ABSTRACT

Chronic inflammatory diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis and infections, such as periodontal disease and HIV, are associated with an increased risk of cardiovascular disease. Patients with these disorders also have an increase in coronary artery calcium measured by CT and carotid intima media thickness measured by ultrasound. Inflammation and infections induce a variety of alterations in lipid metabolism that may initially dampen inflammation or fight infection, but if chronic could contribute to the increased risk of atherosclerosis. The most common changes are decreases in serum HDL and increases in triglycerides. The increase in serum triglycerides is due to both an increase in hepatic VLDL production and secretion and a decrease in the clearance of triglyceride rich lipoproteins. The mechanisms by which inflammation and infection decrease HDL levels are uncertain. With inflammation there is also a consistent increase in lipoprotein (a) levels due to increased apolipoprotein (a) synthesis. LDL levels are frequently decreased but the prevalence of small dense LDL is increased due to exchange of triglycerides from triglyceride rich lipoproteins to LDL followed by triglyceride hydrolysis. In addition to affecting serum lipid levels, inflammation also adversely effects lipoprotein function. LDL is more easily oxidized as the ability of HDL to prevent the oxidation of LDL is diminished. Moreover, there are a number of steps in the reverse cholesterol transport pathway that are adversely affected during inflammation. The greater the severity of the underlying inflammatory disease, the more consistently these abnormalities in lipids and lipoproteins are observed. Treatment of the underlying disease leading to a reduction in inflammation results in the return of the lipid profile towards normal. The changes in lipids and lipoproteins that occur during inflammation and infection are part of the innate immune response and therefore are likely to play an important role in protecting the host. The standard risk calculators for predicting cardiovascular disease (ACC/AHA, Framingham, SCORE, etc.) underestimate the risk in patients with inflammation. It has been recommended to increase the calculated risk by approximately 50% in patients with severe inflammatory disorders. The treatment of lipid disorders in patients with inflammatory disorders is similar to patients without inflammatory disorders. Of note statins, fibrates, and fish oil have anti-inflammatory properties and have been reported to have beneficial effects on some of these inflammatory disorders. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

A number of chronic inflammatory diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis, Sjögren's syndrome, polymyalgia rheumatica, inflammatory bowel disease, and psoriasis are associated with an increased risk of cardiovascular disease (1-9). For example, in a meta-analysis of twenty-four studies comprising 111,758 patients with 22,927 cardiovascular events it was observed that there was a 50% increased risk of CVD death in patients with RA (10). In some studies patients with RA have a similar risk for a cardiovascular event as patients with diabetes (11). Similarly, women with SLE in the 35- to 44-year age group were over 50 times more likely to have a myocardial infarction than were women of similar age in the Framingham Offspring Study (12). As a final example, a meta-analysis of 14 studies reported that in individuals with severe psoriasis the risk for cardiovascular mortality was 1.37, the risk for myocardial infarction was 3.04, and the risk for stroke was 1.59 times higher than the general population (13). It should be noted that the pathology in psoriasis is localized to the skin but nevertheless even this disorder, by inducing systemic inflammation, is associated with an increased risk of cardiovascular disease.

Further, supporting the link of RA, SLE, and psoriasis with atherosclerosis are studies showing that patients with these disorders have an increase in coronary artery calcium measured by CT and carotid intima media thickness measured by ultrasound (14-20). Finally, even children and adolescents with SLE have an increase in carotid intimal-medial thickness (21). Thus, it is clear that patients with a number of different chronic inflammatory diseases have an increased risk of atherosclerotic cardiovascular complications.

In addition, chronic infections are also associated with an increased risk of atherosclerosis (22-24). Since the development of effective anti-viral agents, it has been widely recognized that a major cause of morbidity and mortality in HIV infected patients is due to cardiovascular disease (25,26). Moreover, numerous studies have demonstrated an association of periodontal infections with an increased risk of atherosclerotic vascular disease (27). Additionally, carotid intima-media thickness is increased in patients with periodontal disease (28-31). The link between various chronic infections, such as HIV, dental infections, Helicobacter pylori, chronic bronchitis, and urinary tract infections with cardiovascular disease is presumably due to the chronic inflammation that accompanies these infections (32). For certain infections such as chlamydia pneumonia and cytomegalovirus it is possible that the association with cardiovascular disease is due to a direct role in the vessel wall.

To definitively link inflammation with cardiovascular disease studies determining the effect of anti-inflammatory drugs on cardiovascular events have been carried out. The Cantos study has provided data supporting a link between inflammation and cardiovascular disease (33). In this trial 10,061 patients with a previous myocardial infarction and a hsCRP level of 2 mg/L or more were randomized to canakinumab, a monoclonal antibody targeting interleukin-1β, or placebo. At 48 months canakinumab did not reduce lipid levels from baseline but did reduce hsCRP levels by approximately 30-40% indicating a decrease in inflammation. Most importantly, canakinumab administration led to a significantly lower rate of recurrent cardiovascular events than placebo. In addition, several randomized trials have demonstrated that colchicine reduces cardiovascular events in patients with chronic cardiovascular disease (34-36). These results support the hypothesis that inflammation increases the risk of cardiovascular events and that reducing inflammation will decrease events. In contrast to the positive trials described above, a trial using methotrexate to inhibit inflammation failed to reduce cardiovascular event (37). However, in this trial methotrexate did not reduce levels of interleukin-1β, interleukin-6, or C-reactive protein raising the possibility that methotrexate did not effectively inhibit inflammation and therefore did not reduce cardiovascular events. Clearly further studies determining the effect of drugs that reduce inflammation on cardiovascular events are required.

The mechanisms by which chronic inflammation and infection increase the risk of atherosclerotic cardiovascular disease are likely multifactorial. As will be discussed below inflammation and infection induce a variety of alterations in lipid and lipoprotein metabolism that could contribute to the increased risk of atherosclerosis.

LIPID AND LIPOPROTEIN ABNORMALITIES IN PATIENTS WITH INFLAMMATORY DISORDERS AND INFECTIONS

EFFECT OF ANTI-INFLAMMATORY DRUGS ON LIPID LEVELS

Treatments that reduce inflammation will return the lipid profile towards normal resulting in an increase in plasm HDL levels and a decrease in triglyceride levels. If LDL levels were reduced at baseline, treatment that reduces inflammation will also result in an increase in LDL levels (i.e., a return towards “normal” levels) (101-103). Many of the drugs used for the treatment of RA, SLE, and psoriasis decrease inflammation and have been shown to increase both HDL and LDL levels (9,101,102,104). The increase in HDL tends to be more robust. In a few instances, drugs used to treat inflammatory disorders have effects on lipid metabolism that are independent of the reduction in inflammation. For example, high dose glucocorticoid treatment results in an increase in serum triglyceride and LDL levels due to the increased production and secretion of VLDL by the liver (105-107) and hydroxychloroquine has been reported to lower total cholesterol, LDL, and triglycerides in patients with RA and SLE (108-110).

PATHOPHYSIOLOGY OF THE DYSLIPIDEMIA OF INFLAMMATION AND INFECTION

Inflammation and infections increase the production of a variety of cytokines, including TNF, IL-1, and IL-6, which have been shown to alter lipid metabolism (32). Many of the changes in plasma lipids and lipoproteins that are seen during chronic inflammation and infections are also observed following the acute administration of cytokines (32).

Increased Triglyceride Levels

Multiple cytokines increase serum triglyceride and VLDL levels (TNF, IL-1, IL-2, IL-6, etc.) (32). Following a single administration of a cytokine or LPS (a model of gram-negative infections), which stimulates cytokine production, an increase in serum triglyceride and VLDL levels can be seen within 2 hours and this effect is sustained for at least 24 hours. The increase in serum triglycerides is due to both an increase in hepatic VLDL production and secretion and a decrease in the clearance of triglyceride rich lipoproteins (figure 1) (32). The increase in VLDL production and secretion is a result of increased hepatic fatty acid synthesis, an increase in adipose tissue lipolysis with the increased transport of fatty acids to the liver, and a decrease in fatty acid oxidation in the liver. Together these changes provide an increased supply of fatty acids in the liver that stimulate an increase in hepatic triglyceride synthesis (32). The increased availability of triglycerides leads to the increased formation and secretion of VLDL. The decrease in the clearance of triglyceride rich lipoproteins is due to a decrease in lipoprotein lipase, the key enzyme that metabolizes triglycerides in the circulation (32). A variety of cytokines have been shown to decrease the synthesis of lipoprotein lipase in adipose and muscle tissue (32). Studies have also shown that inflammation also increases angiopoietin like protein 4, an inhibitor of lipoprotein lipase activity, which would further block the metabolism of triglyceride rich lipoproteins (111). In SLE, antibodies to lipoprotein lipase have been reported and are associated with increased triglyceride levels (112,113).

Figure 1.

Pathogenesis of Hypertriglyceridemia

Decreased HDL Levels

In addition to a decrease in HDL, inflammation can also lead to structural changes in this lipoprotein (32). During inflammation HDL particles tend to be larger with a decrease in cholesterol ester and an increase in free cholesterol, triglycerides, and free fatty acids. Furthermore, there are marked changes in HDL associated proteins and the enzymes and transfer proteins involved in HDL metabolism and function (figure 2 and 3).

Figure 2.

Changes in HDL Protein Composition During Inflammation

Figure 3.

Changes in Enzymes and Transfer Proteins During Inflammation

The precise mechanism by which inflammation and infection decrease HDL levels is uncertain and is likely to involve multiple mechanisms (32). Decreases in apolipoprotein A-I synthesis in the liver occur during inflammation and would result in the decreased formation of HDL. However, in acute infection and inflammation HDL decreases faster than would be predicted from decreased synthesis of apolipoprotein A-I. Increased serum amyloid A (SAA) production by the liver and other tissues occurs during inflammation and infection and the SAA binds to HDL displacing apolipoprotein A-I, which can accelerate the clearance of HDL. However, the overexpression in SAA in the absence of the acute phase response does not result in a decrease in HDL levels (114). Inflammation results in a decrease in LCAT leading to decreased cholesterol ester formation, which would prevent the formation of normal HDL, leading to decreased cholesterol carried in HDL. Elevations in triglyceride rich lipoproteins that accompany inflammation and infection can lead to the enrichment of HDL with triglycerides that can accelerate the clearance of HDL. Finally, cytokine induced increases in enzymes such as secretory phospholipase A2 (sPLA2) and endothelial cell lipase, which metabolize key constituents of HDL, could alter the stability and metabolism of HDL. Given the complexity of HDL metabolism it is not surprising that multiple pathways could be affected by inflammation, which together may account for the decrease in HDL levels.

FUNCTIONAL CHANGES IN LIPOPROTEINS THAT INCREASE THE RISK OF ATHEROSCLEROSIS

HDL

In addition to a decrease in serum HDL, inflammation and infection affects the anti-atherogenic properties of HDL (32,125,126). Reverse cholesterol transport plays a key role in preventing cholesterol accumulation in macrophages thereby reducing atherosclerosis. Many steps in the reverse cholesterol transport pathway are adversely affected during inflammation and infection (figure 4 and 5) (43,127). First, cytokines induced by inflammation and infection decrease the production of Apo A-I, the main protein constituent of HDL. Second, pro-inflammatory cytokines decrease the expression of ABCA1, ABCG1, SR-B1, and apolipoprotein E in macrophages, which will lead to a decrease in the efflux of phospholipids and cholesterol from the macrophage to HDL. Third, the structurally altered HDL formed during inflammation is a poor acceptor of cellular cholesterol and in fact may actually deliver cholesterol to the macrophage (43,61,127-134). HDL isolated from patients with RA, SLE, inflammatory bowel disease, psoriasis, ankylosing spondylitis, periodontal disease, and acute sepsis are poor facilitators of cholesterol efflux (61,128-133,135). Similarly, the experimental administration of endotoxin to humans also results in the formation of HDL that is a poor facilitator of the efflux of cholesterol from macrophages (136). Of note treatments that reduce inflammation in patients with RA, psoriasis, or periodontitis can restore towards normal the ability of HDL to remove cholesterol from cells (133,137-139). Fourth, pro-inflammatory cytokines decrease the production and activity of LCAT, which will limit the conversion of cholesterol to cholesteryl esters in HDL. This step is required for the formation of a normal spherical HDL particle and facilitates the ability of HDL to transport cholesterol. Fifth, pro-inflammatory cytokines decrease CETP levels, which will decrease the movement of cholesterol from HDL to Apo B containing lipoproteins, an important step in the delivery of cholesterol to the liver. Sixth, pro-inflammatory cytokines decrease the expression of SR-B1 in the liver. SR-B1 plays a key role in the uptake of cholesterol from HDL particles into hepatocytes. Finally, inflammation and infection decrease both the conversion of cholesterol to bile acids and the secretion of cholesterol into the bile, the two mechanisms by which cholesterol is disposed of by the liver.

Figure 4.

Effect of Inflammation on Reverse Cholesterol Transport (from reference (127))

Figure 5.

Effect of Inflammation on the Factors Involved in Reverse Cholesterol Transport (from reference (127))

Another important function of HDL is to prevent the oxidation of LDL. Oxidized LDL is more easily taken up by macrophages and is pro-atherogenic (124). Paraoxonase is an enzyme that is associated with HDL and plays a key role in preventing the oxidation of LDL. Inflammation and infection decrease the expression of paraoxonase 1 in the liver resulting in a decrease in circulating paraoxonase activity (32). Plasma paraoxonase levels are decreased in patients with RA, SLE, psoriasis, and infections (140-148) Studies have shown that HDL isolated from patients with RA and SLE have a diminished ability to protect LDL from oxidation and in fact may facilitate LDL oxidation (125). Moreover, in patients with RA, reducing inflammation and disease activity with methotrexate treatment restored HDL function towards normal (149). Additionally, treatment with atorvastatin 80mg improved the function of HDL in patients with RA (150).

Thus, it should be recognized that in patients with inflammatory disorders and infections the absolute levels of lipids and lipoproteins may not be the only factor increasing the risk of atherosclerosis (32,54,121,125-127). Rather functional changes in LDL and HDL maybe pro-atherogenic and thereby contribute to the increased risk of atherosclerosis in inflammatory disorders and infections. Additionally, the increase in lipoprotein (a) may also play a role.

Table 2.

Pro-Atherogenic Changes During Inflammation

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Increased triglycerides

Decreased HDL

Increased small dense LDL

Increased Lp(a)

Oxidized LDL

Dysfunctional HDL

BENEFICIAL EFFECTS OF LIPIDS DURING INFECTIONS AND INFLAMMATION

The changes in lipids and lipoproteins that occur during inflammation and infection are part of the innate immune response and therefore are likely to play an important role in protecting from the detrimental effects of infection and inflammatory stimuli (32,151-153). Some of the potential beneficial effects are listed in Table 3. Thus, the changes in lipid and lipoprotein metabolism that occur during inflammation may initially be protective but if chronic can increase the risk of atherosclerosis.

LIPID MANAGEMENT IN A PATIENT WITH AN INFLAMMATORY DISEASE

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