Prognostic Significance of Hypertriglyceridemia in Patients at High and
Very High Cardiovascular Risk Depending on the Concentration of Highsensitivity
C-reactive Protein

Vadim      Genkel; Alla      Kuznetsova; Lubov      Pykhova; Karina      Nikushkina; Albina      Savochkina; Ilya      Dolgushin; Igor      Shaposhnik

doi:10.2174/1871530322666220427094330

Abstract

Background: It has been established that an increase in triglyceride-rich lipoprotein levels is associated with the development of systemic low-grade inflammation. Data on the prognostic role of hypertriglyceridemia (HTG) dependent on the state of low-grade inflammation are limited.

Objective: The study’s objective was to evaluate the predictive value of mild-to-moderate HTG (2.3- 11.2 mmol/L) regarding the development of cardiovascular events in patients at high and very high cardiovascular risk (CVR), depending on the high-sensitivity C-reactive protein (hsCRP) values.

Methods: The study included 185 patients with high and very high CVR. The concentration of hsCRP in blood serum was measured using an enzyme-linked immunosorbent assay kit. The combined endpoint was cardiovascular death, nonfatal myocardial infarction or unstable angina (which required hospitalization), nonfatal stroke, and coronary revascularization.

Results: HTG was revealed in 17.3% of the patients. An increase in hsCRP ≥2.0 mg/L was observed in 51.9% of the patients. The event-free survival of patients with HTG was not statistically different from that in patients with TG <2.3 mmol/L (RR 1.61; 95% CI 0.86-3.00; p=0.133). In the subgroup of patients with hsCRP <2.0 mg/L, patients with HTG were not significantly different from patients without HTG. In the subgroup of patients with hsCRP≥2.0 mg/L, the presence of HTG was associated with a 4.63 times increase in the RR of adverse cardiovascular events (95% CI 1.35-15.8; p=0.015) after adjusting for potential confounders.

Conclusion: In patients with high and very high CVR, an increase in TG ≥2.3 mmol/L was associated with the development of adverse cardiovascular events only in the subgroup of patients with an increase in hsCRP ≥2.0 mg/L. The presence of HTG was associated with a 4.63 times increase in RR of adverse cardiovascular events (95% CI 1.35-15.8; p=0.015).

Keywords: Hypertriglyceridemia, inflammation, high-sensitivity C-reactive protein, adverse cardiovascular events, outcomes.

« Previous Next »

Graphical Abstract

[1]
Fan, W.; Philip, S.; Granowitz, C.; Toth, P.P.; Wong, N.D. Hypertriglyceridemia in statin-treated us adults: the national health and nutrition examination survey. J. Clin. Lipidol.,  2019, 13(1), 100-108.
 [http://dx.doi.org/10.1016/j.jacl.2018.11.008] [PMID: 30594443]

[2]
Nordestgaard, L.T.; Christoffersen, M.; Afzal, S.; Nordestgaard, B.G.; Tybjærg-Hansen, A.; Frikke-Schmidt, R. Triglycerides as a shared risk factor between dementia and atherosclerotic cardiovascular disease: a study of 125 727 individuals. Clin. Chem.,  2021, 67(1), 245-255.
 [http://dx.doi.org/10.1093/clinchem/hvaa269] [PMID: 33418579]

[3]
Varbo, A.; Nordestgaard, B.G. Remnant cholesterol and risk of ischemic stroke in 112,512 individuals from the general population. Ann. Neurol.,  2019, 85(4), 550-559.
 [http://dx.doi.org/10.1002/ana.25432] [PMID: 30723955]

[4]
Toth, P.P.; Fazio, S.; Wong, N.D.; Hull, M.; Nichols, G.A. Risk of cardiovascular events in patients with hypertriglyceridaemia: a review of real-world evidence. Diabetes Obes. Metab.,  2020, 22(3), 279-289.
 [http://dx.doi.org/10.1111/dom.13921] [PMID: 31742844]

[5]
Toth, P.P.; Philip, S.; Hull, M.; Granowitz, C. Elevated Triglycerides (≥150 mg/dl) and high triglycerides (200-499 mg/dl) are significant predictors of new heart failure diagnosis: a real-world analysis of high-risk statin-treated patients. Vasc. Health Risk Manag.,  2019, 15, 533-538.
 [http://dx.doi.org/10.2147/VHRM.S221289] [PMID: 31824165]

[6]
Carr, R.A.; Rejowski, B.J.; Cote, G.A.; Pitt, H.A.; Zyromski, N.J. Systematic review of hypertriglyceridemia-induced acute pancreatitis: a more virulent etiology? Pancreatology,  2016, 16(4), 469-476.
 [http://dx.doi.org/10.1016/j.pan.2016.02.011] [PMID: 27012480]

[7]
Laufs, U.; Parhofer, K.G.; Ginsberg, H.N.; Hegele, R.A. Clinical review on triglycerides. Eur. Heart J.,  2020, 41(1), 99-109c.
 [http://dx.doi.org/10.1093/eurheartj/ehz785] [PMID: 31764986]

[8]
Varbo, A.; Benn, M.; Tybjærg-Hansen, A.; Nordestgaard, B.G. Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation,  2013, 128(12), 1298-1309.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.113.003008] [PMID: 23926208]

[9]
Bernelot Moens, S.J.; Verweij, S.L.; Schnitzler, J.G.; Stiekema, L.C.A.; Bos, M.; Langsted, A.; Kuijk, C.; Bekkering, S.; Voermans, C.; Verberne, H.J.; Nordestgaard, B.G.; Stroes, E.S.G.; Kroon, J. Remnant cholesterol elicits arterial wall inflammation and a multilevel cellular immune response in humans. Arterioscler. Thromb. Vasc. Biol.,  2017, 37(5), 969-975.
 [http://dx.doi.org/10.1161/ATVBAHA.116.308834] [PMID: 28336558]

[10]
Hansen, S.E.J.; Madsen, C.M.; Varbo, A.; Nordestgaard, B.G. Low-Grade inflammation in the association between mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis: a study of more than 115000 individuals from the general population. Clin. Chem.,  2019, 65(2), 321-332.
 [http://dx.doi.org/10.1373/clinchem.2018.294926] [PMID: 30518661]

[11]
Mach, F.; Baigent, C.; Catapano, A.L.; Koskinas, K.C.; Casula, M.; Badimon, L.; Chapman, M.J.; De Backer, G.G.; Delgado, V.; Ference, B.A.; Graham, I.M.; Halliday, A.; Landmesser, U.; Mihaylova, B.; Pedersen, T.R.; Riccardi, G.; Richter, D.J.; Sabatine, M.S.; Taskinen, M.R.; Tokgozoglu, L.; Wiklund, O.; Mueller, C.; Drexel, H.; Aboyans, V.; Corsini, A.; Doehner, W.; Farnier, M.; Gigante, B.; Kayikcioglu, M.; Krstacic, G.; Lambrinou, E.; Lewis, B.S.; Masip, J.; Moulin, P.; Petersen, S.; Petronio, A.S.; Piepoli, M.F.; Pintó, X.; Räber, L.; Ray, K.K.; Reiner, Ž.; Riesen, W.F.; Roffi, M.; Schmid, J-P.; Shlyakhto, E.; Simpson, I.A.; Stroes, E.; Sudano, I.; Tselepis, A.D.; Viigimaa, M.; Vindis, C.; Vonbank, A.; Vrablik, M.; Vrsalovic, M.; Zamorano, J.L.; Collet, J-P.; Koskinas, K.C.; Casula, M.; Badimon, L.; John Chapman, M.; De Backer, G.G.; Delgado, V.; Ference, B.A.; Graham, I.M.; Halliday, A.; Landmesser, U.; Mihaylova, B.; Pedersen, T.R.; Riccardi, G.; Richter, D.J.; Sabatine, M.S.; Taskinen, M-R.; Tokgozoglu, L.; Wiklund, O.; Windecker, S.; Aboyans, V.; Baigent, C.; Collet, J-P.; Dean, V.; Delgado, V.; Fitzsimons, D.; Gale, C.P.; Grobbee, D.; Halvorsen, S.; Hindricks, G.; Iung, B.; Jüni, P.; Katus, H.A.; Landmesser, U.; Leclercq, C.; Lettino, M.; Lewis, B.S.; Merkely, B.; Mueller, C.; Petersen, S.; Petronio, A.S.; Richter, D.J.; Roffi, M.; Shlyakhto, E.; Simpson, I.A.; Sousa-Uva, M.; Touyz, R.M.; Nibouche, D.; Zelveian, P.H.; Siostrzonek, P.; Najafov, R.; van de Borne, P.; Pojskic, B.; Postadzhiyan, A.; Kypris, L.; Špinar, J.; Larsen, M.L.; Eldin, H.S.; Viigimaa, M.; Strandberg, T.E.; Ferrières, J.; Agladze, R.; Laufs, U.; Rallidis, L.; Bajnok, L.; Gudjónsson, T.; Maher, V.; Henkin, Y.; Gulizia, M.M.; Mussagaliyeva, A.; Bajraktari, G.; Kerimkulova, A.; Latkovskis, G.; Hamoui, O.; Slapikas, R.; Visser, L.; Dingli, P.; Ivanov, V.; Boskovic, A.; Nazzi, M.; Visseren, F.; Mitevska, I.; Retterstøl, K.; Jankowski, P.; Fontes-Carvalho, R.; Gaita, D.; Ezhov, M.; Foscoli, M.; Giga, V.; Pella, D.; Fras, Z.; de Isla, L.P.; Hagström, E.; Lehmann, R.; Abid, L.; Ozdogan, O.; Mitchenko, O.; Patel, R.S. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur. Heart J.,  2020, 41(1), 111-188.
 [http://dx.doi.org/10.1093/eurheartj/ehz455] [PMID: 31504418]

[12]
Piepoli, M.F.; Abreu, A.; Albus, C.; Ambrosetti, M.; Brotons, C.; Catapano, A.L.; Corra, U.; Cosyns, B.; Deaton, C.; Graham, I.; Hoes, A.; Lochen, M.L.; Matrone, B.; Redon, J.; Sattar, N.; Smulders, Y.; Tiberi, M. Update on cardiovascular prevention in clinical practice: a position paper of the european association of preventive cardiology of the european society of cardiology. Eur. J. Prev. Cardiol.,  2020, 27(2), 181-205.
 [http://dx.doi.org/10.1177/2047487319893035] [PMID: 31826679]

[13]
Arca, M.; Borghi, C.; Pontremoli, R.; De Ferrari, G.M.; Colivicchi, F.; Desideri, G.; Temporelli, P.L. Hypertriglyceridemia and omega-3 fatty acids: their often overlooked role in cardiovascular disease prevention. Nutr. Metab. Cardiovasc. Dis.,  2018, 28(3), 197-205.
 [http://dx.doi.org/10.1016/j.numecd.2017.11.001] [PMID: 29397253]

[14]
Toth, P.P.; Philip, S.; Hull, M.; Granowitz, C. Elevated triglycerides (≥150 mg/dl) and high triglycerides (200-499 mg/dl) are significant predictors of hospitalization for new-onset kidney disease: a real-world analysis of high-risk statin-treated patients. Cardiorenal Med.,  2019, 9(6), 400-407.
 [http://dx.doi.org/10.1159/000502511] [PMID: 31450229]

[15]
Aday, A.W.; Ridker, P.M. Targeting residual inflammatory risk: a shifting paradigm for atherosclerotic disease. Front. Cardiovasc. Med.,  2019, 6, 16.
 [http://dx.doi.org/10.3389/fcvm.2019.00016] [PMID: 30873416]

[16]
Generoso, G.; Janovsky, C.C.P.S.; Bittencourt, M.S. Triglycerides and triglyceride-rich lipoproteins in the development and progression of atherosclerosis. Curr. Opin. Endocrinol. Diabetes Obes.,  2019, 26(2), 109-116.
 [http://dx.doi.org/10.1097/MED.0000000000000468] [PMID: 30694827]

[17]
Si, S.; Hou, L.; Chen, X.; Li, W.; Liu, X.; Liu, C.; Li, Y.; Yuan, T.; Li, J.; Wang, B.; Li, H.; Xue, F. Exploring the causal roles of circulating remnant lipid profile on cardiovascular and cerebrovascular diseases: mendelian randomization study. J. Epidemiol.,  2021, JE20200305.
 [http://dx.doi.org/10.2188/jea.JE20200305] [PMID: 33441507]

[18]
Toth, P.P. Triglyceride-rich lipoproteins as a causal factor for cardiovascular disease. Vasc. Health Risk Manag.,  2016, 12, 171-183.
 [http://dx.doi.org/10.2147/VHRM.S104369] [PMID: 27226718]

[19]
Sandesara, P.B.; Virani, S.S.; Fazio, S.; Shapiro, M.D. The forgotten lipids: triglycerides, remnant cholesterol, and atherosclerotic cardiovascular disease risk. Endocr. Rev.,  2019, 40(2), 537-557.
 [http://dx.doi.org/10.1210/er.2018-00184] [PMID: 30312399]

[20]
Ye, X.; Kong, W.; Zafar, M.I.; Chen, L.L. Serum triglycerides as a risk factor for cardiovascular diseases in type 2 diabetes mellitus: a systematic review and meta-analysis of prospective studies. Cardiovasc. Diabetol.,  2019, 18(1), 48.
 [http://dx.doi.org/10.1186/s12933-019-0851-z] [PMID: 30987625]

[21]
Cao, Y.X.; Zhang, H.W.; Jin, J.L.; Liu, H.H.; Zhang, Y.; Xu, R.X.; Gao, Y.; Guo, Y.L.; Zhu, C.G.; Hua, Q.; Li, Y.F.; Santos, R.D.; Wu, N.Q.; Li, J.J. Prognostic utility of triglyceride-rich lipoprotein-related markers in patients with coronary artery disease. J. Lipid Res.,  2020, 61(9), 1254-1262.
 [http://dx.doi.org/10.1194/jlr.RA120000746] [PMID: 32641433]

[22]
Liu, H.H.; Li, S.; Cao, Y.X.; Guo, Y.L.; Zhu, C.G.; Wu, N.Q.; Li, J.J. Association of triglyceride-rich lipoprotein-cholesterol with recurrent cardiovascular events in statin-treated patients according to different inflammatory status. Atherosclerosis,  2021, 330, 29-35.
 [http://dx.doi.org/10.1016/j.atherosclerosis.2021.06.907] [PMID: 34225103]

[23]
Johannesen, C.D.L.; Mortensen, M.B.; Langsted, A.; Nordestgaard, B.G. Apolipoprotein B and Non-HDL cholesterol better reflect residual risk than LDL cholesterol in statin-treated patients. J. Am. Coll. Cardiol.,  2021, 77(11), 1439-1450.
 [http://dx.doi.org/10.1016/j.jacc.2021.01.027] [PMID: 33736827]

[24]
Berkley, A.; Ferro, A. Changes in C-reactive protein in response to anti-inflammatory therapy as a predictor of cardiovascular outcomes: a systematic review and meta-analysis. JRSM Cardiovasc. Dis.,  2020, 9, 2048004020929235.
 [http://dx.doi.org/10.1177/2048004020929235]

[25]
Pradhan, A.D.; Aday, A.W.; Rose, L.M.; Ridker, P.M. Residual inflammatory risk on treatment with PCSK9 inhibition and statin therapy. Circulation,  2018, 138(2), 141-149.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.118.034645] [PMID: 29716940]

[26]
Mason, R.P.; Libby, P.; Bhatt, D.L. Emerging mechanisms of cardiovascular protection for the omega-3 fatty acid eicosapentaenoic acid. Arterioscler. Thromb. Vasc. Biol.,  2020, 40(5), 1135-1147.
 [http://dx.doi.org/10.1161/ATVBAHA.119.313286] [PMID: 32212849]

[27]
Koenig, W. Persistent inflammatory residual risk despite aggressive cholesterol-lowering therapy: further evidence fuelling the dual target concept. Eur. Heart J.,  2020, 41(31), 2962-2964.
 [http://dx.doi.org/10.1093/eurheartj/ehaa186] [PMID: 32268369]

[28]
Koenig, W. Low-Grade inflammation modifies cardiovascular risk even at very low LDL-C levels: are we aiming for a dual target concept? Circulation,  2018, 138(2), 150-153.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.118.035107] [PMID: 29986958]

[29]
Bhatt, D.L.; Steg, P.G.; Miller, M.; Brinton, E.A.; Jacobson, T.A.; Ketchum, S.B.; Doyle, R.T., Jr; Juliano, R.A.; Jiao, L.; Granowitz, C.; Tardif, J.C.; Ballantyne, C.M. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N. Engl. J. Med.,  2019, 380(1), 11-22.
 [http://dx.doi.org/10.1056/NEJMoa1812792] [PMID: 30415628]

[30]
Ma, M.; Liu, H.; Yu, J.; He, S.; Li, P.; Ma, C.; Zhang, H.; Xu, L.; Ping, F.; Li, W.; Sun, Q.; Li, Y. Triglyceride is independently correlated with insulin resistance and islet beta cell function: a study in population with different glucose and lipid metabolism states. Lipids Health Dis.,  2020, 19(1), 121.
 [http://dx.doi.org/10.1186/s12944-020-01303-w] [PMID: 32487177]

[31]
McGuire, D.K.; Shih, W.J.; Cosentino, F.; Charbonnel, B.; Cherney, D.Z.I.; Dagogo-Jack, S.; Pratley, R.; Greenberg, M.; Wang, S.; Huyck, S.; Gantz, I.; Terra, S.G.; Masiukiewicz, U.; Cannon, C.P. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol.,  2020, 6(2), 148-158.
 [http://dx.doi.org/10.1001/jamacardio.2020.4511] [PMID: 33031522]

[32]
Lopaschuk, G.D.; Verma, S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC Basic Transl. Sci.,  2020, 5(6), 632-644.
 [http://dx.doi.org/10.1016/j.jacbts.2020.02.004] [PMID: 32613148]

[33]
Sawada, T.; Uzu, K.; Hashimoto, N.; Onishi, T.; Takaya, T.; Shimane, A.; Taniguchi, Y.; Yasaka, Y.; Ohara, T.; Kawai, H. Empagliflozin’s ameliorating effect on plasma triglycerides: association with endothelial function recovery in diabetic patients with coronary artery disease. J. Atheroscler. Thromb.,  2020, 27(7), 644-656.
 [http://dx.doi.org/10.5551/jat.50807] [PMID: 31631099]

[34]
Hattori, S. Empagliflozin decreases remnant-like particle cholesterol in type 2 diabetes patients with insulin resistance. J. Diabetes Investig.,  2018, 9(4), 870-874.
 [http://dx.doi.org/10.1111/jdi.12781] [PMID: 29193767]

[35]
Hattori, S. Anti-inflammatory effects of empagliflozin in patients with type 2 diabetes and insulin resistance. Diabetol. Metab. Syndr.,  2018, 10(1), 93.
 [http://dx.doi.org/10.1186/s13098-018-0395-5] [PMID: 30574207]

[36]
Kim, S.R.; Lee, S.G.; Kim, S.H.; Kim, J.H.; Choi, E.; Cho, W.; Rim, J.H.; Hwang, I.; Lee, C.J.; Lee, M.; Oh, C.M.; Jeon, J.Y.; Gee, H.Y.; Kim, J.H.; Lee, B.W.; Kang, E.S.; Cha, B.S.; Lee, M.S.; Yu, J.W.; Cho, J.W.; Kim, J.S.; Lee, Y.H. SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease. Nat. Commun.,  2020, 11(1), 2127.
 [http://dx.doi.org/10.1038/s41467-020-15983-6] [PMID: 32358544]

[37]
Mancini, S.J.; Boyd, D.; Katwan, O.J.; Strembitska, A.; Almabrouk, T.A.; Kennedy, S.; Palmer, T.M.; Salt, I.P. Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms. Sci. Rep.,  2018, 8(1), 5276.
 [http://dx.doi.org/10.1038/s41598-018-23420-4] [PMID: 29588466]

[38]
Paiva, A.A.; Raposo, H.F.; Wanschel, A.C.; Nardelli, T.R.; Oliveira, H.C.F. Apolipoprotein CIII overexpression-induced hypertriglyceridemia increases nonalcoholic fatty liver disease in association with inflammation and cell death. Oxid. Med. Cell. Longev.,  2017, 2017, 1838679.
 [http://dx.doi.org/10.1155/2017/1838679] [PMID: 28163820]

[39]
Zewinger, S.; Reiser, J.; Jankowski, V.; Alansary, D.; Hahm, E.; Triem, S.; Klug, M.; Schunk, S.J.; Schmit, D.; Kramann, R.; Körbel, C.; Ampofo, E.; Laschke, M.W.; Selejan, S.R.; Paschen, A.; Herter, T.; Schuster, S.; Silbernagel, G.; Sester, M.; Sester, U.; Aßmann, G.; Bals, R.; Kostner, G.; Jahnen-Dechent, W.; Menger, M.D.; Rohrer, L.; März, W.; Böhm, M.; Jankowski, J.; Kopf, M.; Latz, E.; Niemeyer, B.A.; Fliser, D.; Laufs, U.; Speer, T. Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation. Nat. Immunol.,  2020, 21(1), 30-41.
 [http://dx.doi.org/10.1038/s41590-019-0548-1] [PMID: 31819254]

[40]
Basu, D.; Bornfeldt, K.E. Hypertriglyceridemia and atherosclerosis: using human research to guide mechanistic studies in animal models. Front. Endocrinol. (Lausanne),  2020, 11, 504.
 [http://dx.doi.org/10.3389/fendo.2020.00504] [PMID: 32849290]

Rights & Permissions Print Cite

Article Metrics

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1871530322666220427094330	Print ISSN 1871-5303
Publisher Name Bentham Science Publisher	Online ISSN 2212-3873

Endocrine, Metabolic & Immune Disorders - Drug Targets

Prognostic Significance of Hypertriglyceridemia in Patients at High and Very High Cardiovascular Risk Depending on the Concentration of Highsensitivity C-reactive Protein

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract