Association of Very Highly Elevated C-Reactive Protein Concentration with Cardiovascular Events and All-Cause Mortality

Abstract Aims In epidemiologic cohorts initiated >30 years ago, inflammatory biomarkers, such as interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) were shown to independently predict future cardiovascular events with a magnitude of effect comparable to that of low-density lipoprotein cholesterol (LDLC). Whether aggressive contemporary therapy for atherosclerosis has altered these relationships is unknown yet has major implications for future drug development. Methods and results Interleukin-6, hsCRP, and LDLC were measured at baseline in up to 4168 North American patients enrolled in the contemporary Cardiovascular Inflammation Reduction Trial with prior myocardial infarction or multivessel coronary disease who additionally had diabetes or metabolic syndrome and were followed for a period of up to 5 years for incident major recurrent cardiovascular events and all-cause mortality. Three-quarters of the cohort were previously revascularized and the great majority was taking statins, angiotensin blocking agents, beta-blockers, and antithrombotic agents. Participants were randomly allocated to low-dose methotrexate 15 mg weekly or to placebo. Randomized use of methotrexate had no effect on event rates nor plasma levels of IL-6, hsCRP, or LDL over time. Yet, baseline levels of IL-6, hsCRP, and LDLC were all predictors of major recurrent cardiovascular events; adjusted hazard ratios [HR; 95% confidence interval (CI)] for the lowest to highest baseline quartiles of IL-6 were 1.0 (referent), 1.66 (1.18–2.35), 1.92 (1.36–2.70), and 2.11 (1.49–2.99; P < 0.0001), while adjusted HRs for increasing quartiles of hsCRP were 1.0 (referent), 1.28 (0.92–1.79), 1.73 (1.25–2.38), and 1.79 (1.28–2.50; P < 0.0001) and adjusted HRs for increasing quartiles of LDLC were 1.0 (referent), 1.12 (0.78–1.62), 1.25 (0.87–1.79), and 2.38 (1.72–3.30; P < 0.0001). Effect estimates were not statistically different in these analyses for comparisons between IL-6, hsCRP, or LDLC, although IL-6 was the strongest predictor of all-cause mortality. The highest absolute risks were observed among those with elevated levels of both cholesterol and inflammation [HR 6.4 (95% CI 2.9–14.1) for those in the top quartiles of baseline IL-6 and LDLC, HR 4.9 (95% CI 2.6–9.4) for those in the top quartiles of baseline hsCRP and LDLC, both P < 0.0001]. Conclusion Despite aggressive contemporary secondary prevention efforts, the relationships between inflammation, cholesterol, and cardiovascular risk are largely unchanged from those described two decades ago. These data are consistent with the hypothesis that future treatments for atherosclerosis may require a combination of inflammation inhibition and additional cholesterol reduction. Clinical trial ClinicalTrials.gov NCT01594333.

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High homocysteine and low folate plasma concentrations are associated with cardiovascular events but not bleeding during warfarin treatment

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2016-0092 ◽

2016 ◽

Vol 54 (12) ◽

Cited By ~ 1

Author(s):

Marcus Lind ◽

Jan-Håkan Jansson ◽

Torbjörn K. Nilsson ◽

Lars Johansson

Keyword(s):

Major Bleeding ◽

Cardiovascular Events ◽

Plasma Concentrations ◽

Plasma Homocysteine ◽

C Reactive Protein ◽

Reactive Protein ◽

Increased Risk ◽

Warfarin Treatment ◽

All Cause Mortality ◽

Total Homocysteine

AbstractBackground:Previous studies have shown that homocysteine and folate levels in plasma are associated with risk for cardiovascular events and mortality. The aim of this study was to investigate if plasma concentrations of total homocysteine and folate can predict major bleeding, cardiovascular events, and all-cause mortality in patients being treated with warfarin.Methods:In a longitudinal cohort study, 719 patients who were taking warfarin were followed for 3001 treatment years. The following were recorded and classified: major bleeding; cardiovascular events including stroke, arterial emboli, and myocardial infarction (MI); and mortality. Blood samples collected at baseline were analysed for plasma homocysteine and folate levels.Results:After adjustment for age, C-reactive protein, and creatinine, high homocysteine levels were associated with cardiovascular events [hazard ratio (HR) 1.23 per standard deviation (SD); 95% confidence interval (CI): 1.03–1.47], MI (HR 1.38 per SD; 95% CI: 1.03–1.85), and all-cause mortality (HR 1.41 per SD; 95% CI: 1.19–1.68). The highest tertile of folate compared to the lowest tertile was associated with decreased risk for both cardiovascular events (HR 0.64; 95% CI: 0.43–0.91) and MI (HR 0.45; 95% CI: 0.21–0.97). There was no association between major bleeding and homocysteine or folate levels.Conclusions:In patients receiving warfarin treatment, high homocysteine and low folate plasma concentrations are associated with increased risk for cardiovascular events but not major bleeding. For homocysteine levels, there is also an association with all-cause mortality.

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Joint Effects Of Serum 25(OH) D And C-Reactive Protein Concentration On Coronary Heart Disease And All-Cause Mortality In Patients With Diabetes Mellitus

Journal of Heart Health ◽

10.16966/2379-769x.105 ◽

2015 ◽

Vol 1 (1) ◽

Author(s):

Longjian Liu

Keyword(s):

Diabetes Mellitus ◽

Coronary Heart Disease ◽

Heart Disease ◽

Protein Concentration ◽

C Reactive Protein ◽

Joint Effects ◽

Reactive Protein ◽

All Cause Mortality ◽

Patients With Diabetes

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25-Hydroxycholecalciferol Concentration Is Associated with Protein Loss and Serum Albumin Level during the Acute Phase of Burn Injury

Nutrients ◽

10.3390/nu12092780 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2780

Author(s):

Andrzej Krajewski ◽

Krzysztof Piorun ◽

Dominika Maciejewska-Markiewicz ◽

Marta Markowska ◽

Karolina Skonieczna-Żydecka ◽

...

Keyword(s):

Vitamin D ◽

Protein Concentration ◽

Serum Albumin Level ◽

Burn Injury ◽

Albumin Level ◽

Albumin Concentration ◽

Transaminase Activity ◽

C Reactive Protein ◽

Reactive Protein ◽

25 Hydroxycholecalciferol

Background: Burned patients have an increased need for vitamin D supply related to the maintenance of calcium–phosphate homeostasis and the regulation of cell proliferation/differentiation. This study aimed to analyze the concentration of 25-hydroxycholecalciferol and its relationship with severe condition after burn injury. Methods: 126 patients were enrolled in the study. Patients were qualified due to thermal burns—over 10% of total body surface area. On the day of admission, the following parameters were assessed: 25-hydroxycholecalciferol concentration, total protein concentration, albumin concentration, aspartate transaminase activity, alanine transaminase activity, albumin concentration, creatinine concentration, c-reactive protein concentration, procalcitonin concentration, and interleukin-6 concentration. Results: Almost all patients (92%) in the study group had an improper level of vitamin D (<30 ng/mL), with the average of 11.6 ± 10.7 ng/mL; 17.5% of patients had levels of vitamin D below the limit of determination—under 3 ng/mL. The study showed that there are several factors which correlated with vitamin D concentration during the acute phase of burn injury, including: total protein (r = 0.42, p < 0.01), albumin, (r = 0.62, p < 0.01), percentage of body burns (r = 0.36, p < 0.05), aspartate aminotransferase (r = 0.21, p < 0.05), and c-reactive protein (r = 0.22, p < 0.05). We did not find any significant correlation between vitamin D concentration and body mass index. Conclusions: The burn injury has an enormous impact on the metabolism and the risk factors of the deficiency for the general population (BMI) have an effect on burned patients. Our study showed that concentration of 25-hydroxycholecalciferol is strongly correlated with serum albumin level, even more than total burn surface area and burn degrees as expected. We suspect that increased supplementation of vitamin D should be based on albumin level and last until albumin levels are balanced.

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Evaluation of serum C-reactive protein concentration as a marker of impending parturition and correlation with progesterone profile in peri-partum bitches

Animal Reproduction Science ◽

10.1016/j.anireprosci.2019.03.011 ◽

2019 ◽

Vol 204 ◽

pp. 111-116 ◽

Cited By ~ 1

Author(s):

Ada Rota ◽

Chiara Milani ◽

Barbara Contiero ◽

Elisa Artusi ◽

Bodil Ström Holst ◽

...

Keyword(s):

Protein Concentration ◽

C Reactive Protein ◽

Reactive Protein

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C-Reactive Protein and All-Cause Mortality in a Large Hospital-Based Cohort

Clinical Chemistry ◽

10.1373/clinchem.2007.091959 ◽

2008 ◽

Vol 54 (2) ◽

pp. 343-349 ◽

Cited By ~ 62

Author(s):

Claudia Marsik ◽

Lili Kazemi-Shirazi ◽

Thomas Schickbauer ◽

Stefan Winkler ◽

Christian Joukhadar ◽

...

Keyword(s):

Hospital Admission ◽

Acute Phase ◽

Cox Regression ◽

Disease Risk ◽

C Reactive Protein ◽

Reactive Protein ◽

Increased Risk ◽

All Cause Mortality ◽

Low Sensitivity

Abstract Background: C-reactive protein (CRP), an acute-phase protein, is a sensitive systemic marker of inflammation and acute-phase reactions. Testing CRP concentrations at hospital admission may provide information about disease risk and overall survival. Methods: All first-ever transmittals to the department of medical and chemical laboratory diagnostics for determination of low-sensitivity CRP (n = 274 515, 44.5% male, median age 51 years) between January 1991 and July 2003 were included [median follow-up time: 4.4 years (interquartile range, 2.3–7.4 years)]. The primary endpoint was all-cause mortality. Multivariate Cox regression adjusted for sex and age was applied for analysis. Results: Compared to individuals within the reference category (CRP <5 mg/L), hazard ratios (HR) for all-cause mortality increased from 1.4 (5–10 mg/L category) to 3.3 in the highest category (>80 mg/L, all P <0.001). CRP was associated with various causes of death. The relation of CRP to cancer death was stronger than to vascular death. Younger patients with increased CRP had relatively far worse outcome than older patients (maximal HR: ≤30 years: 6.7 vs >60 years: 1.7–3.7). Interestingly, both short- and long-term mortality were associated with increasing CRP concentrations (>80 mg/L: HR 22.8 vs 1.4). Conclusion: Measurement of low-sensitivity CRP at hospital admission allowed for the identification of patients at increased risk of unfavorable outcome. Our findings indicate that close attention should be paid to hospitalized patients with high CRP not only because of very substantial short-term risk, but also long-term excess risk, the basis for which needs to be determined.

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Elevated C-Reactive Protein, Depression, Somatic Diseases, and All-Cause Mortality: A Mendelian Randomization Study

Biological Psychiatry ◽

10.1016/j.biopsych.2013.10.009 ◽

2014 ◽

Vol 76 (3) ◽

pp. 249-257 ◽

Cited By ~ 47

Author(s):

Marie Kim Wium-Andersen ◽

David Dynnes Ørsted ◽

Børge Grønne Nordestgaard

Keyword(s):

Mendelian Randomization ◽

C Reactive Protein ◽

Reactive Protein ◽

All Cause Mortality ◽

Somatic Diseases

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Serum Levels of Anticyclic Citrullinated Peptide Antibodies, Interleukin-6, Tumor Necrosis Factor-α, and C-Reactive Protein Are Associated with Increased Carotid Intima-Media Thickness: A Cross-Sectional Analysis of a Cohort of Rheumatoid Arthritis Patients without Cardiovascular Risk Factors

BioMed Research International ◽

10.1155/2015/342649 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 9

Author(s):

Mónica Vázquez-Del Mercado ◽

Lourdes Nuñez-Atahualpa ◽

Mauricio Figueroa-Sánchez ◽

Eduardo Gómez-Bañuelos ◽

Alberto Daniel Rocha-Muñoz ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Cardiovascular Risk ◽

Cardiovascular Events ◽

Tumor Necrosis ◽

Intima Media Thickness ◽

Carotid Intima Media Thickness ◽

C Reactive Protein ◽

Reactive Protein ◽

Citrullinated Peptide ◽

Necrosis Factor

The main cause of death in rheumatoid arthritis (RA) is cardiovascular events. We evaluated the relationship of anticyclic citrullinated peptide (anti-CCP) antibody levels with increased carotid intima-media thickness (cIMT) in RA patients.Methods. Forty-five anti-CCP positive and 37 anti-CCP negative RA patients, and 62 healthy controls (HC) were studied. All groups were assessed for atherogenic index of plasma (AIP) and cIMT. Anti-CCP, C-reactive protein (CRP), and levels of tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA).Results. The anti-CCP positive RA patients showed increased cIMT compared to HC and anti-CCP negative (P<0.001). Anti-CCP positive versus anti-CCP negative RA patients, had increased AIP, TNFαand IL-6 (P<0.01), and lower levels of high density lipoprotein cholesterol (HDL-c) (P=0.02). The cIMT correlated with levels of anti-CCP (r=0.513,P=0.001), CRP (r=0.799,P<0.001), TNFα(r=0.642,P=0.001), and IL-6 (r=0.751,P<0.001). In multiple regression analysis, cIMT was associated with CRP (P<0.001) and anti-CCP levels (P=0.03).Conclusions. Levels of anti-CCP and CRP are associated with increased cIMT and cardiovascular risk supporting a clinical role of the measurement of cIMT in RA in predicting and preventing cardiovascular events.

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C-reactive protein: a marker or a player?

Clinical Science ◽

10.1042/cs20070121 ◽

2007 ◽

Vol 113 (2) ◽

pp. 79-81 ◽

Cited By ~ 18

Author(s):

Thomas Nyström

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Events ◽

Protein A ◽

Low Grade ◽

Phase Reaction ◽

Clinical Markers ◽

C Reactive Protein ◽

Reactive Protein ◽

Hs Crp

It has been suggested that Type 2 diabetes may, in part, be precipitated or accelerated by an acute-phase reaction as part of the innate immune response, in which large amounts of cytokines are released from adipose tissue, creating a low-grade inflammatory milieu. There is also firm evidence that atherosclerosis is an immune-mediated inflammatory disease. Therefore it is reasonable to imply that low-grade inflammation is an important pathogenetic factor in atherosclerosis and cardiovascular events in patients with Type 2 diabetes. Over the last few years, there have been a lot of promising clinical markers proposed to link inflammation and atherosclerosis. Of these markers, hs-CRP (high-sensitivity C-reactive protein) might be a prognostic marker for further cardiovascular events, although this has been refuted recently. In this issue of Clinical Science, Castoldi and co-workers have demonstrated that, in patients with Type 2 diabetes categorized into low (<1.0 mg/l), medium (1.0–3.0 mg/l) and high (>3.0 mg/l) hs-CRP groups, serum levels of hs-CRP correlated with lipopolysaccharide-stimulated release of interleukin-1β and interleukin-6 in whole blood. This finding may indicate that low-grade inflammatory activity might influence cytokine production in these patients.

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