noise exposure and noise annoyance in the SAPALDIA study. Environ Int 2020;144:106014.
  9. Münzel T, et al. Adverse cardiovascular effects of traffic noise with a focus on nighttime noise and the new WHO Noise Guidelines. Annu Rev Public Health 2020;41:309-328.
  10. Childs BG, et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science  2016;354:472-477.