|Year : 2019 | Volume
| Issue : 2 | Page : 189-192
Lipoprotein(a) and high-sensitive C-reactive protein as risk factors of coronary heart disease
Debasis Debadatta Behera1, Bratati Singh2, Suresh Kumar Behera3, Subhashree Ray2, Kamal Lochan Das1
1 Department of Biochemistry, Hi-Tech Medical College and Hospital, Bhubaneswar, Odisha, India
2 Department of Biochemistry, IMS and SUM Hospital, Bhubaneswar, Odisha, India
3 Department of Cardiology, IMS and SUM Hospital, Bhubaneswar, Odisha, India
|Date of Web Publication||18-Jul-2019|
Debasis Debadatta Behera
Plot No. 940/3549, Behera Sahi, Nayapalli, Bhubaneswar - 751 012, Odisha
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Atherosclerotic process is considered to be the product of several influences, and there is no selective agent responsible for it. Around 50% of coronary heart disease (CHD) cases lack traditional risk factors such as hypertension, diabetes mellitus, smoking, dyslipidemia, and obesity in Indian subcontinent. Hence, nontraditional risk factors are increasingly used to determine patients at risk. The Aim of the Study: The study aimed to assess the nontraditional risk factors such as lipoprotein(a) (Lp[a]) and high-sensitivity C-reactive protein (Hs-CRP) as potential biomarkers in CHD patients and to correlate these factors with disease severity. Materials and Methods: This cross-sectional study was undertaken in 50 CHD patients and 50 healthy controls. Lp(a) and Hs-CRP along with other biochemical parameters were assessed in these patients. Results and Conclusion: Hypertriglyceridemia and hypertension were present in 74% and 62% of cases, respectively. Fasting blood sugar, triglyceride, and high-density lipoproteins were significantly altered in cases in comparison to control. Lp(a) (50.85 ± 23.42 mg/dl vs. 17.10 ± 5.18 mg/dl) and Hs-CRP (2.932 ± 0.605 vs. 0.379 ± 0.202 mg/dl) levels were raised significantly in cases when compared with the control (P < 0.001). A significant positive correlation was observed between Lp(a) and Hs-CRP. Hence, in addition to conventional parameters, the estimation of Lp(a) and Hs-CRP can prove to be a valuable tool in risk assessment of population and management of the disease.
Keywords: Atherosclerosis, coronary heart disease, high-sensitivity C-reactive protein, lipoprotein(a)
|How to cite this article:|
Behera DD, Singh B, Behera SK, Ray S, Das KL. Lipoprotein(a) and high-sensitive C-reactive protein as risk factors of coronary heart disease. J Nat Sc Biol Med 2019;10:189-92
|How to cite this URL:|
Behera DD, Singh B, Behera SK, Ray S, Das KL. Lipoprotein(a) and high-sensitive C-reactive protein as risk factors of coronary heart disease. J Nat Sc Biol Med [serial online] 2019 [cited 2019 Oct 19];10:189-92. Available from: http://www.jnsbm.org/text.asp?2019/10/2/189/262946
| Introduction|| |
The dawn of the 20th century witnessed the beginning of a global epidemic of coronary heart disease (CHD). It began its course in the US from the early 1920s, in the UK from 1930s, and in other parts of Europe from 1940s. This modern epidemic of CHD, as described by the World Health Organization, has not spared developing nations like India.
According to the Global Burden of Disease Report released on September 15, 2017, heart disease is the leading cause of death in India, killing 1.7 million Indians in 2016. According to this report, ischemic heart disease (IHD) is responsible for 53% more deaths in 2016 in comparisons to 2005. The projections of the report estimate that developing countries will account for 7.8 million of the 11.1 million deaths due to CHD in 2020.
Obstructive changes in coronary circulation by atheromatous plaque, building up along the inner walls of the arteries of the heart, causing impairment in the heart function is known as CHD. CHD is also known as coronary artery disease (CAD), atherosclerotic heart disease, or IHD. CHD manifests as angina pectoris, acute myocardial infarction, cardiac failure, and sudden death.
The etiology of CHD is multifactorial. It is the result of interaction between polygenic, lifestyle, and environmental factors. Hypertension and diabetes mellitus (DM) account for about 40% of all factors. Other risk factors are smoking, deranged lipid profile, obesity, and family history of CHD. Apart from these conventional factors, there are some emerging risk factors such as endothelin, lipoprotein(a) (Lp[a]), high-sensitivity C-reactive protein (Hs-CRP), homocysteine, prothrombotic, and proinflammatory factors which are considered to play a pivotal role in the pathogenesis of atherosclerosis.
Lp(a) is a novel biomarker which consists of a low-density lipoproteins (LDLs) particle with its apoB-100 component linked by a disulfide bridge to apolipoprotein(a) (apo[a]), a complex variable length protein that has sequence homology to plasminogen. Plasma Lp(a) concentrations vary depending on apo(a) isoform size. Many retrospective and cross-sectional studies suggest a positive association between Lp(a) and vascular risk.
CRP is the prototype acute-phase protein primarily synthesized in the liver and its release is stimulated by interleukin-6 (IL-6) and other pro-inflammatory cytokines. Hs-CRP has been shown to have prognostic value in patients with acute coronary syndromes; however, the most promising use of Hs-CRP has been in the primary prevention setting. Studies have shown that Hs-CRP is not only a marker of low-grade chronic systemic inflammation but also may be directly involved in atherosclerosis.
Lp(a) concentrations were closely correlated with Hs-CRP concentrations in CHD patients, suggesting that Lp(a) may also act as an acute-phase reactant.
The present study attempts to assess Lp(a) and Hs-CRP as emerging biomarkers and to correlate these markers with metabolic and biochemical profiles such as blood sugar and lipid profile in CHD patients.
| Materials and Methods|| |
This study was conducted in the Department of Biochemistry in collaboration with the Department of Cardiology, Hi-Tech Medical College and Hospital, Bhubaneswar, from December 2016 to November 2017. The study protocol was approved by the Institutional Ethical Committee.
The study group was selected from patients attending the cardiology outpatient department and consists of 50 CHD patients and 50 age-matched healthy controls.
All newly diagnosed CHD patients within the age group of 35–75 years are taken as cases based on the clinical evidence, electrocardiography (ECG), treadmill test, and elevated cardiac enzymes (cTnT, CK-MB). We have included only those patients who undergo angiography subsequently to assess the severity of vessels involved and exclude cases not forming part of CHD. The control group consists of persons with no clinical and ECG evidence of CHD and negative history of the past event of CHD or stroke, DM, hypertension, smoking, dyslipidemia, and family history of CHD.
We have excluded patients suffering from any type of cancer, history of cerebrovascular event within last 8 weeks, patients on hormone replacement therapy, major hematological/hepatic/renal disorder, and HIV/AIDS patients.
Venous blood was collected from the participants under sterile conditions after overnight fasting. Blood sample was collected in fluoride vial for blood sugar and plain vial for routine biochemical investigations and lipid profile. Specific tests for Hs-CRP and Lp(a) (particle-enhanced immunoturbidimetric assay) were also performed. Human Lp(a) agglutinates with latex particles coated with anti-Lp(a) antibodies, whereas human CRP agglutinates with latex particles coated with monoclonal anti-CRP antibodies. The precipitates obtained in both methods were determined turbidimetrically at 552 nm.
All the tests were performed in Autoanalyzer COBAS Integra 400 plus using the commercially available kits. The results obtained were analyzed by Student's t-test and Pearson correlation coefficient (IBM SPSS Statistics for windows, version 20.0, IBM Corp., Armonk, NY, USA).
| Results|| |
In the present study, majority (20 out of 50, 40%) were in the age group of 51–60 years with a male predominance of 68%.
Among the traditional risk factors hypertriglyceridemia and hypertension were present in 74% and 62% of the cases, respectively, followed by DM and smoking [Figure 1].
We observed a significant increase (P < 0.001) in blood sugar level in cases when compared to control. Triglyceride and high-density lipoprotein (HDL) components of lipid profile show a significant difference between cases and control [Table 1].
Plasma Lp(a) values were 50.85 ± 23.42 mg/dl in CHD cases and 17.10 ± 5.18 mg/dl in controls which showed a statistically significant rise (P < 0.001) in cases in comparison to controls. Serum Hs-CRP values were 2.932 ± 0.605 mg/dl in CHD cases and 0.379 ± 0.202 mg/dl in controls which showed a significant rise (P < 0.0001) between both the groups [Table 2].
|Table 2: Plasma lipoprotein(a) and serum high-sensitivity C-reactive protein level in study and control group|
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Correlation (positive) between plasma Lp(a) and serum Hs-CRP was significant (P < 0.001 and r = 0.671) in our patient population [Figure 2].
|Figure 2: Correlation of Lp(a) and Hs-CRP. Lp(a): Lipoprotein(a), Hs-CRP: High-sensitivity C-reactive protein|
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Positive correlation between LDL-cholesterol (LDL-C) and serum Lp(a) was significant (P < 0.05, r = 0.45) in our study group, but no significant correlation was found between LDL-C and serum Hs-CRP [Table 3].
|Table 3: Correlation between low-density lipoprotein cholesterol and lipoprotein(a) and high-sensitivity C-reactive protein|
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| Discussion|| |
CHD is a major cause of mortality and morbidity around the world. CHD epidemic in India has entered into an epidemiological transition phase. At present, 25% deaths among Indians are attributable to CAD. Surprisingly, majority of CAD population in India present with malignant form and commonly manifest at earlier age, usually a decade earlier (around 45–50 years).
There are several established metabolic and lifestyle risk factors for CAD. The fact that traditional risk factors have failed to explain the excess risk of CAD has raised the possibility of a genetic (ethnic) susceptibility to CAD among Asian Indians.
There is usually 5–10 years earlier onset of CAD in Indians in comparison to other population. Our study population consisted of 68% males and 32% females. The underrecognition of heart disease and difference in clinical presentation in women led to lower representation of women in clinical trials. As seen in many observational studies, menopausal women have higher risk of CHD. The estrogens deprivation may be related to accelerating the risk of atherosclerotic process after menopause.
The distribution of risk factors among the study group shows that hypertension (62%) and hypertriglyceridemia (74%) are the most prevalent risk factors in CAD patients [Figure 1].
Hypertension is associated with marked increase in the risk of CAD and prevalence of hypertension was significantly higher among those with CHD. Hypertension accelerates the atherosclerotic process, especially if hyperlipidemia is also present and contributes importantly to CHD. Many investigators feel that systolic blood pressure is a better predictor of CHD than the diastolic. A high triglyceride level was observed in patients with myocardial infarction and it is also suggested that hypertriglyceridemia predisposes to thrombosis by increasing factor VII coagulant activity.,
In some study, it is observed that low-HDL and high-LDL/HDL ratio has been associated with increased risk of CAD. Low levels of HDL-C are reported to increase the risk of CHD even when total cholesterol is not elevated. This may be an incidental finding or may be due to the use of lipid-lowering drugs in some patients of the study group shifting the mean to the lower side. More ever, the total cholesterol in Indians has been observed to be lower than people in the Western countries.
Lp(a) is emerging as a strong risk marker for CAD. Lp(a) levels above 25 mg/dl are commonly accepted cutoff points for categorizing high plasma Lp(a), in which the risk of CAD increases by about three-fold than those with low plasma levels. Lp(a) is suggested to be an independent risk factor for CAD and it also appears to be related to the severity of CAD as assessed angiographically. Studies done in the Indian population have higher Lp(a) levels compared to other ethnic groups suggestive of inherently high Lp(a) levels in this genetic pool. In a study conducted in the South Indian population, it is observed that Lp(a) levels correlate well with the extent and severity of atherosclerosis. Thus, the estimation of Lp(a) can prove to be a valuable tool in the risk assessment of CAD population.
Inflammation which plays an important role in the development of CAD is likely an important component of changes in vessel wall morphology. It has been proved that inflammation of arteries results in an increased production of cytokines, especially IL-6 and activation of clotting factors, increased platelet aggregation, and smooth muscle cell proliferation. It was found that elevated Hs-CRP was significantly correlated with electrocardiogram defined CAD. Levels of Hs-CRP of <1, 1–3, and ≥3 mg/dl are used to represent low, moderate, and high vascular risk, respectively. Chronic inflammation characterized by increased CRP concentrations strongly predicts cardiovascular disease and acute coronary events in patients with CHD.
Furthermore, Lp(a) may act an acute-phase reactant, and thus, possibly contribute to acute cardiac events. There is a significant relationship between Lp(a) and Hs-CRP and other inflammatory factors, such as fibrinogen, IL-6, complement 3 and 4, and soluble cellular adhesion molecules, which suggests that Lp(a) may be involved in atherogenesis through an inflammatory mechanism.
Significant correlation between Lp(a) and Hs-CRP shows inducibility of CRP by Lp(a) in atherosclerosis.
Since Lp(a) and LDL-C have a common synthetic pathway, Lp(a) levels were higher in patients with LDL-C >130 mg/dl than patients having LDL-C <130 mg/dl (P < 0.001).
| Conclusion|| |
CHD has been a subject of research for decades. Its alarming rise in recent years in the Indian population has brought the debate to identify factors which can be added to conventional risk factors for proper timely diagnose of this multifactorial disease. Discovery of its association with Lp(a), Hs-CRP, dyslipidemia, hypertension, and DM have now become emerging areas of concern.
The novel biomarkers Lp(a) and Hs-CRP have been found to be significantly higher in this study group. However, it is recommended that studies from different areas involving larger sample size are required to confirm the findings of the present study. Moreover, interventional studies are needed to determine whether decreasing the concentration of these biomarkers indeed reduce the risk of CAD.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
GBD 2016 Causes of Death Collaborators. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: A systematic analysis for the global burden of disease study 2016. Lancet 2017;390:1151-210.
Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al.
Heart disease and stroke statistics-2017 update: A report from the American Heart Association. Circulation 2017;135:e146-603.
Gupta R, Gupta VP. Meta-analysis of coronary heart disease prevalence in India. Indian Heart J 1996;48:241-5.
Nayak SR, Jena I, Mishra PK, Behera S, Ray S. Evaluation of serum nitric oxide in essential hypertension and its correlation with severity of disease. Asian J Pharm Clin Res 2016;9:179-82.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult treatment panel III). JAMA 2001;285:2486-97.
Ridker PM, Brown NJ, Vaughan DE, Harrison DG, Mehta JL. Established and emerging plasma biomarkers in the prediction of first atherothrombotic events. Circulation 2004;109:IV6-19.
Hackam DG, Anand SS. Emerging risk factors for atherosclerotic vascular disease: A critical review of the evidence. JAMA 2003;290:932-40.
Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: An 8-year follow-up of 14 719 initially healthy American women. Circulation 2003;107:391-7.
Liu L, Zhao SP, Cheng YC, Li YL. Xuezhikang decreases serum lipoprotein(a) and C-reactive protein concentrations in patients with coronary heart disease. Clin Chem 2003;49:1347-52.
Park K. Epidemiology of chronic non communicable diseases and conditions. Preventive Soc Med 2005;18:287-8.
Mohan V, Deepa R, Haranath SP, Premalatha G, Rema M, Sastry NG, et al.
Lipoprotein(a) is an independent risk factor for coronary artery disease in NIDDM patients in South India. Diabetes Care 1998;21:1819-23.
Enas E, Senthilkumar A. Coronary Artery Disease in Asian Indians: An Update and Review. Int J Cardiol 2001;1:1-22.
Gupta R, Gupta VP. Hypertension epidemiology in India: Lessons from Jaipur heart watch. Curr Sci 2009;97:349-55.
Bulatao RA, Stephens PW. Global Estimates and Projection of Mortality by Cause. Pre Working Paper 1007. Washington, DC: Population, Health & Nutrition Department, World Bank; 1992.
Singh BK, Mehta JL. Management of dyslipidemia in the primary prevention of coronary heart disease. Curr Opin Cardiol 2002;17:503-11.
Carew JA, Basso F, Miller GJ, Hawe E, Jackson AA, Humphries SE, et al.
A functional haplotype in the 5' flanking region of the factor VII gene is associated with an increased risk of coronary heart disease. J Thromb Haemost 2003;1:2179-85.
Ramachandran A, Sathyamurthy I, Snehalatha C, Satyavani K, Sivasankari S, Misra J, et al.
Risk variables for coronary artery disease in Asian Indians. Am J Cardiol 2001;87:267-71.
Robbins DC, Welty TK, Wang WY, Lee ET, Howard BV. Plasma lipids and lipoprotein concentrations among American Indians: Comparison with the US population. Curr Opin Lipidol 1996;7:188-95.
Maranhäo R, Arie S, Vinagre CG, Guimarães JB, Strunz C, Pileggi F, et al.
Lipoprotein(a) plasma levels in normal subjects and patients with coronary disease confirmed by coronary cineangiography. Arq Bras Cardiol 1991;56:121-5.
Hearn JA, DeMaio SJ Jr., Roubin GS, Hammarstrom M, Sgoutas D. Predictive value of lipoprotein(a) and other serum lipoproteins in the angiographic diagnosis of coronary artery disease. Am J Cardiol 1990;66:1176-80.
Enas EA, Dhawan J, Petkar S. Coronary artery disease in Asian Indians: Lessons learnt and the role of lipoprotein(a). Indian Heart J 1997;49:25-34.
Geethanjali FS, Jose VJ, Kanagasabapathy AS. Lipoprotein(a) phenotypes in South Indian patients with coronary artery disease. Indian Heart J 2002;54:50-3.
Vahdat K, Jafari SM, Pazoki R, Nabipour I. Concurrent increased high sensitivity C-reactive protein and chronic infections are associated with coronary artery disease: A population-based study. Indian J Med Sci 2007;61:135-43.
] [Full text]
Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd
, Criqui M, et al.
Markers of inflammation and cardiovascular disease: Application to clinical and public health practice: A statement for healthcare professionals from the centers for disease control and prevention and the American Heart Association. Circulation 2003;107:499-511.
Nagy E, Osan A, Fekete T, Kosa K, Pota S, Vita I, et al
. Clinical study regarding the relationship between Lipoprotein(a) and C reactive protein serum levels in peripheral arterial disease. Famracea 2009;57:43-51.
Rajasekhar D, Saibaba KS, Srinivasa Rao PV, Latheef SA, Subramanyam G. Lipoprotein(a): Better assessor of coronary heart disease risk in South Indian population. Indian J Clin Biochem 2004;19:53-9.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]