The rise of cardiometabolic disease

News from EAS Helsinki 2021 Virtual:

Not only are we living in a COVID-19 pandemic, but also an accelerating pandemic of cardiometabolic disease, requiring renewed focus. The third plenary session discussed options to address this escalation in cardiometabolic disease.

Professor Juleen Zierath (Karolinska Institute, Stockholm, Sweden and University of Copenhagen, Denmark) discussed new insights into re-setting the clock in metabolic disease. Ongoing work suggests that synchronising exercise to the circadian clock maximises beneficial effects, of particular relevance for managing individuals with metabolic disease. For example, studies in subjects with type 2 diabetes show that high-intensity exercise undertaken in the afternoon had superior and persistent effects on blood glucose lowering compared with morning exercise.  Tissue analysis of samples taken the morning after exercise suggested ‘time of day’ specific effects, consistent with findings in animal studies (1). Thus, ‘time of day’ appears to amplify the metabolic effect of exercise, with metabolomic findings indicating that exercise appears to ‘rewire’ inter- and intra tissue metabolic communication via effects on mitochondrial function and inner mitochondrial rhythmicity. These encouraging findings reinforce the molecular benefits of exercise in countering metabolic stress.

Diet is another fundamental component of prevention strategies. Professor Miguel Martinez-Gonzalez (CIBEROBN and University of Navarra, Spain) highlighted the Mediterranean diet, characterised by high intake of olive oil and plant foods, low-to-moderate intake of dairy products, fish and poultry, moderate intake of alcohol, and low intake of red meat and sweets, which persistently ranks as the best evidence-based dietary strategy for cardiometabolic health. Better conformity with this diet associated with improved cardiovascular health outcomes (2). The SUN (Seguimiento Universidad de Navarra) project also showed that higher adherence with the Mediterranean diet was associated with greater absolute reduction in cardiovascular risk (3).

PREDIMED provided randomised controlled trial evidence to support the cardiovascular benefits of the Mediterranean diet (4,5). Subsequent metabolomic analysis identified a metabolic signature that reflected adherence and metabolic response to the Mediterranean diet and associated with cardiovascular risk (6). PREDIMED-Plus aims to investigate whether physical activity promotion and weight loss, on top of the dietary interventions of PREDIMED, provide additional cardiovascular benefit (7) to inform future guidelines in cardiovascular disease prevention.

Gender and cardiovascular disease were discussed by Dr. DeLisa Fairweather (Mayo Clinic in Jacksonville, Florida, USA). The basic physiology of the heart differs by sex. For example, men have larger hearts, larger coronary vessels, lower contractility and, in the ageing heart, greater hypertrophy, apoptosis and fibrosis than women. Such differences in physiology contribute to different cardiovascular disease characteristics in men and women. Age is another consideration; premenopausal women are generally protected from cardiovascular disease, which may in part relate to the effects of oestrogen on the immune system. As women tend to have smaller coronary vessels, this affects shear stress and turbulent flow, resulting in milder remodelling in coronary artery disease, compared with that seen in men. Thus, in the future, preventive strategies need to be tailored to the individual’s sex.

In the concluding plenary lecture, Professor Thomas Lüscher (Imperial College, London UK and University of Zurich, Switzerland) introduced the past and discussed the future for cardiovascular disease prevention.  While there have been important therapeutic developments, there are also limitations in terms of the potency of available treatments, side effects, failure of many patients to attain LDL-C goal, as well as lack of options for other atherogenic lipoproteins. Additionally, there has been short-sightedness in failing to take into account lifetime risk.  This scenario underlines the need for genetic tools such as antisense or siRNA approaches that are specific and long-lasting and offer compliance advantages (8). Inclisiran, the first siRNA targeting PCSK9 in the liver provides a potent, sustained and durable lowering of LDL-C with infrequent dosing (9). Antisense therapies targeting apolipoprotein(a) (10), ANGPTL3 (11) and apoCIII (12) have also been developed. Finally, there are also possibilities for human epigenome modulation, using long noncoding RNA to control LDL uptake, as well as CRISPR cas technology. The evolution of genomic therapy will provide new pharmacotherapeutic tools to revolutionise both lipid management and cardiology.

Find more at the meeting: 

These lectures are available on demand: Session archive June 02, 2021, Plenary 3: The rise of cardiometabolic disease as global health threat: towards the UN 2030 goals.

References

  1. Sato S, Basse AL, Schönke M, et al. Time of exercise specifies the impact on muscle metabolic pathways and systemic energy homeostasis. Cell Metab 2019;30:91-110.
  2. Martínez-González MA, Gea A, Ruiz-Canela M. The Mediterranean Diet and cardiovascular health. Circ Res 2019;124:779-98.
  3. Mata-Fernández A, Hershey MS, Pastrana-Delgado JC, et al. A mediterranean lifestyle reduces the risk of cardiovascular disease in the “Seguimiento Universidad de Navarra” (SUN) cohort. Nutr Metab Cardiovasc Dis 2021 Feb 27:S0939-4753(21)00093-4.
  4. Estruch R, Ros E, Salas-Salvadó J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279-90.
  5. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts. N Engl J Med. DOI: 10.1056/NEJMoa1800389
  6. Li J, Guasch-Ferré M, Chung W, et al. The Mediterranean diet, plasma metabolome, and cardiovascular disease risk. Eur Heart J 2020;41:2645-56.
  7. Martínez-González MA, Buil-Cosiales P, Corella D, et al. Cohort Profile: Design and methods of the PREDIMED-Plus randomized trial. Int J Epidemiol 2019;48: 387-8.
  8. Landmesser U, Poller W, Tsimikas S, et al. From traditional pharmacological towards nucleic acid-based therapies for cardiovascular diseases. Eur Heart J 2020;41:3884-99.
  9. Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 2017;376:1430-40.
  10. Viney NJ, van Capelleveen JC, Geary RS, et al. 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.
  11. Graham MJ, Lee RG, Brandt TA, et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med 2017;377:222-32.
  12. Gaudet D, Alexander VJ, Baker BF, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med 2015;373:438-47.
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