Skip to main content

High-sensitivity C-reactive protein and low-density lipoprotein cholesterol association with incident of cardiovascular events: Isfahan cohort study



There are many studies on high-sensitivity C-reactive protein (hs-CRP) association with cardiovascular disease (CVD); however, just a few studies investigated whether the low-density lipoprotein cholesterol (LDL-C) could participate in hs-CRP prognostic strength. This study aimed to determine the alliance of hs-CRP and LDL-C in different concentrations in occurrence cardiovascular events in the Isfahan Cohort Study (ICS).


3277 participants aged 35 and above were included in the current analysis. We evaluated the association of elevated hs-CRP levels (≥ 3 mg/dL) and CVD events including myocardial infarction, ischemic heart disease, stroke, CVD, CVD mortality, and all-cause mortality in those with LDL-C ≥ or < 130 mg/dL Cox frailty models was used to determine possible interactions.


In both crude and fully adjusted models, there was no significant interaction between LDL-C and hs-CRP levels with the incidence of MI, stroke, CVD mortality, and all-cause death. Neither elevated LDL-C alone nor elevated CRP alone were associated with the risk of all cardiovascular events and all-cause death. However, participants with elevated concentrations of both hs-CRP and LDL-C had a greater risk of ischemic heart disease (IHD) (hazards ratio (HR) 1.44; 95% CI 1.03–2.02) and CVD (HR 1.36; 95% CI 1.01–1.83) than those with low LDL-C and hs-CRP.


These results indicate that despite a null association between elevated levels of CRP or LDL-C alone and CVD events, concurrent rise in LDL-C and hs-CRP levels is associated with higher risk of IHD and CVD.

Peer Review reports


Cardiovascular diseases (CVDs) are recognized globally as the first leading cause of death [1]. CVDs claimed the lives of 17.9 million individuals worldwide in 2019, accounting for 32% of all deaths [2]. About 31% of global deaths was attributed to CVDs in 2016 [3]. Iran was among the countries with the highest age-standardized CVD incidence with over 9000 cases per 100,000 people [4].

Various metabolic abnormalities play a crucial role in the pathogenesis of CVDs. The pathogenicity of these biochemical markers might differ from one population to another due to the differences in the ethnicity, genetic, dietary habits, environmental factors, and lifestyle variables. For instance, the Iranian population have a different lipid profile from other countries. To be more precise, the upper limits of reference values for total cholesterol (TC), triglyceride (TG), and low density lipoprotein-cholesterol (LDL-C) in Tehranian individuals are higher than most Asian countries and lower than most Western countries [5]. Therefore, it is necessary to examine the relevance of various biochemical markers in the pathogenesis of CVDs in each population separately.

In addition, vascular inflammation is an essential process in the pathophysiology of CVDs [6]. C-reactive protein (CRP), a reactant in the acute phase, is a participating factor in the systemic response to low-grade inflammation. As a direct participant in atherogenesis, CRP binds to ligands exposed to dead and damaged cells to release chemotactic factors, thereby increasing inflammatory cells' penetration [7]. Elevated high-sensitivity CRP (hs-CRP) has a prognostic association with the long‐term cardiovascular risk [8, 9]. CRP can selectively bound to LDL-C through calcium-dependent reaction and is present in atherosclerotic plaques [10, 11].

Although hs-CRP is an established risk determinant for CVDs [12], it is not clear whether lower hs-CRP concentrations can reduce cardiovascular risk independent of LDL-C. This question poses an argument, chiefly with individuals whose LDL-C levels are in normal range but still manifest high level of hs-CRP. In other words, these observations raise this question that whether LDL-C levels affect the interaction between hs-CRP and CVDs. Hence, in order to evaluate the role of hs-CRP in relation with LDL-C as a risk factor for CVDs, this study aimed to examine the association of hs-CRP with the risk of CVD in different LDL-C levels in the framework of the Isfahan Cohort Study (ICS), an ongoing prospective cohort study, with primary endpoints of CVD in Iran as a Middle East country.

Materials and methods

Study design and subjects

The ICS is an ongoing longitudinal cohort study established in 2001 and followed for 13 years until 2013. This study recruited 6504 participants (3168 men and 3336 women) aged 35 years and over from Isfahan (n = 2153), Arak (n = 3323) and Najafabad (n = 1028), three counties of central Iran, from 2nd January till 28th September of 2001. Sampling was done by stratified cluster random method in eligible individual including Iranian, mentally competent and not pregnant, not having inflammatory states like cancers, autoimmune disease, liver and kidney diseases. To apply stratified cluster random sampling, we stratified the subjects by their living district and selected participants from chosen clusters in each district. Interviews, laboratory measurements, and physical examinations were conducted at baseline and repeated in those without any CVD events every six years. The lifestyle factors including dietary intake, smoking and physical activity; medical history and medication use through face-to-face interviews; laboratory measurement like serum lipids, blood sugar and CRP; physical examinations were collected in 2001, 2007 and 2013. However, as hs-CRP missing data was high, we used data in 2001 and 2007 in our analysis. To identify major cardiovascular events, participants were followed up biannually. Details of study design, subjects’ recruitment and data collection methods have been described elsewhere [13].

Obtaining a written informed consent, demographic and socioeconomic status, lifestyle behaviors, all measurements and physical examination were collected at enrolment. Participants were followed every two years by telephone call and in cases of unsuccessful calls, home-interviews were done. The data also were collected at baseline survey every 6 years [14]. In the current study, we excluded subjects with a previous history of CVD (n = 181) As the hs-CRP missing data was high in 2013, we excluded this stage from the current analysis. Finally, 5432 amongst subjects in 2001 and 2007, 3277 and 3205 participants who had one and two, measurements, respectively. Therefore, we had a total of 6482 observations during 13 years of follow-up (Fig. 1). The study was approved by Ethics Committee of the Research Council of Isfahan Cardiovascular Research Center (ICRC), a WHO collaborating center in Isfahan, Iran in accordance with Declarations of Helsinki.

Fig. 1
figure 1

Flowchart of study design

Data collection

At baseline, information about demographic and socioeconomic status, lifestyle behaviors including dietary intakes, smoking status, physical activity, and medical history (e.g. the history of dyslipidemia, diabetes mellitus, hypertension, and medicine use) was collected using standard questionnaires through a 30-min home interview by trained staff [14, 15]. Anthropometric, blood pressure and laboratory measurements and physical examination were collected through participants’ attendance in the nearest health care clinic. Blood pressure was measured using calibrated mercury sphygmomanometers twice after five minutes resting, and the mean was calculated as individual’s blood pressure [16]. Height was measured using nonelastic tape without shoes to the nearest 0.5 cm, and weight was measured without shoes and with light clothing with a precision of 0.1 kg using a Seca scale. Individuals with systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg and/or undergoing anti-hypertensive therapy were identified as hypertensive [17]. Body mass index (BMI) assessment was performed by weight division (kg) by square height (m2). Subjects with BMI ≥ 30 kg/m2 were categorized as obese [18].

Biochemical measurements

Blood samples were gathered after 12 h fasting status and stored in laboratory of Isfahan Cardiovascular Research Institute at − 70 °C. Fasting blood glucose (FBG), serum total cholesterol (TC) and triglycerides (TG) were measured by the enzymatic method by a Hitachi auto-analyzer (Hamburg-Eppendorf Hamburg, Germany) using special kits (Immunodiagnostic, Frankfurt, Germany). High-density lipoprotein cholesterol (HDL-C) was determined enzymatically after precipitating other lipoproteins with dextran sulfate magnesium chloride [19]. The Friedewald formula was utilized to calculate LDL-C in individuals with TG < 400 mg/dL. However, direct measurement of LDL-C was performed with a turbidimetric method for those with TG ≥ 400 mg/dL [20]. In addition, apolipoprotein (apo) A and apo B were measured by photometric method [21]. Abnormal serum lipid profiles were defined based on the National Cholesterol Education Panel Adult Treatment Panel III (NCEP-ATP III) as diabetes mellitus was defined as FBG ≥ 126 mg/dL and/or taking hypoglycemic medications [22]. The participants with any of the TC ≥ 200 mg/dL, TG ≥ 150 mg/dL, LDL-C ≥ 130 mg/dL and/or HDL-C < 40 mg/dL for men and < 50 mg/dL for women were diagnosed with dyslipidemia [23]. Hs-CRP measurement was carried out by the Cobas e-411 auto analyzer immunoturbidimetric method (Roche Diagnostics International Ltd, Basel, Switzerland) [24]. Hs-CRP ≥ 3 mg/L has been indicated as a risk factor for CVD [25].

Ascertainment of CVD events

The follow up of participants continued until the occurrence of CVD events or their last successful interview mostly before 2013, whichever happened first.

Over the 13 years of follow-up, subjects or their families had six biannual telephone interviews. Trained nurses performed structured primary interviews with three main questions; ‘is he/she alive?’, ‘has he/she been hospitalized for any reason? Specifically focus on cardiovascular and cerebrovascular events. In the occurrence of death or hospitalization, the nurses obtained the date of the events, physician diagnosis and the hospital's name during the interviews. If death occurred out of hospital, death certificates were attained from the provincial mortality database and a trained expert nurse conducted verbal autopsy including medical history, signs and symptoms before death through secondary interview with surviving family members. In the case of hospitalization events, trained nurses obtained related documents about reported hospitalization events through medical records and hospital records.

The documents related to each event were evaluated by the specialists’ outcome adjudication panel consisted of four cardiologists and two neurologists [24]. In the present study, cardiovascular events were defined as myocardial infarction (MI), fatal and non-fatal stroke (which was defined as death from cerebrovascular disease), unstable angina and sudden cardiac death (SCD), using modified criteria of WHO Expert Committee[26] Our definition for MI was based on the presence of at least two of the following criteria: 1) typical chest pain lasting more than 30 min, 2) ST (an isoelectric segment on the EKG which represents the interval between repolarization and depolarization of ventricular) elevation > 0.1 mV in at least 2 adjacent electrocardiograph leads, and 3) an increase in serum level of cardiac biomarkers (including creatine kinase (CK), creatine kinase-myoglobin binding (CK-MB), CK-MB mass (CK-MBm), or troponin (cTn). The order of diagnostic value is cTn > CK-MBm > CK-MB > CK [26]. The definition of UA required typical chest discomfort lasting more than 20 min within the 24 h preceding hospitalization and representing a change in the usual pattern of angina or pain: occurring with a crescendo pattern, being severe and described as a frank pain (REF). The diagnosis of UA might be new or be based on dynamic ST-segment or T-wave changes in at least two adjacent electrocardiogram leads [27]. Death within 1 h of onset, a witnessed cardiac arrest, or abrupt collapse not preceded by > 1 h of symptoms was considered as SCD. Moreover, the WHO stroke definition was used, that is, a rapid-onset focal neurological disorder persisting at least 24 h with probable vascular origin. We considered the first CVD events in our analysis.

Statistical analysis

For quantitative variables, the independent sample t-test were used and manifested by mean ± standard deviation (SD). Categorical variable was analyzed using the Chi-square test and Fisher exact test and reported as numbers (percentages). We first categorized participants into four groups according to their serum levels of LDL-C (< 130 or ≥ 130 mg/dL) and hs-CRP (< 3 or ≥ 3 mg/dL). frailty cox models were fitted to examine the association between LDL-C and hs-CRP and cardiovascular events, with time to events as the time variable and the LDL-C and hs-CRP as the independent variable.The HRs and 95% CI for cardiovascular events across quartiles of LDL-C and hs-CRP were estimated based on four modeling processes: (1) crude model; (2) adjusted model by age (continuous) and also sex (male/female); (3) additionally adjusted by education (illiterate, primary school, and guidance and high school), residence area (urban/rural), smoking status (never, ex-smoker, current smoker), daily physical activity (METS minutes per week), original Global Dietary Index(score); (4) further adjustment for BMI, diabetes mellitus (yes/no) and hypertension (yes/no). To determine the linear trend of relative risks across quartiles of LDL-C and hs-CRP, we considered the LDL-C and hs-CRP as a continuous variable in Cox frailty models since we used three measurements in 2001, 2007 and 2013. Statistical analyses were carried out using Stata software, version 14 and R software version 4. In this report, p-values less than 0.05 were found statistically significant.


Overall, participants' baseline characteristics showed that from 3,277 eligible subjects for including in this study, with mean age of 50.89 ± 11.0 years, 48% had LDL-C ≥ 130 mg/dL and 53.6% had hs-CRP ≥ 3 mg/dL (Table1). The frequency of male sex was higher in individuals with low LDL-C and hs-CRP ≥ 3 (P = 0.020) compared to those with hs-CRP < 3. Also the prevalence of diabetes mellitus (P = 0.008) was higher in those with high hs-CRP compared to those with hs-CRP < 3, in high LDL-C group. However, there were no significant differences in mean age, BMI, WC and blood pressure and also the frequency of educational level, current smoking, obesity, hypertension and dyslipidemia in different categories.

Table 1 Baseline characteristics of participants stratified by low-density lipoprotein and high-sensitivity C—reactive protein concentrations

Table 2 presents the mean comparison of metabolic risk factors in participants with low and high hs-CRP in both LDL-C categories. The means TC (P = 0.031), LDL-C (P = 0.007) and FBG (P = 0.033) were higher in individuals having concurrent elevated levels of hs-CRP and LDL-C. While there was no significant association between other metabolic indicators in both categories.

Table 2 Biochemical measurement participants stratified by low-density lipoprotein and high-sensitivity c-reactive protein concentrations

The median of follow-up was 11.25 years. During 33,121.8 person-years of follow-up, we documented 102 new cases of MI, 95 new case of stroke, 355 new cases of IHD, 450 total CVD events, 102 CVD mortality and 274 all-cause mortality. Crude and multivariable-adjusted HR (95% CIs) of CVD events for different LDL-C and hs-CRP levels are demonstrated in Table 3. There was no significant association between the interaction of LDL-C and hs-CRP levels and the incidence of MI, stroke, CVD mortality and all-cause death in both crude and fully adjusted models. Contrary, compared with reference category the risk of IHD significantly increased by 42%, 50% and 44% in individuals with both high LDL-C and hs-CRP levels in the crude and adjusted model 2 and 3 [(HR: 1.42; 95% CI 1.02–1.97) and (HR: 1.50; 95% CI 1.08–2.08) and (HR: 1.44; 95% CI 1.03–2.02, respectively). Likewise, CVD risk significantly increased among participants who had concurrent elevated levels of LDL-C and hs-CRP with the hazards of 1.43 (95% CI 1.06–1.92) in crude model, 1.43 (95% CI: 1.08–1.90) in model 2 and 1.36 (95%: 1.01, 1.83) in the fully adjusted model.

Table 3 Hazard ratio and confidence intervals of major cardiovascular events in high sensitivity C-reactive protein and low density lipoprotein cholesterol interaction


In this study, we aimed to investigate whether elevated levels of LDL-C can synergistically alter the predicting strength of hs-CRP for different CVDs. We found an increased risk of IHD and total major CVD events in participants with a higher level of both LDL-C and hs-CRP compared to those with normal levels of LDL-C and hs-CRP after adjustment for potential confounders. However, elevated levels of either LDL-C or hs-CRP were not related to the risk of any of the CVD events. In addition, there was no significant association between different high LDL-C and/or hs-CRP and MI, stroke, all-cause and CVD mortality.

The previous studies suggested that hs-CRP is a better indicator of future cardiovascular events than LDL-C [28]. Moreover, some studies demonstrated that low levels of both LDL-C and hs-CRP prevented the recurrent stroke and ischemic attack effectively [29]. CRP has been shown to accelerate atherosclerosis by directly increasing LDL-C transcytosis across endothelial cells [30].

Oxidized LDL-C (Ox-LDL-C) and L5 stimulate endothelial cells to produce CRP, which then increases endothelial cells lectin-like OX-LDL-C receptor-1 (LOX-1) expression. As a consequence, CRP imposes a positive feedback loop with LOX-1 which promotes the Ox-LDL-C or L5 uptake [31]. Ox-LDL-C, in turn, upregulates CRP expression through the IGF2 pathway in macrophages [32]. Hye Jin Yoo investigated the severity of vascular inflammation using 18F-FDG PET in healthy participants. Although the maximum target to background ratio level appeared to have the highest correlation in individuals with raised hs-CRP ≥ 2 mg/L and high LDL-C (≥ 130 mg/dL). Subjects with high hs-CRP and low LDL-C levels had a significantly higher maximum target to background ratio than those with low hs-CRP and low or high LDL-C levels [33]. It has been previously determined that the risk of CVD in Iranian populations was associated with the increasing hs-CRP [34]. Previous studies have shown the same line of results suggesting that the prognosis of CVD is more accurate by methods that examine inflammatory markers beside lipids [35].

In Penson et al.’s study, compared to subjects with low hs-CRP concentration but high concentration of LDL-C, individuals with concurrent high concentrations of hs-CRP and LDL-C showed a higher risk of CHD and stroke. However, in subjects with the same hs-CRP level and low LDL-C concentration, no significant association was observed. This study also demonstrated that the high level of hs-CRP in patients with low level of LDL-C was linked with the highest all-cause mortality risk, even more than that of in the patients with high levels of both hs-CRP and LDL-C [36].

In the You‐Cheol Hwang et al. ‘s study, cardiovascular events in patients with diabetes mellitus and recent acute coronary syndrome were correlated with elevated hs-CRP regardless of the LDL-C levels achieved by statins [37]. These findings contradict with those of ours, which might be attributable to non-lipid-lowering effects of statins on inflammation.

Our study demonstrated the same results shown in a recent study in which both LDL-C and hs-CRP continued to predict high cardiovascular risk in 4168 atherosclerosis patients [38]. In our study, the incidence of any cardiovascular events was independent of diabetes, BMI, hypertension, family history of CVD, lipid-lowering medications, and aspirin. Similarly, in Multi-Ethnic Study of Atherosclerosis with 10.3 years of follow-up, the risk of CHD was higher among participants with elevated hs-CRP and LDL-C who did not receive any lipid-lowering medication[39]. It is interesting to note that our findings revealed that adjustment for age and sex disappeared the significant association between concurrent elevated LDL-C and CRP and IHD and CVD. However, further control for demographic and lifestyle variables and also some medical conditions again lead to a higher risk for IHD and CVD in patients with both elevated LDL-C and CRP levels. On the other hand, although higher risk for IHD and CVD in patients with both elevated LDL-C and CRP levels is dependent on age and sex, demographic and lifestyle variables and medical conditions may mediate this association. This is possibly owing to the alterations in lifestyle and medical conditions by sex and age [40, 41].

In addition, Jinglin Mo et al. study showed that a lower LDL-C and hs-CRP level significantly reduced major adverse cardiac events risk [42]. Another study also demonstrated that targeting both LDL-C and hs-CRP by statin therapy in patients with acute coronary syndrome could further reduce the frequency of primary adverse cardiac events and the residual cardiovascular risk LDL-C single target [43].

Strengths and limitations

To the best of our knowledge, this is the first longitudinal study in the Middle East that has investigated the simultaneous changes in hs-CRP and LDL-C levels in predicting cardiovascular events using repeated measurements of biochemical biomarkers over time. The current study's strengths include a vast variety of variables for which we adjusted and thoroughly conducted CVD events adjudications, as well as an appropriate sample size and a sufficient time period for CVD events incidence follow-up. Nonetheless, there were some limitations in this study. In our study, as in previous cohort studies, we could not detect causality effect. Consequently, reverse causation bias could have occurred. Our study is also susceptible to unobserved variable bias and is unable to establish causality.


In conclusion, our results demonstrated that concurrent elevated levels of LDL-C and hs-CRP were associated with a greater risk of cardiovascular events, such as IHD and CVD. Therefore, it would be worthwhile taking into account both of these parameters in diagnosis, treatment and prevention approach towards cardiovascular events. In addition, further studies are required to validate the causative link of LDL-C with hs-CRP in CVDs.

Availability of data and materials

The datasets analyzed during the current study available from the corresponding author on reasonable request.


  1. Wang H, Naghavi M, Allen C, Barber RM, Bhutta ZA, Carter A, et al. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1459–544.

    Article  Google Scholar 

  2. WHO. Cardiovascular diseases (CVDs) 2021 [updated 11 June 2021. Available from:

  3. Sadeghi M, Simani M, Mohammadifard N, Talaei M, Roohafza H, Hassannejad R, et al. Longitudinal association of dietary fat intake with cardiovascular events in a prospective cohort study in Eastern Mediterranean region. Int J Food Sci Nutr. 2021;72:1–10.

    Article  Google Scholar 

  4. Roth GA, Johnson C, Abajobir A, Abd-Allah F, Abera SF, Abyu G, et al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J Am Coll Cardiol. 2017;70(1):1–25.

    Article  Google Scholar 

  5. Rahmani M, Jeddi S, Ghanbari M, Momenan AA, Azizi F. Ghasemi AJAoIm. Reference values for serum lipid profiles in Iranian adults: Tehran lipid and glucose study. 2019;22(1):24–31.

    Google Scholar 

  6. Golia E, Limongelli G, Natale F, Fimiani F, Maddaloni V, Pariggiano I, et al. Inflammation and cardiovascular disease: from pathogenesis to therapeutic target. Curr Atheroscler Rep. 2014;16(9):435.

    Article  Google Scholar 

  7. Casas J, Shah T, Hingorani A, Danesh J, Pepys M. C-reactive protein and coronary heart disease: a critical review. J Intern Med. 2008;264(4):295–314.

    Article  CAS  Google Scholar 

  8. Yousuf O, Mohanty BD, Martin SS, Joshi PH, Blaha MJ, Nasir K, et al. High-sensitivity C-reactive protein and cardiovascular disease: a resolute belief or an elusive link? J Am Coll Cardiol. 2013;62(5):397–408.

    Article  CAS  Google Scholar 

  9. Silva D, de Lacerda AP. High-sensitivity C-reactive protein as a biomarker of risk in coronary artery disease. Revista Portuguesa de Cardiologia (English Edition). 2012;31(11):733–45.

    Article  Google Scholar 

  10. Pepys M, Rowe I, Baltz M. C-reactive protein: binding to lipids and lipoproteins. Int Rev Exp Pathol. 1985;27:83–111.

    CAS  PubMed  Google Scholar 

  11. De Beer F, Soutar AK, Baltz ML, Trayner I, Feinstein A, Pepys M. Low density lipoprotein and very low density lipoprotein are selectively bound by aggregated C-reactive protein. J Exp Med. 1982;156(1):230–42.

    Article  Google Scholar 

  12. Clearfield MB. C-reactive protein: a new risk assessment tool for cardiovascular disease. J Am Osteopath Assoc. 2005;105(9):409–16.

    PubMed  Google Scholar 

  13. Sarrafzadegan N, Talaei M, Sadeghi M, Kelishadi R, Oveisgharan S, Mohammadifard N, et al. The Isfahan cohort study: rationale, methods and main findings. J Hum Hypertens. 2011;25(9):545–53.

    Article  CAS  Google Scholar 

  14. Sarrafzadegan N, Azadbakht L, Mohammadifard N, Esmaillzadeh A, Safavi M, Sajadi F, et al. Do lifestyle interventions affect dietary diversity score in the general population? Public Health Nutr. 2009;12(10):1924–30.

    Article  Google Scholar 

  15. Sarrafzadegan N, Kelishadi R, Sadri G, Malekafzali H, Pourmoghaddas M, Heidari K, et al. Outcomes of a comprehensive healthy lifestyle program on cardiometabolic risk factors in a developing country: the Isfahan Healthy Heart Program. Archives of Iranian medicine. 2013;16(1).

  16. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA. 2003;289(19):2560–71.

    Article  CAS  Google Scholar 

  17. Risk WGo, Pressure HB. An epidemiological approach to describing risk associated with blood pressure levels. Hypertension. 1985;7:641–51.

    Article  Google Scholar 

  18. Organization WH. Obesity: preventing and managing the global epidemic. 2000.

  19. Warnick G, Benderson J, Albers J. Dextran sulfate-Mg2+ precipitation procedure for quantitation of high-density-lipoprotein cholesterol. Clin Chem. 1982;28(6):1379–88.

    Article  CAS  Google Scholar 

  20. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18(6):499–502.

    Article  CAS  Google Scholar 

  21. Schaefer EJ, Lamon-Fava S, Cohn SD, Schaefer MM, Ordovas J, Castelli W, et al. Effects of age, gender, and menopausal status on plasma low density lipoprotein cholesterol and apolipoprotein B levels in the Framingham Offspring Study. J Lipid Res. 1994;35(5):779–92.

    Article  CAS  Google Scholar 

  22. Organization WH. WHO draft protocol and manual of operations population survey for cardiovascular disease risk factors in the Eastern Mediterranean Region. Alexandria: World Health Organization; 1995. p. 35.

    Google Scholar 

  23. Detection NCEPEPo, Adults ToHBCi. 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): The Program; 2002.

  24. Kazemi-Saleh D, Koosha P, Sadeghi M, Sarrafzadegan N, Karbasi-Afshar R, Boshtam M, et al. Predictive role of adiponectin and high-sensitivity C-reactive protein for prediction of cardiovascular event in an Iranian cohort study: the Isfahan Cohort study. ARYA Atherosclerosis. 2016;12(3):132.

    PubMed  PubMed Central  Google Scholar 

  25. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO III, 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(3):499.

    Article  Google Scholar 

  26. Luepker RV, Apple FS, Christenson RH, Crow RS, Fortmann SP, Goff D, et al. Case definitions for acute coronary heart disease in epidemiology and clinical research studies: a statement from the AHA Council on Epidemiology and Prevention; AHA Statistics Committee; World Heart Federation Council on Epidemiology and Prevention; the European Society of Cardiology Working Group on Epidemiology and Prevention; Centers for Disease Control and Prevention; and the National Heart. Lung, and Blood Institute. 2003;108(20):2543–9.

    Google Scholar 

  27. Members C, Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, et al. ACC/AHA guideline update for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction—2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). 2002;106(14):1893–900.

  28. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347(20):1557–65.

    Article  CAS  Google Scholar 

  29. Kitagawa K, Hosomi N, Nagai Y, Kagimura T, Ohtsuki T, Maruyama H, et al. Cumulative effects of LDL cholesterol and CRP levels on recurrent stroke and TIA. J Atheroscler Thromb. 2019;26(5):432–41.

    Article  CAS  Google Scholar 

  30. Bian F, Yang X, Zhou F, Wu PH, Xing S, Xu G, et al. C-reactive protein promotes atherosclerosis by increasing LDL transcytosis across endothelial cells. Br J Pharmacol. 2014;171(10):2671–84.

    Article  CAS  Google Scholar 

  31. Stancel N, Chen C-C, Ke L-Y, Chu C-S, Lu J, Sawamura T, et al. Interplay between CRP, atherogenic LDL, and LOX-1 and its potential role in the pathogenesis of atherosclerosis. Clin Chem. 2016;62(2):320–7.

    Article  CAS  Google Scholar 

  32. Kim HJ, Paul F, Lana-Peixoto MA, Tenembaum S, Asgari N, Palace J, et al. MRI characteristics of neuromyelitis optica spectrum disorder: an international update. Neurology. 2015;84(11):1165–73.

    Article  Google Scholar 

  33. Yoo HJ, Kim S, Park MS, Yang SJ, Kim TN, Seo JA, et al. Vascular inflammation stratified by C-reactive protein and low-density lipoprotein cholesterol levels: analysis with 18F-FDG PET. J Nucl Med. 2011;52(1):10–7.

    Article  CAS  Google Scholar 

  34. Koosha P, Roohafza H, Sarrafzadegan N, Vakhshoori M, Talaei M, Sheikhbahaei E, et al. High sensitivity C-reactive protein predictive value for cardiovascular disease: a nested case control from Isfahan cohort study (ICS). Glob Heart. 2020;15(1):3.

    Article  Google Scholar 

  35. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342(12):836–43.

    Article  CAS  Google Scholar 

  36. Penson PE, Long DL, Howard G, Toth PP, Muntner P, Howard VJ, et al. Associations between very low concentrations of low density lipoprotein cholesterol, high sensitivity C-reactive protein, and health outcomes in the Reasons for Geographical and Racial Differences in Stroke (REGARDS) study. Eur Heart J. 2018;39(40):3641–53.

    Article  CAS  Google Scholar 

  37. Hwang YC, Morrow DA, Cannon CP, Liu Y, Bergenstal R, Heller S, et al. High-sensitivity C-reactive protein, low-density lipoprotein cholesterol and cardiovascular outcomes in patients with type 2 diabetes in the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial. Diabetes Obes Metab. 2018;20(3):654–9.

    Article  CAS  Google Scholar 

  38. Ridker PM, MacFadyen JG, Glynn RJ, Bradwin G, Hasan AA, Rifai N. Comparison of interleukin-6, C-reactive protein, and low-density lipoprotein cholesterol as biomarkers of residual risk in contemporary practice: secondary analyses from the Cardiovascular Inflammation Reduction Trial. Eur Heart J. 2020;41(31):2952–61.

    Article  CAS  Google Scholar 

  39. Lin G-M, Liu K, Colangelo LA, Lakoski SG, Tracy RP, Greenland P. Low-density lipoprotein cholesterol concentrations and association of high-sensitivity C-reactive protein concentrations with incident coronary heart disease in the multi-ethnic study of atherosclerosis. Am J Epidemiol. 2016;183(1):46–52.

    Article  Google Scholar 

  40. Mosca L, Barrett-Connor E, Kass Wenger NJC. Sex/gender differences in cardiovascular disease prevention: what a difference a decade makes. 2011;124(19):2145–54.

    Google Scholar 

  41. Wang T, Zhao Z, Yu X, Zeng T, Xu M, Xu Y, et al. Age-specific modifiable risk factor profiles for cardiovascular disease and all-cause mortality: a nationwide, population-based, prospective cohort study. 2021;17:100277.

  42. Mo J, Chen Z, Xu J, Wang A, Meng X, Zhao X, et al. The impact of the cumulative burden of LDL-c and hs-CRP on cardiovascular risk: a prospective, population-based study. Aging (Albany NY). 2020;12(12):11990.

    Article  CAS  Google Scholar 

  43. Fang M, Qian Q, Zhao Z, Zhu L, Su J, Li X. High-sensitivity C-reactive protein combined with low-density lipoprotein cholesterol as the targets of statin therapy in patients with acute coronary syndrome. International heart journal. 2018:17–101.

Download references


We greatly appreciate the help from Mrs. Mansoureh Boshtam with her assistance in data collection. We would like to express our thanks to the staff of surveillance department that assisted us to find death records. The baseline survey was supported by grant number 31309304. The Isfahan Cardiovascular Research Center, affiliated to Isfahan University of Medical Sciences funded the biannual follow-ups.


The baseline survey was supported by grant number 31309304. The Isfahan Cardiovascular Research Center, affiliated to Isfahan University of Medical Sciences funded the biannual follow-ups.

Author information

Authors and Affiliations



NM, AN, and NS designed the research study; FH and HR conducted research; NS, MS and JN confirmed the events in event committee; SN analyzed data; and AN, NM and FH wrote the paper. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Noushin Mohammadifard.

Ethics declarations

Ethics approval and consent to participate

Ethics committee of the Research Council of Isfahan Cardiovascular Research Center (ICRC), a WHO collaborating center in Isfahan, Iran was approved the study. The written informed consent was obtained from all subjects and/or their legal guardian(s).

Consent for publication

Not applicable.


All methods were carried out in accordance with Declarations of Helsinki.

Competing of interests

The authors report no relationships that could be construed as a competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nafari, A., Mohammadifard, N., Haghighatdoost, F. et al. High-sensitivity C-reactive protein and low-density lipoprotein cholesterol association with incident of cardiovascular events: Isfahan cohort study. BMC Cardiovasc Disord 22, 241 (2022).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: