What is the future of CVD management?

Tuesday News from EAS Helsinki 2021:

The second of the plenary sessions focused on new approaches to the detection and management of atherosclerotic cardiovascular disease (ASCVD), harnessing genetics, imaging, and innovation in pharmaceutical design.

Dr Mark Daly (Institute for Molecular Medicine Finland) discussed how collaborative approaches using the FinnGen Biobank offer the opportunity for new therapeutic approaches. FinnGen (1) was launched in Finland in late 2017 with the mission to alleviate disease in the population. The initiative combines genome information with digital health care data and represents one of the very first personalized medicine projects at this scale with public-private collaborative support. Importantly, the initiative incorporates longitudinal data from biobanks extending to over 50 years to provide a lifelong dynamic view of health and disease.

By nature of its position in Europe and language, Finland is an example of isolation advantage and thus interrogation of genetic data provides a means to investigate novel loci that impact disease. Dr Daly discussed several examples of novel variants influencing susceptibility to coronary atherosclerosis. Three novel loci in the MFGE8 gene were shown to be protective against ASCVD with no evidence to suggest association with other risk factors. Thus, harnessing genetics offers the opportunity to identify novel targets with therapeutic potential.

Professor Charalambos Antoniades (University of Oxford, UK) discussed how improved understanding of inflammatory mechanisms has led to technological advances in the noninvasive detection of coronary artery inflammation. Currently available tests for the detection of coronary inflammation are either non-specific for the cardiovascular system or expensive and not readily available. As about half of those individuals who develop obstructive coronary disease are asymptomatic, new tools are needed to characterise plaques and identify those patients with high vascular inflammation (2). Studies have identified the perivascular adipose tissue as a biosensor of vascular inflammation (3). The perivascular fat attenuation index (FAI), a novel method for assessing coronary inflammation by analysing routine coronary computed tomography angiography (CCTA), captures changes in the perivascular adipose tissue composition driven by inflammatory signals coming from the inflamed coronary artery. With the integration of artificial intelligence, the FAI has shown prognostic value beyond atherosclerotic plaque characteristics as demonstrated in the CRISP-CT outcomes study. Identification of high levels of inflammation in the coronary arteries was associated with 5 to 9-fold higher risk of fatal myocardial infarction during follow-up (4-6). Beyond use as a prognostic marker, the FAI may have application in monitoring responsiveness to treatment (7).

In concluding remarks, Professor Antoniades discussed the Oxford Cohort for Heart Vessels and Fat (oxHVF), which comprises a cluster of clinical studies aiming for deployment of a multi-level strategy to understand the mechanisms of cardiovascular disease. One of these studies, ORFAN, is evaluating the use of the FAI, complementary to CCTA-defined plaque characteristics, to identify individuals with a significant inflammatory component to their residual risk so as to predict their risk of an ASCVD event. To date, the study has enrolled more than 10,000 patients who will be followed for up to 10 years. 

In the third state-of-the art lecture, Professor Jean-Charles Fruchart (Pasteur Institute, Lille, France) overviewed the rationale for the development of a novel class of therapeutic agents, the selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) to target atherogenic dyslipidaemia. Trials which have tested current peroxisome proliferator-activated receptor alpha (PPARα) agonists have so far been less than successful for decreasing residual risk associated with this dyslipidaemia. Thus, the rationale for SPPARMα development was to improve on the selectivity, potency and safety of current fibrates. Precision pharmaceutical design incorporating selective nuclear receptor modulation of the cofactor binding profile to the ligand underpinned this approach (8). Pemafibrate, the first in this class of SPPARMα, has shown substantial lowering of triglycerides and remnant cholesterol, improved cholesterol efflux capacity, and a favourable safety profile in clinical trials, as well as effects on other metabolic, inflammatory and anti-thrombogenic biomarkers (9). Whether targeting elevated triglycerides with pemafibrate will reduce residual cardiovascular risk is being tested in the PROMINENT study (10). PROMINENT has randomized approximately 10,000 patients with type 2 diabetes mellitus and elevated triglycerides (200-499 mg/dL or 2.3-5.6 mmol/L) and low high-density lipoprotein cholesterol to treatment with pemafibrate (0.2 mg twice daily) or matching placebo. With an average expected follow-up period of nearly 4 years, results are anticipated during 2022.  

Find more at the meeting

  • Session on demand: Tuesday June 01, 2021. Plenary Session 02: Future CVD management: from gene to phenotype to treatment.

References

  1. FinnGen. For more information: https://www.finngen.fi/en
  2. Antoniades C, Antonopoulos AS, Deanfield J. Imaging residual inflammatory cardiovascular risk. Eur Heart J 2020;41:748-78.
  3. Antonopoulos AS , Sanna F , Sabharwal N, et al. Detecting human coronary inflammation by imaging perivascular fat. Sci Transl Med 2017;9(398):eaal2658.
  4. Oikonomou EK , Marwan M , Desai MY, et al. Non-invasive detection of coronary inflammation using computed tomography and prediction of residual cardiovascular risk (the CRISP CT study): a post-hoc analysis of prospective outcome data. Lancet 2018;392:929–39.
  5. Oikonomou EK, Desai MY, Marwan M, et al. Perivascular fat attenuation index stratifies cardiac risk associated with high-risk plaques in the CRISP-CT study. J Am Coll Cardiol 2020;76:755–7.
  6. Oikonomou EK, Williams MC, Kotanidis CP, et al. A novel machine learning-derived radiotranscriptomic signature of perivascular fat improves cardiac risk prediction using coronary CT angiography. Eur Heart J 2019;40:3529–43.
  7. Elnabawi YA, Oikonomou EK, Dey AK, et al. Association of biologic therapy with coronary inflammation in patients with psoriasis as assessed by perivascular fat attenuation index. JAMA Cardiol 2019;4:885-91.
  8. Fruchart JC. Selective peroxisome proliferator-activated receptor α modulators (SPPARMα): the next generation of peroxisome proliferator-activated receptor α-agonists. Cardiovasc Diabetol 2013;12:82.
  9. Yamashita S, Masuda D, Matsuzawa Y. Pemafibrate, a new selective PPARalpha Modulator: drug concept and its clinical applications for dyslipidemia and metabolic diseases. Curr Atheroscler Rep 2020;22(1):5.
  10. Pradhan AD, Paynter NP, Everett BM, et al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J 2018;206:80-93.
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