Prof Juan Carlos Kaski, St George's, University of London, UK

Yet another “promising” marker or the real thing?

The search for suitable markers of risk of cardiovascular (CV) events that can be useful in the individual patient, as opposed to large populations, continues in different centres worldwide. Lipidomic analyses –one of the byproducts of the “omics” revolution in biomedical science- have identified potentially useful markers of CV risk (1-3). Ceramide (Cer) species were found to be associated with CV disease risk of events among coronary artery disease (CAD) patients (1) and also with plaque instability (necrotic core tissue type and lipid core burden), predictive of clinical outcome in both ACS and stable CAD patients (4). In these studies, circulating Cer molecules (Cer (d18:1/16:0), Cer (d18:1/ 18:0), and Cer (d18:1/24:1)), and their ratios with Cer (d18:1/24:0), appeared to be useful to risk stratify CAD patients (1). Ceramides, which are produced by fatty acyl selective Cer synthases, have been shown to be associated with atherogenic mechanisms such as lipoprotein uptake, inflammation, and apoptosis, as well as having several other biological action (5-9).

A recent multicentre investigation (10) assessed the prognostic value of plasma Cer in three different CAD patient groups.  The prospective Corogene study compared the predictive value of several lipid biomarkers, C-reactive protein and plasma Cer (d18:1/16:0), Cer (d18:1/18:0), Cer (d18:1/24:0), and Cer (d18:1/24:1) in 160 stable Finnish CAD patients. Subsequently, the investigators assessed the association between Cer and CV mortality in the prospective Swiss Special Program University Medicine—Inflammation in Acute Coronary Syndromes (SPUM-ACS) cohort (n = 1637). The third study involved the Bergen Coronary Angiography Cohort (BECAC), a prospective Norwegian study of stable CAD patients. Cer, particularly when ratios were assessed, were associated with CV death in all studies, independent of other lipid markers and C-reactive protein. The authors reported that “adjusted odds ratios per standard deviation for the Cer (d18:1/16:0)/Cer (d18:1/24:0) ratio were 4.49 (95% CI, 2.24–8.98), 1.64 (1.29–2.08), and 1.77 (1.41–2.23) in the Corogene, SPUM-ACS, and BECAC studies, respectively”. Of importance, the authors showed that the Cer (d18:1/16:0)/Cer (d18:1/24:0) ratio improved the predictive value of the GRACE score in ACS patients and the predictive value of the Marschner score in stable CAD patients.  The results of this recent study showing that plasma Cer ratios can predict CV death both in patients with stable CAD and ACS, over and above currently used lipid markers, are of interest but should be further validated in larger prospective studies.

References

  1. Tarasov K, Ekroos K, Suoniemi M, Kauhanen D, Sylvanne T, Hurme R, Gouni-Berthold I, Berthold HK, Kleber ME, Laaksonen R, Marz W. Molecular lipids identify cardiovascular risk and are efficiently lowered by simvastatin and PCSK9 deficiency. J Clin Endocrinol Metab 2014;99:E45–E52.
  1. Meikle PJ, Wong G, Tsorotes D, Barlow CK, Weir JM, Christopher MJ, MacIntosh GL, Goudey B, Stern L, Kowalczyk A, Haviv I, White AJ, Dart AM, Duffy SJ, Jennings GL, Kingwell BA, Weir M. Plasma lipidomic analysis of stable and unstable coronary artery disease. Arterioscler Thromb Vasc Biol 2011;31: 2723 – 2732.
  1. Fernandez C, Sandin M, Sampaio JL, Almgren P, Narkiewicz K, Hoffmann M, Hedner T, Wahlstrand B, Simons K, Shevchenko A, James P, Melander O. Plasma lipid composition and risk of developing cardiovascular disease. PLoS ONE 2013;8: e71846.
  1. Cheng JM, Garcia-Garcia HM, de Boer SPM, Kardys I, Heo JH, Akkerhuis KM, Oemrawsingh RM, van Domburg RT, Ligthart J, Witberg KT, Regar E, Serruys PW, van Geuns R-J, Boersma E. In vivo detection of high-risk coronary plaques by radiofrequency intravascular ultrasound and cardiovascular outcome: results of the ATHEROREMO-IVUS study. Eur Heart J 2014;35:639–647.
  1. BismuthJ, Lin P, Yao Q, Chen C. Ceramide: a common pathway for atherosclerosis? Atherosclerosis 2008;196:497–504.
  1. Menuz V, Howell KS, Gentina S, Epstein S, Riezman I, Fornallaz-mulhauser M, Hengartner MO, Gomez M, Riezman H, Martinou J. Protection of C. elegans from Anoxia by HYL-2 Ceramide Synthase. Science 2009;324:381–384.
  1. Park J-W, Park W-J, Futerman AH. Ceramide synthases as potential targets for therapeutic intervention in human diseases. Biochim Biophys Acta 2014;1841: 671 – 681.
  1. Turpin SM, Nicholls HT, Willmes DM, Mourier A, Brodesser S, Wunderlich CM, Mauer J, Xu E, Hammerschmidt P, Bronneke HS, Trifunovic A, LoSasso G, Wunderlich FT, Kornfeld J-W, Bluher M, Kronke M, Bruning JC. Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab 2014;20:678–686.
  1. Raichur S, Wang ST, Chan PW, Li Y, Ching J, Chaurasia B, Dogra S, Ohman MK, Takeda K, Sugii S, Pewzner-Jung Y, Futerman AH, Summers SA. CerS2 haplo insufficiency inhibits beta-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metab 2014;20:687–695.
  1. Laaksonen R et al. Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol. European Heart Journal (2016) 37, 1967–1976 doi:10.1093/eurheartj/ehw148
Cardio Debate Expert Comments

While many biomarkers have been proposed for the assessment of cardiovascular event risk, only very few have made it through clinical and analytical validation allowing for their use in practice.  Such novel risk assessment tools are in use for only a fraction of the potential patient population as the classical lipid panel dominates the diagnostic choice. For gaining widespread adoption a candidate test will have to demonstrate significant benefit in clinical utility. While the final evidence for a paradigm shift will be delivered through lengthy and sizeable prospective clinical studies a lot can be accomplished prior to that. One of the more promising candidates for advancing the testing field is the ceramide risk score, now analyzed in more than 20 000 patients. Indeed, clinical practice of the score will now be put to practical use at the Mayo Clinic which will offer the assay still this year.

Ceramide test results are reported as physician friendly ceramide risk score (1). Approximately 10% of all coronary artery disease patients belong in the high risk category. Based on existing data these patients have a 5-fold CVD death risk compared to patients in low risk category. Targeting the often limited healthcare resources to patients at the highest risk could curb both cardiovascular events as well as health care costs. Low treatment adherence is one of the most important obstacles in preventive practice. Based on the risk score patients should be better motivated to be treatment compliant and potentially follow life-style management including physical exercise, quantitative and qualitative balanced nutrition and smoking cessation. Ceramide utility can be already further probed using many current bio-banked studies and several soon to be completed trials looking into cardiovascular outcomes. It is likely that the ceramide risk score may serve as a reliable stratifier for the identification of high risk patients eligible for various lipid or inflammation lowering treatments, ranging from more aggressive statin doses to PSCK9 inhibition.

  1. Laaksonen R et al. Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol. European Heart Journal (2016) 37, 1967–1976 doi:10.1093/eurheartj/ehw148

Traditional risk markers explain only a proportion of total cardiovascular risk. Secondary Prevention of cardiovascular events remains an ongoing clinical challenge and, in spite of different risk scores, estimation of new events in patients with coronary artery disease needs to improve in order to identify patients at high risk.

The search of biomarkers has occupied scientific research in the last decades, many investigations have found independent predictors of new myocardial infarction, stroke and/or mortality, but not many have had success over time, because independence depends on the variables included in the model and non-causal risk factors can be independent risk factors 1

A good example is C-Reactive protein (CRP), this non-specific acute-phase protein has battled in many scenarios with good results and, showed an independent prediction value. The drama has been that this biomarker (and others) do not improve the area under the receiver-operating-characteristic curve (AUC).

Pencina et al suggested reconsidering how to evaluate changes in the AUC because a small increase could lead to a substantial improvement in the reclassification of patients by the net reclassification improvement (NRI). 2

Due to this in 2009 3 the American Heart Association recognized that there was a need to assess the value of the use of biomarkers and a consensus was published with the phases of evaluation that a novel risk marker must follow.

In an elegant study Laaksonen et al 4 showed, in patients with acute (ACS) or chronic coronary artery disease (CAD), the significant association of ceramides with cardiovascular mortality in three different cohorts, independent of other lipid markers and CRP. Moreover, they have found that the Cer ratio (d18:1/16:09/Cer(d18:1/24:0) improved the predictive value of the GRACE score NRI=0.17 and AUC=0.09) in ACS and the predictive value of the Marschner score in stable CAD (NRI=0.15 and AUC=0.02).

In the analysis of the study we found that they have followed the suggested recommendation of Scientific Societies and have found promising results that could lead us to include in the future these biomarkers in the available risk scores.

The question still remains as to how much needs to be known before these markers can be incorporated into risk prediction algorithms? Two aspects are a must:  validation of these results and cost-effectiveness.

References

1.- Brotman DJ, Walker E, Lauer MS, O’Brien RG. In search of fewer independent risk factors. Arch Intern Med 2005; 165:138-45.

2.- Pencina MJ, D’Agostino RB, D’Agostino RB Jr, Vasan R. Evaluating the added predictive ability of a new marker: from área under the ROC curve to reclassification and beyond. Stat Med 2008; 27:157-72.

3.-Hlatky MA, Greenland P, Arnett DK,Ballantyne CM, et al. Criteria for evaluation of novel markers of cardiovascular risk: A scientific statement from the American Heart Association. Circulation 2009; 119:2408-16.

4.- Laaksonen R et al. Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol. European Heart Journal (2016) 37, 1967–76