C-Reactive Protein and Other Circulating Markers of Inflammation in the Prediction of Coronary Heart Disease

Danesh, John; Wheeler, Jeremy G; Hirschfield, Gideon M.; Eda, Shinichi; Eiríksdóttir, Guðný; Rumley, Ann; Lowe, G. D. O.; Pepys, Mark B.; Gudnason, Vilmundur

doi:10.1056/nejmoa032804

Cited by 2,548 publications

(1,091 citation statements)

References 36 publications

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“…The protective role of statin in pig coronary atherosclerosis may come about via some pleiotropic mechanism rather than via its lipid‐lowering effect. Inflammation plays a crucial role in atherogenesis,13, 30 and the inflammatory biomarker CRP independently predicts vascular events and has been shown to be a stronger predictor of coronary heart disease than is LDL‐C 31, 32, 33. The serum CRP concentration was significantly increased in our LDLR −/− pigs after 3 months of being fed the HCHF diet.…”

Section: Discussionmentioning

confidence: 67%

Development of Human‐Like Advanced Coronary Plaques in Low‐Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques

Fuchimoto

Sudo

et al. 2016

JAHA

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BackgroundAlthough clinical trials have proved that statin can be used prophylactically against cardiovascular events, the direct effects of statin on plaque development are not well understood. We generated low‐density lipoprotein receptor knockout (LDLR −/−) pigs to study the effects of early statin administration on development of atherosclerotic plaques, especially advanced plaques.Methods and Results LDLR −/− pigs were generated by targeted deletion of exon 4 of the LDLR gene. Given a standard chow diet, LDLR −/− pigs showed atherosclerotic lesions starting at 6 months of age. When 3‐month‐old LDLR −/− pigs were fed a high‐cholesterol, high‐fat (HCHF) diet for 4 months (HCHF group), human‐like advanced coronary plaques developed. We also fed 3‐month‐old LDLR −/− pigs an HCHF diet with pitavastatin for 4 months (Statin Prophylaxis Group). Although serum cholesterol concentrations did not differ significantly between the 2 groups, intravascular ultrasound revealed 52% reduced plaque volume in statin‐treated pigs. Pathological examination revealed most lesions (87%) in the statin prophylaxis group were early‐stage lesions, versus 45% in the HCHF diet group (P<0.01). Thin‐cap fibroatheroma characterized 40% of the plaques in the HCHF diet group versus 8% in the statin prophylaxis group (P<0.01), intraplaque hemorrhage characterized 11% versus 1% (P<0.01), and calcification characterized 22% versus 1% (P<0.01).ConclusionsResults of our large animal experiment support statin prophylaxis before the occurrence of atherosclerosis. Early statin treatment appears to retard development of coronary artery atherosclerosis and ensure lesion stability. In addition, the LDLR −/− pigs we developed represent a large animal model of human‐like advanced coronary plaque suitable for translational research.

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Section: Discussionmentioning

confidence: 67%

Development of Human‐Like Advanced Coronary Plaques in Low‐Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques

Fuchimoto

Sudo

et al. 2016

JAHA

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“…Previous studies linking CRP levels to CHD were performed largely in populations with a lower prevalence of obesity than that of the current US population 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32. In the 2 largest published studies of CRP and CHD disease,25, 27 the mean body mass index (in kg/m 2 ) of participants ranged from 25 to 26, lower than the recently reported mean of 28.7 in US adults,33 indicating the clinical need for data regarding CRP in obese populations. The Strong Heart Study examined the relationship between CRP levels and CHD in an obese population with a mean body mass index >30 34.…”

Section: Discussionmentioning

confidence: 99%

C‐Reactive Protein Identifies Low‐Risk Metabolically Healthy Obese Persons: The European Prospective Investigation of Cancer–Norfolk Prospective Population Study

Wijk

Boekholdt

Arsenault

et al. 2016

JAHA

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BackgroundConflicting data exist about the cardiovascular risk of metabolically healthy obese persons. The prognostic value of C‐reactive protein (CRP) in this intriguing group is unknown. We assessed the association between CRP levels and the risk of coronary heart disease (CHD) in metabolically healthy persons with abdominal obesity.Methods and ResultsIn the European Prospective Investigation of Cancer–Norfolk prospective cohort, CRP levels and information on metabolic syndrome criteria were available for 7279 participants, of whom 825 (11%) developed CHD during a follow‐up period of 10.9±1.8 years. There was a trend toward a higher multivariable‐adjusted hazard ratio for CHD in metabolically healthy obese participants with CRP levels >2 mg/L compared with <2 mg/L (hazard ratio 1.59, 95% CI 0.97–2.62, P=0.066). Metabolically unhealthy obese participants had significantly higher CHD risk compared with metabolically healthy obese participants with CRP levels <2 mg/L (hazard ratio 1.88, 95% CI 1.20–2.94, P=0.006). Most important, we found that the risk of CHD among metabolically healthy obese persons with CRP levels <2 mg/L was comparable to that of metabolically healthy nonobese persons (hazard ratio 0.91, 95% CI 0.60–1.39, P=0.674).ConclusionsAmong metabolically healthy obese persons, low CRP levels were associated with a CHD risk comparable to that of metabolically healthy nonobese persons. CRP appears to be an easy and widely available method for identifying a low‐risk subpopulation among metabolically healthy obese persons.

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“…Most epidemiological studies have reported a moderate dose‐responsive relationship between CRP and clinically relevant CVD outcomes after adjusting for TRFs. Increase in relative risk estimates for CVD ranges from 1.45‐ to ≈2‐fold when comparing the highest with the lowest CRP tertile 44. This is comparable to the effect of TRFs, such as blood cholesterol and blood pressure 44.…”

Section: Discussionmentioning

confidence: 82%

“…Increase in relative risk estimates for CVD ranges from 1.45‐ to ≈2‐fold when comparing the highest with the lowest CRP tertile 44. This is comparable to the effect of TRFs, such as blood cholesterol and blood pressure 44. A meta‐analysis comprising individual participant records from 54 long‐term prospective studies3 reported 1.37 (95% CI, 1.27–1.48) relative risk increase for coronary heart disease and 1.27 (95% CI, 1.15– 1.40) relative risk increase for IS per SD increase in log‐transformed CRP after adjustment for TRFs.…”

Section: Discussionmentioning

confidence: 99%

Joint Effect of Carotid Plaque and C‐Reactive Protein on First‐Ever Ischemic Stroke and Myocardial Infarction?

Eltoft

Arntzen

Wilsgaard

et al. 2018

JAHA

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BackgroundThe joint effect of atherosclerosis and CRP (C‐reactive protein) on risk of ischemic stroke (IS) and myocardial infarction (MI) has been sparsely studied. The aim of this study was to explore whether CRP mediates the risk of events in subjects with prevalent carotid plaque, examine synergism, and test whether CRP and carotid plaque add to risk prediction beyond traditional risk factors.Methods and Results CRP and carotid total plaque area (TPA) were measured in 10 109 participants in the Tromsø Study from 1994 to 2008. Incident IS (n=671) and MI (n=1079) were registered until December 31, 2013. We calculated hazard ratios (HRs) of MI and IS according to categories of CRP (<1, 1–3, and >3 mg/L) and plaque status (no plaque and TPA below and above median) in Cox proportional hazard models with time‐varying covariates. Multivariable‐adjusted CRP >3 versus <1 mg/L was associated with risk of IS (HR, 1.84; 95% confidence interval, 1.49–2.26) and MI (HR, 1.46; 95% confidence interval, 1.23–1.73). TPA above median versus no plaque was associated with risk for IS (HR, 1.65; 95% confidence interval, 1.36–2.01) and MI (HR, 1.64; 95% confidence interval, 1.41–1.92). In participants with plaque, adjustment for CRP minimally attenuated the risk estimates. The highest incidence rates for MI and IS were seen in the group with both CRP >3 mg/L and TPA is above the median. TPA and CRP combined added to risk prediction beyond traditional risk factors.ConclusionsThe simultaneous presence of subclinical atherosclerosis and elevated CRP was associated with increased risk of IS and MI. The combined assessment of subclinical atherosclerosis and inflammatory biomarkers may improve cardiovascular disease risk stratification.

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C-Reactive Protein and Other Circulating Markers of Inflammation in the Prediction of Coronary Heart Disease

Abstract: C-reactive protein is a relatively moderate predictor of coronary heart disease. Recommendations regarding its use in predicting the likelihood of coronary heart disease may need to be reviewed.

Cited by 2,548 publications

References 36 publications

Development of Human‐Like Advanced Coronary Plaques in Low‐Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques

Development of Human‐Like Advanced Coronary Plaques in Low‐Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques

C‐Reactive Protein Identifies Low‐Risk Metabolically Healthy Obese Persons: The European Prospective Investigation of Cancer–Norfolk Prospective Population Study

Joint Effect of Carotid Plaque and C‐Reactive Protein on First‐Ever Ischemic Stroke and Myocardial Infarction?

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