|
 
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| REVIEW ARTICLE |
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| Year : 2018 | Volume
: 2
| Issue : 2 | Page : 40-44 |
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Research progress of hypertriglyceridemia and coronary heart disease
Yanyue Ji, Chunlin Bai
Department of Cardiology, Second Hospital of Shanxi Medical University, Taiyuan, China
| Date of Web Publication | 22-Aug-2019 |
Correspondence Address:
Dr. Chunlin Bai
Department of Cardiology, Second Hospital of Shanxi Medical University, Taiyuan
China
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/hm.hm_2_19
At present, the relationship between hypertriglyceridemia (HTG) and coronary heart disease (CHD) is still uncertain. In recent years, many researchers have tried to clarify the relationship between HTG, atherosclerosis, and CHD. This article will review the relationship between HTG and CHD from the aspects of epidemiology, pathogenesis, and cardiovascular benefits of HTG treatment to further understand the relationship between the two. Dyslipidemia is closely related to the occurrence and development of the atherosclerotic cardiovascular disease. Elevated low-density lipoprotein cholesterol (LDL-C) has been recognized as an independent risk factor for cardiovascular events. Statins can effectively reduce LDL-C and reduce the incidence of cardiovascular events. HTG is the most common dyslipidemia in China, and the correlation between HTG and CHD deserves attention. Therefore, as for the progress of HTG and CHD in recent years, we will make a review on the relationship between HTC and CHD, the mechanism of atherosclerosis and the cardiovascular benefits of treatment, so as to further clarify the role and significance of triglyceride in the process of atherosclerosis and provide new ideas for the prevention an d treatment of CHD. Keywords: Atherosclerosis, coronary heart disease, triglyceride
How to cite this article:
Ji Y, Bai C. Research progress of hypertriglyceridemia and coronary heart disease. Heart Mind 2018;2:40-4 |
| Epidemiological Study on Hypertriglyceridemia and Coronary Heart Disease | |  |
Coronary heart disease (CHD) is a serious threat to human health. Although the death rate of CHD is decreasing after strong intervention measures and effective secondary prevention of risk factors, CHD is still the most common cause of death in the world, ranking the first cause of death.
Hypertension, diabetes, hypercholesterolemia, and smoking have been identified as independent risk factors of CHD, and hypertriglyceridemia (HTG) has been controversial for a long time. However, some prospective studies published in recent years support that HTG is an independent risk factor for CHD. A meta-analysis involving 26 studies in the Asia-Pacific region (a total of 96,244 people) found that the level of serum triglyceride (TG) is an important independent predictor of CHD.[1] A meta-analysis of 29 prospective studies in the western population shows that TG is moderately or highly correlated with CHD.[2] Another meta-analysis involving 61 prospective studies further confirmed that high TG levels were associated with all-cause death of cardiovascular diseases.[3] JDCS study[4] found that TG is a risk factor of CHD equivalent to low-density lipoprotein cholesterol (LDL-C) as for Japanese patients with type 2 diabetes. For every 1 mmol/L increase in TG and LDL-C levels, the risk of CHD increases by 63% and 64%, respectively. BIP study,[5] which analysis death date of 15,355 patients with CHD, found that the level of TG was independently related to all-cause mortality of patients with CHD. A large sample cohort study with a follow-up of 15 years in many provinces and cities in China found that high TG was a predictor of CHD in low LDL-C population.[6] The 23-year follow-up results of Daqing study showed that the study evaluated the cardiovascular disease risk of 833 subjects, 34% of whom were HTG (baseline plasma TG level ≥1.7 mmol/L), and the cardiovascular disease risk in high TG group was 27% higher than that in nonhigh TG group. If the basic level of TG increases by 1 mmol/L, the first cardiovascular disease risk increases by 8% in the following 20 years.[7]
Some studies further show that[8] since there is a closer relationship between postprandial TG level and plasma lipoprotein remnant concentration, postprandial TG level is more effective than fasting TG in predicting the risk of CHD in the general population. At the same time, Copenhagen Heart Institute randomly selected 13,981 subjects from 1976 to 1978 for follow-up until the end of 2004. The results showed that after being corrected by other risk factors such as hypertension, diabetes, body mass index, the increase of nonfasting TG level can predict the risks of myocardial infarction, ischemic heart disease, and death.[9],[10] It can be seen that observational prospective cohort studies, randomized controlled studies, and meta-analysis have confirmed that elevated TG is closely related to increased risk of cardiovascular diseases and is an independent risk factor for cardiovascular diseases.
In addition, many studies have shown that[11],[12] even after statins control LDL-C, patients with high TG still have higher cardiovascular risks. In ACCORD study, the incidence of major cardiovascular events in patients with TG ≥2.3 mmol/L and high-density lipoprotein cholesterol (HDL-C) ≤0.9 mmol/L was 71% higher than that in other patients.[13] PROVE IT-TIMI 22 study[11] shows that as for acute coronary syndrome (ACS) patients who have been treated with statin and whose level of LDL-C <1.8 mmol/l, the risk of major cardiovascular events in HTG patients is 27% higher than that in patients with TG <2.3 mmol/L. A meta-analysis of data from 15,817 patients in the dal-OUTCOMES study[14] and 1501 ACS patients in the MARICL study treatment group shows that fasting TG level is closely related to short-term and long-term risks of ACS patients: for every 0.113 mmol/L (10 mg/dl) increase in TG, the risk of long-term cardiovascular events increases by 1.8%, and the risk of short-term cardiovascular events in ACS increases by 1.4%. After-the-fact analysis of IDEAL and TNT studies shows that TG levels are associated with the risk of recurrence of cardiovascular events such as myocardial infarction in patients with stable CHD who have already used moderate or large doses of statin.[15]
Analysis of data from two prospective randomized trials, namely, PERFORM and SPARCL, shows that among stroke or transient ischemic attack patients receiving the best drug treatment including statin, the residual risk of cardiovascular events in patients with HTG and low HDL-C is increased.[16]
| Hypertriglyceridemia and Atherosclerosis | | |
At present, the mechanism of atherosclerosis caused by HTG is not clear, but according to many domestic and foreign studies, it may be related to the following aspects.
Promoting the formation of foam cells
External experiments have proved that very LDL (VLDL) and macrophages can aggregate intracellular TG and cholesterol ester (CE) and promote foam cell generation.[17] VLDL can be oxidized into oxidized VLDL by vascular endothelial cells and smooth muscle cells. By damaging vascular endothelium, recruiting monocytes, promoting foam cell generation, promoting smooth muscle cell proliferation and migration, VLDL has the effect of atherosclerosis. In addition, due to the large size of chylomicrons (CM) and VLDL particles, it was thought that CM and VLDL could not penetrate through the arterial endothelium and enter the arterial wall, but after catabolism, CM and VLDL could generate remnant lipoprotein (RLP), which could not only penetrate through the arterial endothelium but also remain in the tissue matrix of the vascular subendothelial layer.[18] Studies using rabbits and mice atherosclerosis experimental models have found that high-level CM and VLDL residues penetrate into the intima of blood vessels, remain in the tissue matrix of the vascular subendothelial layer, and form foam cells after being ingested by macrophages, thus promoting the occurrence and development of atherosclerosis.[19] Zhang et al.[20] knocked out lipoprotein lipase (LPL) in mice, and found that plasma TG of mice was significantly increased, and atherosclerosis plaque rich in foam cells appeared in the aortic root, suggesting that elevated TG can promote the occurrence and development of atherosclerosis.
Promoting lipid exchange
In the study of lipoprotein metabolism, it was found that the content of CM and VLDL in plasma of patients with high TG increased, which promoted the activity of cholesteryl ester transfer protein in plasma to increase. TG in CM and VLDL is exchanged with CE in HDL and LDL. The results of the lipid exchange were as follows: small dense low-density lipoprotein (SLDL) concentration increased, HDL and HDL-C levels decreased. HDL particles and HDL-C play a key role in maintaining endothelial vascular reactivity, resisting oxidative stress, inhibiting endothelial cell apoptosis, promoting repair of damaged endothelium, inhibiting monocyte activation, and reducing the expression of adhesion factors and cytokines, while the above effects can slow down the formation of atherosclerotic plaques.[21] Moreover, the higher the TG level in plasma, the more active lipid exchange will be. The SLDL produced is an LDL with strong atherosclerosis effect. Experimental studies have clarified some mechanisms of SLDL-induced atherosclerosis: SLDL particles are small and easy to enter the arterial intima and SLDL is easy to combine with proteoglycan and remain in the arterial wall. SLDL has low affinity for LDL receptor. Therefore, SLDL clearance is slow, and the residence time in plasma is long. SLDL is highly sensitive to oxidation and is easily absorbed by scavenger receptors of macrophages after oxidation, thus promoting the formation of foam cells. These properties make SLDL have strong AS-inducing effect.[22]
Promoting vascular endothelial dysfunction
VLDL and CM have direct cytotoxic effect on vascular endothelial cells, which can cause endothelial cell permeability to increase and deposit in the arterial wall through the endothelial barrier. Chen et al.[23] found that increasing the negative charge of VLDL can induce up-regulation of reactive oxygen species expression in endothelial cells and promote endothelial cell apoptosis in patients with metabolic syndrome, suggesting that VLDL rich in negative charge has damaging effect on vascular endothelium. VLDL isolated from HTG patients' blood can increase the transcription and expression of plasminogen activator inhibitor-1 (PAI-1) cultured in vitro, suggesting that VLDL can reduce vascular endothelial fibrinolytic activity and increase the risk of AS formation.[24] Other studies have shown that triglyceride rich lipoproteins residues can increase the expression of vascular endothelial adhesion molecules, reduce arterial vasodilation function, and cause vascular endothelial dysfunction.[25] TRL residues can also inhibit telomerase activity, enhance vascular endothelial oxidative stress reaction, accelerate endothelial progenitor cell aging, and affect the repair function of endothelial progenitor cells on the vascular injury.[26],[27] Therefore, TRL and its residues can accelerate the formation of AS by promoting vascular endothelial injury, inhibiting endothelial repair, inhibiting endothelial relaxation, and inducing endothelial dysfunction.
Promoting inflammatory response
Many studies have shown that atherosclerosis caused by HTG may be related to inflammatory reaction. Some studies have observed that RLP can accelerate the aging of endothelial progenitor cells and affect their functions, and these cells play an important role in the repair of vascular wall injury.[26] Postprandial TRL has been proved to increase the expression of inflammatory factors (such as interleukin [IL]-6, intercellular adhesion factor, and vascular cell adhesion factor 1) genes, induce cell apoptosis, and also enhance the inflammatory response of endothelial cells cultured in vitro α (tumor necrosis factor-α [TNF-α]). Research[28] results support that the role of fatty acid binding proteins derived from adipocytes and macrophages in the body's inflammatory response can be enhanced by the high TG load generated by RLP decomposition. Macrophages were incubated with VLDL, and the expressions of various inflammatory factors such as α (TNF-α) and IL-1 β in macrophages were significantly up-regulated.[29] TRL particles were separated from human postprandial serum and incubated with human aortic endothelial cells. Under the stimulation of low dose TNF-α, the expressions of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin on the cell membrane surface were up-regulated.[30] Studies further show that CM residues can directly activate monocytes and increase monocyte migration by decreasing MCP-1 expression.[31]
Promoting coagulation and inhibit fibrinolysis
Many studies have found that patients with high TG have various coagulation defects, such as enhanced platelet aggregation, increased factor VII, increased factor X activity, and excessive PAI-I release which promote coagulation under the participation of various tissue factors. The appearance of this procoagulant state will accelerate the development of atherosclerosis and increase the severity of myocardial infarction.[32] TRL residue contains free fatty acid, which generates a large amount of negative charge. FVII is activated by endogenous coagulation pathway and activated FXII. The increase of activated FVII molecules triggers exogenous coagulation system. The concentration of VII molecules increases. Coagulation is easily generated under the action of excessive tissue factors, which is an independent risk factor for CHD onset.[33] In vitro tests found that VLDL can induce vascular endothelial cells and hepatocytes to secrete PAI-1 to increase.[34] Plasma PAI-1 level in patients with hyperthermia is significantly increased. Studies found that PAI-1 gene expression in human AS artery intima is increased. PAI-1 gene expression in smooth muscle cells is too high in developing atherosclerotic plaques. Excessive production of PAI-1 may inhibit local plasmin synthesis and promote intra-arterial fibrin deposition. Therefore, increased PAI-1 activity can lead to myocardial infarction.
| Cardiovascular Benefits After Hypertriglyceridemia Treatment | | |
Lifestyle improvement
Lifestyle improvement is the cornerstone for the treatment of HTG.[35] For the treatment of HTG, artificial lifestyle intervention is more cost-effective and safer than drug therapy.
Fibrates
Fibrates regulate the expression of target genes LPL, apolipoprotein AI, and apolipoprotein AII by exciting peroxisome proliferator-activated receptor α, thus playing a role in lowering plasma TG level and increasing HDL-C level, transforming small and dense LDL particles into large and loose LDL particles,[36] and promoting reverse transportation of cholesterol.[37] In FIELD and ACCORD studies, fenofibrate can significantly reduce cardiovascular events in HTG patients with low HDL-C.[13],[38],[39] In the FIELD study, subgroup analysis of HTG patients with low HDL-C showed that the risk of cardiovascular events in the fenofibrate group decreased by 27% compared with the placebo group.[13] In the preset subgroup analysis of HTG patients with low HDL-C, compared with the placebo group, the risk of cardiovascular death, myocardial infarction or stroke in the fenofibrate group was reduced by 31% (P < 0.05).[39] Multiple meta-analyses have shown that fenofibrate reduces the risk of cardiovascular events in patients with hypertriglyceridemia.[38],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52] At the same time, many evidence-based medical evidences show that fibrate drugs can reduce coronary artery events or cardiovascular events.[38],[44],[45],[46] Fibrate drugs can significantly reduce coronary artery events or cardiovascular events in diabetic patients. Three large-sample prospective clinical trials of fibrate drugs to reduce cardiovascular events, including Helsinki Heart Study, Benzene Zabyti Prevention of Infarct Study and US Veterans Administration HDL-C Intervention Test, have all shown that cardiovascular events are reduced and the curative effect of diabetic patients is better than that of nondiabetic patients.[46],[47],[48]
Therefore, fibrates can improve blood lipid level and reduce the risk of cardiovascular events.
n-3 fatty acid
The main active components of n-3 fatty acid are eicosapentaenoic acid and docosahexenoic acid extracted from fish oil, which can reduce TG by 30%–40% when used alone or in combination with fibrates or statins. In the GISSI-P study, 11,324 patients after myocardial infarction received n-3 fatty acid or placebo randomly on the basis of statins. The results showed that n-3 fatty acid can reduce the mortality rate of cardiovascular diseases of patients after myocardial infarction: the overall mortality rate decreased by 20%, and the cardiovascular mortality rate decreased by 45%.[49] Meta-analysis shows that increasing n-3 fatty acid in food and reducing saturated fatty acid can reduce the risk of CHD. Taking n-3 fatty acid or increasing the content of n-3 fatty acid in food can reduce the mortality of patients with CHD such as all-cause mortality, myocardial infarction, and death due to CHD.[50] The adverse reactions of this drug are less, and the most common is slight dyspepsia.[51]
Nicotinic acid and its derivatives
Nicotinic acid drugs belong to B vitamins, which can reduce TG level and increase HDL-C. AIM-HIGH study shows that on the basis of maintaining LDL-C at <1.8 mmol/L through intensive statin therapy, adding sustained-release nicotinic acid to increase HDL-C level cannot further reduce the risk of cardiovascular events in patients with stable CHD.[52] Arterial physiology research results of cholesterol-lowering therapy suggest that in patients with known CHD or CHD and other dangerous diseases and treated with statins, the addition of sustained-release nicotinic acid therapy can delay or even partially reverse AS.[53] Meta-analysis shows that nicotinic acid treatment can reduce cardiovascular events by about 25% and delay the progression of coronary AS by about 41%.[54] HP2-THRIVE study[55] also shows that the combination of nicotinic acid and statin drugs does not reduce the incidence of major cardiovascular events and increases the risk of serious adverse events compared with statin drugs alone. As a result, nicotinic acid has faded out of European and American markets.
To sum up, although the relationship between HTG and CHD is still inconclusive, it is proved that HTG is closely related to the occurrence and development of CHD from both epidemiological and pathophysiological perspectives. However, fibrates can reduce cardiovascular events in HTG patients treated with statins. Therefore, we should fully improve the understanding of HTG in cardiovascular diseases, which is helpful to control the risk factors of CHD, reduce the incidence of CHD, and improve the prognosis.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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| Eric Y. F. Wan,Esther Y. T. Yu,Weng Y. Chin,Jessica K. Barrett,Anna H. Y. Mok,Christie S. T. Lau,Yuan Wang,Ian C. K. Wong,Esther W. Y. Chan,Cindy L. K. Lam | | Diabetes, Obesity and Metabolism. 2020; | | [Pubmed] | [DOI] | |
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