The remnant-cholesterol/CRP nexus: Trouble and strife when the fat hits the fire

Atherosclerotic cardiovascular disease (ASCVD) has a multifactorial aetiology, considered to be driven principally by elevated plasma concentrations of low-density lipoprotein (LDL) [[1]Mach F. Baigent C. Catapano A.L. Koskinas K.C. Casula M. Badimon L. et al.2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.Eur. Heart J. 2020; 41: 111-188Crossref PubMed Scopus (1) Google Scholar]. Vascular inflammation also plays a key role by interacting with lipid metabolism in development of plaques and induction of thrombogenesis [[2]van Diepen J.A. Berbée J.F. Havekes L.M. Rensen P.C. Interactions between inflammation and lipid metabolism: relevance for efficacy of anti-inflammatory drugs in the treatment of atherosclerosis.Atherosclerosis. 2013; 228: 306-315Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar]. Elevated triglyceride-rich lipoproteins (TRLs), particularly remnant particles, and low-grade vascular inflammation may synergistically impact on the development of ASCVD. In this issue of the journal, Doi et al. investigated whether remnant-cholesterol (fasting or non-fasting) and high-sensitivity C-reactive protein (hs-CRP) independently predicted risk of myocardial infarction (MI), ASCVD, and all-cause mortality in the Copenhagen General Population Study [[3]Doi T. Langsted A. Nordestgaard B.G. Dual elevated remnant cholesterol and low-grade inflammation in atherosclerotic cardiovascular disease and mortality.Atherosclerosis. 2023; 379117141Abstract Full Text Full Text PDF Scopus (1) Google Scholar]. The investigation comprised 103,221 adults, who were followed for 9.5 years. The authors found that the hazard ratios (HRs) for MI, ASCVD, and all-cause mortality increased with higher serum concentrations of both remnant-cholesterol and hs-CRP, in a multivariable analyses that included age, sex, smoking status, systolic blood pressure, and LDL-cholesterol. Notably, individuals with the highest tertile of both remnant-cholesterol and hs-CRP had the highest risk of MI (HR 2.2; 95%CI 1.9–2.7), ASCVD (HR 1.9; 95%CI 1.7–2.2) and all-cause mortality (HR 1.4; 95%CI 1.3–1.5) compared with subjects in the lowest tertile of both of these indices. These results are consistent with a recent study from the Multi-Ethnic Study of Atherosclerosis (MESA) showing that the combination of elevated remnant-cholesterol and hs-CRP was associated with an increased risk of future ASCVD events [[4]Chevli P.A. Islam T. Pokharel Y. Rodriguez F. Virani S.S. Blaha M.J. et al.Association between remnant lipoprotein cholesterol, high-sensitivity C-reactive protein, and risk of atherosclerotic cardiovascular disease events in the Multi-Ethnic Study of Atherosclerosis (MESA).J Clin Lipidol. 2022; 16: 870-877Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. They also suggest that the predictive value of CRP is incompletely explained by levels of remnant cholesterol, and vice versa. Remnant-cholesterol is the cholesterol concentration of TRLs, including apolipoprotein B-100 (apoB-100) containing very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) in the fasting state, as well as apoB-48 containing chylomicron remnant (CRs) in the postprandial state. Remnant-cholesterol differs from non-HDL-cholesterol (i.e. total cholesterol minus HDL-cholesterol), which refers to the cholesterol content of all atherogenic apoB-containing lipoproteins, including LDL particles. Although plasma triglyceride concentrations can serve as a surrogate measure of TRLs and remnant-cholesterol, it is probably the cholesterol content in TRLs, rather than the triglyceride content, that contributes most to ASCVD [[5]Ginsberg H.N. Packard C.J. Chapman M.J. Borén J. Aguilar-Salinas C.A. Averna M. et al.Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society.Eur. Heart J. 2021; 42: 4791-4806Crossref PubMed Scopus (186) Google Scholar]. Remnant-cholesterol can be calculated from a standard lipid profile by subtracting LDL-cholesterol and high-density lipoprotein (HDL)-cholesterol from total cholesterol. While this approach provides a convenient method for estimating remnant-cholesterol without additional costs, accuracy is affected by the imprecision of the measurements of all the components used in the formula. Nevertheless, the authors found that calculated remnant-cholesterol was highly correlated with directly measured remnant-cholesterol levels using a Denka Seiken assay. The contribution that lipoprotein(a) [Lp(a)]-cholesterol made to the estimation of remnant-cholesterol was not evaluated, however. Fig. 1 depicts the roles of remnant-cholesterol and CRP in inflammation and atherosclerosis. Genetic and non-genetic factors can cause transport defects in the circulation of TRLs (chylomicrons and VLDL), leading to hypertriglyceridaemia. After TRL remnants enter the subendothelial space, they are trapped by extracellular matrix proteoglycans and phagocytosed by macrophages to form "foam cells". TRL remnants induce endothelial dysfunction, inhibit fibrinolysis, activate the complement system and enhance coagulation and vascular inflammation. TRL lipolysis also releases toxic products, such as oxidized free fatty acis (FFAs) and lysophospholipids, which further induce the local release of pro-inflammatory cytokines [[2]van Diepen J.A. Berbée J.F. Havekes L.M. Rensen P.C. Interactions between inflammation and lipid metabolism: relevance for efficacy of anti-inflammatory drugs in the treatment of atherosclerosis.Atherosclerosis. 2013; 228: 306-315Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar,[5]Ginsberg H.N. Packard C.J. Chapman M.J. Borén J. Aguilar-Salinas C.A. Averna M. et al.Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society.Eur. Heart J. 2021; 42: 4791-4806Crossref PubMed Scopus (186) Google Scholar]. This is consistent with the present study by Doi et al., which showed that higher remnant cholesterol levels were associated with higher hs-CRP levels [[3]Doi T. Langsted A. Nordestgaard B.G. Dual elevated remnant cholesterol and low-grade inflammation in atherosclerotic cardiovascular disease and mortality.Atherosclerosis. 2023; 379117141Abstract Full Text Full Text PDF Scopus (1) Google Scholar]. CRP is an acute phase reactant that is intrinsically regulated by interleukin-1β (IL-1β), IL-6 and tumor necrosis factor alpha (TNF-α) [[6]Badimon L. Peña E. Arderiu G. Padró T. Slevin M. Vilahur G. Chiva-Blanch G. C-reactive protein in atherothrombosis and angiogenesis.Front. Immunol. 2018; 9: 430Crossref PubMed Scopus (153) Google Scholar]. Some experimental data suggest that CRP has direct pro-inflammatory and prothrombotic effects on human endothelial cells [[6]Badimon L. Peña E. Arderiu G. Padró T. Slevin M. Vilahur G. Chiva-Blanch G. C-reactive protein in atherothrombosis and angiogenesis.Front. Immunol. 2018; 9: 430Crossref PubMed Scopus (153) Google Scholar]. However, Mendelian randomization studies suggest that CRP is unlikely to be a causal factor for vascular risk, but is rather a surrogate biomarker for the activation of the pro-inflammatory pathways mediated by IL-1β and IL-6 [[7]Ridker P.M. Rane M. Interleukin-6 signaling and anti-interleukin-6 therapeutics in cardiovascular disease.Circ. Res. 2021; 128: 1728-1746Crossref PubMed Scopus (150) Google Scholar]. By contrast, observational and genetic data have affirmed a causal role of IL-6 in atherothrombotic disease through its pro-inflammatory, prothrombotic and proatherogenic properties [[8]Arroyo-Espliguero R. Viana-Llamas M.C. Silva-Obregón A. Avanzas P. The role of C-reactive protein in patient risk stratification and treatment.Eur. Cardiol. 2021; 16: e28Crossref PubMed Google Scholar]. Several observational and genetic studies, including prospective population cohorts from Copenhagen, have clearly showed that remnant-cholesterol levels correlate with major adverse cardiovascular events (MACEs) in primary and secondary prevention settings [[9]Ganda O.P. Triglyceride-rich lipoproteins, remnant-cholesterol, and atherosclerotic cardiovascular disease.Curr. Opin. Lipidol. 2023; 34: 105-113Crossref PubMed Scopus (4) Google Scholar]. This notion is confirmed in the present study by Doi et al. showing that levels of remnant-cholesterol are independently associated with the incidence of ASCVD. The same group have previously demonstrated that adding remnant-cholesterol to traditional risk factors improved risk classification of ASCVD [[10]Doi T. Langsted A. Nordestgaard B.G. Elevated remnant cholesterol reclassifies risk of ischemic heart disease and myocardial infarction.J. Am. Coll. Cardiol. 2022; 79: 2383-2397Crossref PubMed Scopus (16) Google Scholar]. Given that apoB concentration reflects the total number of atherogenic particles including TRLs, it was not unexpected in the present study that the significant association of remnant-cholesterol with MI and ASCVD events was attenuated after adjustment for apoB. The clinical value of remnant-cholesterol compared with apoB therefore remains unclear. There is also substantial evidence to support the usefulness of hs-CRP as a biomarker for the assessment of cardiovascular risk in primary and secondary prevention [7Ridker P.M. Rane M. Interleukin-6 signaling and anti-interleukin-6 therapeutics in cardiovascular disease.Circ. Res. 2021; 128: 1728-1746Crossref PubMed Scopus (150) Google Scholar, 8Arroyo-Espliguero R. Viana-Llamas M.C. Silva-Obregón A. Avanzas P. The role of C-reactive protein in patient risk stratification and treatment.Eur. Cardiol. 2021; 16: e28Crossref PubMed Google Scholar]. In particular, high hs-CRP can identify a group of patients with residual inflammatory cardiovascular risk despite adequate control of LDL-cholesterol. Inclusion of hs-CRP levels can improve the overall predictive value of lipid or lipoprotein parameters in determining the risk of ASCVD in the primary prevention setting [8Arroyo-Espliguero R. Viana-Llamas M.C. Silva-Obregón A. Avanzas P. The role of C-reactive protein in patient risk stratification and treatment.Eur. Cardiol. 2021; 16: e28Crossref PubMed Google Scholar, 11Quispe R. Michos E.D. Martin S.S. Puri R. Toth P.P. Al Suwaidi J. et al.High-sensitivity C-reactive protein discordance with atherogenic lipid measures and incidence of atherosclerotic cardiovascular disease in primary prevention: the ARIC Study.J. Am. Heart Assoc. 2020; 9e013600Crossref PubMed Scopus (33) Google Scholar]. The clinical usefulness of remnant-cholesterol as a therapeutic target needs to be demonstrated in outcome studies. Currently, to the best of our knowledge, no clinical trial has been undertaken in which subjects were selected on the basis of having elevated remnant-cholesterol. Insight may derive from triglyceride-lowering trials that selected patients for high triglycerides and by proxy high remnant-cholesterol. In this regard, a meta-analysis of more than 40 lipid-lowering trials found that triglyceride lowering was associated with lower risk of MACEs, even after adjusting for LDL-cholesterol lowering [[12]Marston N.A. Giugliano R.P. Im K. Silverman M.G. O'Donoghue M.L. Wiviott S.D. et al.Association between triglyceride lowering and reduction of cardiovascular risk across multiple lipid-lowering therapeutic classes: a systematic review and meta-regression analysis of randomized controlled trials.Circulation. 2019; 140: 1308-1317Crossref PubMed Scopus (139) Google Scholar]. However, the association was attenuated when REDUCE-IT was excluded. In the REDUCE-IT trial, administration of icosapent ethyl resulted in significant reduction in plasma triglyceride and apoB levels, as well as 25% fewer cardiovascular events [[13]Bhatt D.L. Steg P.G. Miller M. Brinton E.A. Jacobson T.A. Ketchum S.B. et al.Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.N. Engl. J. Med. 2019; 380: 11-22Crossref PubMed Scopus (1781) Google Scholar]. However, the benefit of intervention was greatest with higher baseline triglyceride levels, but did not appear to be related to the change, or on-treatment levels, of triglycerides. The discordant findings from the REDUCE-IT and other contemporary trials of triglyceride lowering, including STRENGTH (omega-3 carboxylic acid) and PROMINENT (pemafibrate) trials [[12]Marston N.A. Giugliano R.P. Im K. Silverman M.G. O'Donoghue M.L. Wiviott S.D. et al.Association between triglyceride lowering and reduction of cardiovascular risk across multiple lipid-lowering therapeutic classes: a systematic review and meta-regression analysis of randomized controlled trials.Circulation. 2019; 140: 1308-1317Crossref PubMed Scopus (139) Google Scholar,[14]Ridker P.M. Danielson E. Fonseca F.A. et al.Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.N. Engl. J. Med. 2008; 359: 2195-2207Crossref PubMed Scopus (5459) Google Scholar], cannot provide a clear answer as to whether remnant-cholesterol per se can be used as a therapeutic target for cardiovascular risk reduction. New gene-silencing agents that target TRLs (such as ANGPTL3 and apoC-III inhibition) are underway and may help clarify questions concerning the therapeutic value of remnant-cholesterol. In the JUPITER trial, rosuvastatin treatment was associated with significant lowering of hs-CRP and MACE in patients with "normal" LDL-cholesterol and high hs-CRP [[15]Ridker P.M. Bhatt D.L. Pradhan A.D. Glynn R.J. MacFadyen J.G. Nissen S.E. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials.Lancet. 2023; 401: 1293-1301Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]. In a recent collaborative analysis of three triglyceride-lowering trials in patients on statins (REDUCE-IT, STRENGTH and PROMINENT) [[14]Ridker P.M. Danielson E. Fonseca F.A. et al.Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.N. Engl. J. Med. 2008; 359: 2195-2207Crossref PubMed Scopus (5459) Google Scholar], hs-CRP was found to be a more potent predictor of future MACEs, cardiovascular mortality and all-cause mortality than LDL-cholesterol after adjusting for treatment effect. In the CANTOS trial of canakinumab, a therapeutic monoclonal antibody targeting IL-1β, the greatest cardiovascular benefits were seen among those who achieve the greatest reductions in levels of IL-6 and hs-CRP [[16]Ridker P.M. Everett B.M. Thuren T. MacFadyen J.G. Chang W.H. Ballantyne C. et al.Antiinflammatory therapy with canakinumab for atherosclerotic disease.N. Engl. J. Med. 2017; 377: 1119-1131Crossref PubMed Scopus (5278) Google Scholar]. In two other anti-inflammatory trials (COLCOT and LoDoCo2), colchicine lowered the risk of cardiovascular events, with COLCOT showing no statistically significant reduction in plasma hs-CRP [[17]Kofler T. Kurmann R. Lehnick D. Cioffi G.M. Chandran S. Attinger-Toller A. et al.Colchicine in patients with coronary artery disease: a systematic review and meta-analysis of randomized trials.J. Am. Heart Assoc. 2021; 10e021198Crossref PubMed Scopus (22) Google Scholar]. Unlike CANTOS, the two colchicine trials did not select patients on the basis of having high hs-CRP levels. Whether the effect of colchicine on cardiovascular outcome would be more pronounced in patents with elevated hs-CRP merits further investigation. Such information will help to establish whether hs-CRP can be used as a suitable prognostic marker for patient selection in clinical outcome trials of anti-inflammatory agents. The findings of the present study by Doi et al. clearly demonstrate the clinical value of elevation in both remnant-cholesterol and hs-CRP in prediction of cardiovascular risk beyond LDL-cholesterol. Recent European Society of Cardiology (ESC)/European Atherosclerosis Society guidelines recommend measurement of both non-HDL-cholesterol and apoB for risk assessment in patients with hypertriglyceridaemia [[1]Mach F. Baigent C. Catapano A.L. Koskinas K.C. Casula M. Badimon L. et al.2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.Eur. Heart J. 2020; 41: 111-188Crossref PubMed Scopus (1) Google Scholar]. Non-HDL-cholesterol and apoB (but not remnant-cholesterol) have also been proposed as second-line targets for treatment [[1]Mach F. Baigent C. Catapano A.L. Koskinas K.C. Casula M. Badimon L. et al.2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.Eur. Heart J. 2020; 41: 111-188Crossref PubMed Scopus (1) Google Scholar,[18]Wilson P.W.F. Jacobson T.A. Martin S.S. Jackson E.J. Le N.A. Davidson M.H. et al.Lipid measurements in the management of cardiovascular diseases: practical recommendations a scientific statement from the national lipid association writing group.J Clin Lipidol. 2021; 15: 629-648Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar]. In our view, remnant-cholesterol may not yet be ready for routine use in clinical practice until a consensus method of standardized measurement is established (fasting vs non-fasting condition; calculated vs directly measured by specific assays [[18]Wilson P.W.F. Jacobson T.A. Martin S.S. Jackson E.J. Le N.A. Davidson M.H. et al.Lipid measurements in the management of cardiovascular diseases: practical recommendations a scientific statement from the national lipid association writing group.J Clin Lipidol. 2021; 15: 629-648Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar]. Calculated remnant-cholesterol may be at present preferred for pragmatic reasons because it is convenient and inexpensive. Unlike remnant-cholesterol, measurement of hs-CRP is a widely available, validated and standardized approach for quantifying low grade systemic inflammation in both fasting and non-fasting conditions. However, the ESC guidelines concluded that the determination of hs-CRP adds little to the existing methods of cardiovascular risk assessment [[19]Piepoli M.F. Hoes A.W. Agewall S. Albus C. Brotons C. Catapano A.L. et al.European guidelines on cardiovascular disease prevention in clinical practice.Eur. Heart J. 2016; 37: 2315-2381Crossref PubMed Google Scholar]. The American College of Cardiology (ACC) expert consensus statement identifies elevated hs-CRP as a risk-enhancing factor to initiate statin therapy in moderate risk patents, including those with persistent hypertriglyceridaemia [[20]Virani S.S. Morris P.B. Agarwala A. Ballantyne C.M. Birtcher K.K. Kris-Etherton P.M. et al.2021 ACC Expert Consensus Decision Pathway on the management of ASCVD risk reduction in patients with persistent hypertriglyceridemia.J. Am. Coll. Cardiol. 2021; 78: 960-993Crossref PubMed Scopus (95) Google Scholar]. However, there are currently no expert recommendations for a therapeutic goal for hs-CRP. Ongoing anti-inflammatory trials should allow a definitive assessment of the clinical use of hs-CRP in ASCVD prevention [[2]van Diepen J.A. Berbée J.F. Havekes L.M. Rensen P.C. Interactions between inflammation and lipid metabolism: relevance for efficacy of anti-inflammatory drugs in the treatment of atherosclerosis.Atherosclerosis. 2013; 228: 306-315Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar]. There is an ongoing effort to clarify how we should approach residual cardiovascular risk. Remnant-cholesterol and hs-CRP may help quantify residual lipoprotein and inflammatory-related risk in those who have adequate control of LDL-cholesterol. In an era of personalised medicine, targeting elevated remnant-cholesterol and hs-CRP in patients already on statins, or other therapies, has the potential to efficiently identify a group of patients who may benefit the most from more intensive lipid-lowering and anti-inflammatory treatments.