|Year : 2019 | Volume
| Issue : 3 | Page : 790-796
Effect of adiponectin and highly sensitive C-reactive protein on the severity of coronary artery disease
Ahmed A Reda1, Waleed A Ibrahim1, Ahmed O Elsisy2
1 Department of Cardiology, Menoufia University, Menoufia, Egypt
2 Department of Cardiology, Elsahel Teaching Hospital, Cairo, Egypt
|Date of Submission||22-Dec-2017|
|Date of Acceptance||29-Jan-2018|
|Date of Web Publication||17-Oct-2019|
Ahmed O Elsisy
Nasr City, Cairo
Source of Support: None, Conflict of Interest: None
The objective of our study was to estimate the effect of adiponectin (ADPN) and highly sensitive C-reactive protein (hsCRP) level on the severity of coronary artery disease (CAD) in patients with chronic stable angina.
Materials and methods
MEDLINE databases (PubMed, Journal of Clinical Endocrinology and Metabolism, British Medical Journal, Journal of American College of Cardiology, and European Heart Journal) and also materials available in the internet were searched. The search was performed in the electronic databases from 2000 to 2017. The initial search presented 122 articles of which 29 met the inclusion criteria. The articles studied ADPN, hsCRP, and severity of CAD. If the studies did not fulfill the inclusion criteria, they were excluded. Study quality assessment included whether ethical approval was gained, eligibility criteria specified, appropriate controls, adequate information, and defined assessment measures. Comparisons were made by structured review with the results tabulated.
In total, 29 potentially relevant publications were included. The studies indicate an association between ADPN and hsCRP and severity of CAD in patients with CAD.
ADPN and hsCRP are markers of poor prognosis in patients with CAD.
Keywords: adiponectin, atherosclerosis, biomarker, C-reactive protein, coronary artery disease, epicardial adipose tissue, metabolic syndrome
|How to cite this article:|
Reda AA, Ibrahim WA, Elsisy AO. Effect of adiponectin and highly sensitive C-reactive protein on the severity of coronary artery disease. Menoufia Med J 2019;32:790-6
|How to cite this URL:|
Reda AA, Ibrahim WA, Elsisy AO. Effect of adiponectin and highly sensitive C-reactive protein on the severity of coronary artery disease. Menoufia Med J [serial online] 2019 [cited 2019 Nov 14];32:790-6. Available from: http://www.mmj.eg.net/text.asp?2019/32/3/790/268858
| Introduction|| |
The stable coronary artery disease (SCAD) is generally characterized by episodes of reversible myocardial demand/supply mismatch, related to ischemia or hypoxia, which are usually inducible by exercise, emotion, or other stress and are reproducible but may also occur spontaneously.
One of the most important risk factors of SCAD is atherosclerosis. Atherosclerosis is the ongoing process of plaque formation that involves primarily the intima of large- and medium-sized arteries; the condition progresses relentlessly throughout a person's lifetime, before finally manifesting itself as an acute ischemic event. Several coronary risk factors influence this process, including hypercholesterolemia, hypertension, diabetes, and smoking .
These risk factors damage the endothelium of the blood vessel and result in endothelial dysfunction, which plays a pivotal role in initiating the atherosclerotic process. Once the endothelium has been damaged, the inflammatory cells, especially monocytes, migrate into the subendothelium by binding to endothelial adhesion molecules, and once in the subendothelium, they undergo differentiation and become macrophages .
Among novel risk markers, elevated highly sensitive C-reactive protein (hsCRP) is an independent predictor of new cardiovascular events. Indeed, several cohort studies have shown that hsCRP evaluation adds prognostic information to the cardiovascular risk .
Adiponectin (ADPN), an adipocytokine, is the most abundant gene product in the adipose tissue and regulates glucose and lipid homeostasis, energy metabolism, and anti-inflammatory activity .
Dysregulation of ADPN has been implicated in metabolic X syndrome and atherosclerosis as well as in insulin resistance, obesity, type 2 diabetes mellitus (T2DM), hypertension, coronary artery disease (CAD), and ischemic strokes . ADPN can potentially inhibit all the molecular pathways of atherosclerosis, which include monocyte adhesion to endothelial cells by adhesion molecules, oxidized low-density lipoprotein (LDL) uptake of macrophages through scavenger receptors, and proliferation of migrated smooth muscle cells by the action of platelet-derived growth factors and heparin-binding epidermal growth factor-like growth factor .
ADPN levels decreased in presence of hypertension, diabetes mellitus (DM), and metabolic syndrome (MetS). It has been also suggested that normal or high levels of ADPN may prevent development of cardiovascular diseases and complications in healthy individuals .
The objective of our study was to estimate the effect of ADPN and hsCRP on the severity of CAD in patients with chronic stable angina.
| Materials and Methods|| |
We reviewed papers on the ADPN, hsCRP, and assessment of severity of CAD from MEDLINE databases, which are PubMed, Journal of Clinical Endocrinology and Metabolism, British Medical Journal, Journal of American College of Cardiology, and European Heart Journal, and also materials available in the internet. We used ADPN and hsCRP in CAD as searching terms. The search was performed in the electronic databases from 2000 to 2017.
All the studies were independently assessed for inclusion. They were included if they fulfilled the following criteria:
- Published in English language
- Published in peer-reviewed journals
- Focused on ADPN level and cardiovascular disease
- Discussed the relation between ADPN, hsCRP, and severity of CAD.
If the studies did not fulfill the aforementioned criteria, they were excluded such as, report without peer-review or not within national research program, letters/comments/editorials/news.
The analyzed publications were evaluated according to evidence-based medicine (EBM) criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM in addition to the evidence pyramid [Figure 1].
|Figure 1: Evidence pyramid. MA, meta-analysis; RCT, randomized controlled trial; SR, systematic review.|
Click here to view
US Preventive Services Task Force classification is as follows:
- Level I: evidence obtained from at least one properly designed randomized controlled trial
- Level II-1: evidence obtained from well-designed controlled trials without randomization
- Level II-2: evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group
- Level II-3: evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence
- Level III: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.
The quality of all the studies was assessed. Important factors included study design, attainment of ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis made in addition to an explanation of missing data.
A structured systematic review was performed with the results tabulated.
| Results|| |
Study selection and characteristics
In total, 80 potentially relevant publications were identified. Of them, 53 articles were excluded as they did not meet our inclusion criteria. A total of 27 studies were included in the review as they were deemed eligible by fulfilling the inclusion criteria. All of these 27 articles included in this review were human studies. Most studies evaluated the relationship between ADPN and hsCRP and the severity of CAD. The studies were analyzed for study design using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM.
Association of adiponectin levels with the severity of coronary artery disease
One cohort study  clarified that plasma ADPN levels in men with SCAD and complex coronary lesions were significantly lower than in those with simple lesions, and patients with acute coronary syndrome with multiple complex lesions had significantly lower ADPN levels than those with single complex lesions. Another cross-sectional study  showed that even after adjustment for known cardiovascular risk factors, elevated serum levels of ADPN were associated with a lower risk of CHD in the prospective analysis. Two case–control studies , clarified that serum ADPN levels are decreased in patients with CAD compared with controls. This decrease is more prominent with increasing levels of CAD severity, which may be a helpful clue of multivessel disease [Table 1].
|Table 1: Studies investigating association of adiponectin levels with the severity of coronary artery disease|
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Decreased adiponectin and increased inflammation expression in epicardial adipose tissue of coronary artery disease
Three case–control studies ,, confirmed that immunologic endocrine disorders in epicardial adipose tissue are strongly linked to CAD. High production of proinflammatory factors in patients with CAD is because of changes in the biological properties of epicardial adipose tissue, which may be independently associated with increased plasma glucose and lipid levels [Table 2].
|Table 2: Studies investigating decreased adiponectin and increased inflammation expression in epicardial adipose tissue of coronary artery disease|
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Association of adiponectin levels with other risk factors of coronary artery disease
Two cohort studies, one shows that even after adjustment for known cardiovascular risk factors, elevated serum levels of ADPN were associated with a lower risk of CHD in the prospective analysis. Furthermore, this association was independent of measurements associated with insulin resistance or obesity, suggesting an obesity-independent effect of ADPN on atherosclerosis . Another follow-up study  provided evidence for an inverse association between serum concentrations of ADPN and subsequent risk of T2DM and CHD in apparently healthy middle-aged men. Four case–control studies, one study shows that diabetic patients with myocardial infarction (MI) have significantly lower ADPN levels during the postinfarction recovery period, which may suggest a higher and longer utilization of ADPN in reparative and regenerative processes in this patient group . A case study showed that ADPN deficiency in the setting of MetS may contribute to the development of atherosclerosis . Another study showed that obesity and T2DM are associated with low plasma ADPN concentrations, which in large part attributable to insulin resistance and/or hyperinsulinemia  [Table 3].
|Table 3: Studies investigating association of adiponectin levels with other risk factors of coronary artery disease|
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Association between adiponectin level and future cardiovascular events in patients with coronary artery disease
Three cohort studies, one of them proved that ADPN action/metabolism paradoxically causes increased cardiovascular events and mortality risk . The other two cohort studies clarified that high plasma ADPN levels are associated with a lower risk of MI ,. One case–control study suggested that the amount of ADPN production in the coronary circulation may be able to predict future cardiovascular events and mortality in patients with CAD  [Table 4].
|Table 4: Studies investigating association between adiponectin level and future cardiovascular events in patients with coronary artery disease|
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Serum high-sensitivity C-reactive protein levels and the severity of coronary atherosclerosis and prediction of cardiovascular events
One cross-sectional study clarified that elevate serum hsCRP levels correlate with the severity of CAD as assessed by angiographic Gensini score . A cohort study suggested that the C-reactive protein (CRP) level is a stronger predictor of cardiovascular events than the LDL-cholesterol level . An observational study stated that elevated preprocedural serum hsCRP levels are associated with long-term clinical outcomes in patients having SCAD with chronic kidney disease and might be useful to predict long-term adverse events after first-generation drug-eluting stent implantation in patients with chronic kidney disease  [Table 5].
|Table 5: Studies investigating association between serum high-sensitivity C-reactive protein levels and the severity of coronary atherosclerosis and prediction of cardiovascular events|
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| Discussion|| |
ADPN is an important secreted serum protein. The human ADPN gene is located on chromosome 3q27, and it codes for a 244-amino acid polypeptide with a signal sequence. It is present in human plasma and adipose tissue and is induced during adipogenesis. ADPN has beneficial roles for the vascular system, and it has been proven that decreased plasma levels of ADPN are associated with vascular events such as diabetic foot and coronary atherosclerosis . Reviewing the recent studies about high-molecular-weight (HMW) ADPN, which is an active form of ADPN, it is observed that it makes up the majority of intracellular ADPN and has more effective role in glucose and lipid metabolism compared with total ADPN . In a study conducted by Inoue et al.  on 149 patients, it was shown that decreased HMW ADPN level was associated with vasospastic angina pectoris, stable angina pectoris, and MI. The study showed that HMW ADPN levels were lower in patients with CAD with multivessel disease compared with those with single-vessel disease and that decreased HMW ADPN level together with DM, insulin resistance, and hsCRP was a predictor of cardiovascular events . It has been also shown that ADPN acts as an endogenous regulator of endothelial cells in response to inflammatory stimuli, inhibits cell proliferation and migration of vascular smooth muscles, and has anti-inflammatory and antiatherogenic effects on macrophages together with endothelial cells. Moreover, it has also been shown to increase nitric oxide production in endothelial cells . Numerous observations link low levels of ADPN with undesirable conditions such as CHD, insulin resistance, and low-grade inflammation, and accordingly, one would expect high ADPN levels to be advantageous and to reflect a more healthy condition. However, the association between health (in a broad sense) and ADPN is not that simple. Thus, studies in patients with chronic heart failure have shown that elevated ADPN levels independently of other risk factors are linked to an increased mortality, and in patients with type 1 diabetes, participants with macroalbuminuria, who are at increased risk for CHD, have higher levels of ADPN than patients without clinical signs of diabetic nephropathy. Similarly, patients with chronic renal failure, who have a high mortality from cardiovascular disease, have 2.5-fold elevated ADPN levels. However, in the latter condition, patients with low ADPN levels had an even higher risk for cardiovascular events than those with high ADPN levels, again stressing that ADPN may be vasoprotective .
ADPN levels in the peripheral circulation were also better related to intracoronary ADPN. The studies show that a combination of the concentration of peripheral plasma ADPN and the thickness of epicardial adipose tissue may be used as a highly sensitive predictor for coronary atherosclerosis in nonobese populations . This research confirms that immunologic endocrine disorders in epicardial adipose tissue are strongly linked to CAD. High production of proinflammatory factors in patients with CAD is because of changes in the biological properties of epicardial adipose tissue, which may be independently associated with increased plasma glucose and lipid levels. Otherwise, obesity-associated endocrine disorders in adipocytes can activate monocytes and subsequently trigger atherosclerosis, and ADPN can inhibit this process through decreasing TLR4 expression on macrophage/monocytes . All studies have consistently reported relationships between ADPN and metabolic and lipid measures, the strongest correlation being present between ADPN and high-density lipoprotein-cholesterol and apolipoprotein A1. Thus, the molecular mechanism of this relationship is of particular interest. Consequently, ADPN may directly stimulate the expression of lipoprotein lipase, which then will result in increased high-density lipoprotein-cholesterol levels. Therefore, the associations of both molecules with T2DM and CHD may operate through different mechanisms. The mechanisms whereby ADPN exerts its physiological actions are not entirely understood. Apart from its role as an insulin-sensitizing agent, and its implication in metabolic disorders, ADPN might also be involved in the regulation of inflammatory processes that are contributing to atherosclerosis by, for instance, inhibiting the expression of adhesion molecules, and by preventing the attachment of monocytes to the endothelial surface through inhibition of nuclear factor-κ-B signaling. Furthermore, through the inhibition of macrophage scavenger receptor A gene expression, ADPN reduces cholesterol ester accumulation and decreases oxidized low-density lipoprotein uptake, thereby diminishing the transformation of macrophages into foam cells, a crucial step in atherogenesis. Finally, smooth muscle cell proliferation and migration is also suppressed by ADPN . It seems reasonable to suggest that the patients with MetS and hypoadiponectinemia are more prone to develop coronary atherosclerosis compared with patients without decreased plasma ADPN, probably because of the blunted inhibitory effect of ADPN on endothelial inflammation and atherogenesis. On the contrary, experimental data indicated that ADPN accumulates in the subendothelial space of the vascular wall from the plasma when the vascular endothelium is injured, which may result in accelerated degradation and eventually reduced circulating ADPN . The risk associated with having MetS is expected to be higher than the risk associated with each of the components of the syndrome, which are related with decreased circulating ADPN levels. In the case of MetS, the relative contributions of the individual components of this syndrome determine the risk for developing CAD. The coexistence of these metabolic disorders may have additive effect on lowering plasma ADPN levels and thereby increasing the susceptibility for the initiation and progression of atherosclerosis in patients with MetS . These results suggest that ADPN has an important role in insulin actions and hypoadiponectinemia may result in insulin resistance and DM. Although it has not been clarified whether hypoadiponectinemia absorbed in diabetic patients is genetic or is attributed to visceral fat accumulation, ADPN may play a crucial role in the development of DM, and high ADPN levels should protect the impairment of glucose metabolism, as demonstrated in the study of Pima Indians . Therefore, it is conceivable that, under normal and noninflammatory conditions, higher baseline levels of ADPN may in fact be beneficial and both a marker and mediator of decreased cardiovascular risk. However, in a high-risk population with either active vascular or myocardial remodeling (such as that which occurs in the acute coronary syndrome or chronic heart failure), there may be a counter-regulatory or a compensatory increase in ADPN levels. Alternatively, the increased levels may be because of resistance at the level of the ADPN receptor, a mechanism potentially akin to that seen in diabetics with elevated insulin levels. Thus, in such conditions, elevated ADPN levels may be a marker of either the underlying inflammatory state or of ADPN resistance . The possible mechanistic role of CRP in plaque deposition is highly complex, exerting proatherogenic effects in many cells involved in atherosclerosis. CRP may facilitate monocyte adhesion and transmigration into the vessel wall, a critical early step in the atherosclerotic process. Furthermore, M1 macrophage polarization, catalyzed by CRP, is a proinflammatory trigger in plaque deposition, leading to macrophage infiltration of both adipose tissue and atherosclerotic lesions . Beyond its role in triggering immunity in plaque deposition, in-vitro studies have also shown an association among CRP, inhibition of endothelial nitric oxide synthase, and impaired vasoreactivity. An isoform of CRP, monomeric CRP, is stimulated by platelet activation and has prothrombotic and inflammatory properties of its own . Monomeric CRP has also been found in plaques, particularly in regions of monocyte-mediated inflammatory activity, and within lipid microdomains of endothelial cells. In humans, treatment with statin therapy reduces levels of both LDL-C and CRP, and concurrently there is a reduction in the number of cardiovascular events . The 2010 American Heart Association guidelines are the most favorable, giving a class IIa designation for measurement of hsCRP in asymptomatic individuals .
| Conclusion|| |
ADPN and hsCRP are markers of poor prognosis in patients with CAD.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]