Elevated C-reactive protein in acute coronary syndrome presentation is an independent predictor of long-term mortality and heart failure

doi:10.1016/j.clinbiochem.2006.10.025

Clinical Biochemistry

Volume 40, Issues 5–6, March 2007, Pages 326-329

https://doi.org/10.1016/j.clinbiochem.2006.10.025 Get rights and content

Abstract

Objectives:

To assess the ability of C-reactive protein (CRP) to predict long-term outcomes in a chest pain population.

Design and methods:

CRP was measured at presentation in 446 emergency department patients with acute coronary syndromes. All-cause mortality and hospital discharges for acute myocardial infarction (AMI) and congestive heart failure (CHF) were obtained for up to 8 years following the event.

Results:

Kaplan–Meier analyses indicated that patients with CRP concentrations above the American Heart Association scientific statement cut-off had a higher rate for death and CHF admissions. After adjusting for troponin concentrations, in a Cox proportional hazard model, only CRP concentrations indicative of an acute phase response (i.e., > 7.44 mg/L) were associated with a significant risk for death after 5 years and CHF readmission after 2 years.

Conclusions:

Patients presenting early with chest pain with elevated CRP concentrations have a greater long-term risk for death and heart failure.

Introduction

C-reactive protein (CRP) is an acute phase protein [1]. In short-term studies of patients with acute coronary syndromes (ACS), high CRP concentrations have been shown to be predictive of death, but not recurrent acute myocardial infarction (AMI) [2], [3]. There are few studies assessing the long-term risks of an elevated CRP in the ACS population [4], [5], [6]. The physiological role for human CRP is unknown [7] and thus the mechanisms involved in patients with ACS are likely multifactorial. CRP can exacerbate tissue damage [8] and in animal models of acute myocardial infarction inhibition of human but not rat CRP decreases the size of the infarctions [7]. Furthermore, it is clear that, in the ACS setting, inflammation is systemic and not simply focused within the coronary vascular tree [9]. Therefore, unresolved questions pertain to the relevance of high CRP prior to cardiac necrosis, as well as the interaction between CRP and cardiac troponin (cTn) elevations during ACS. The present study explored the synergism between CRP and troponin levels on long-term health outcomes of patients presenting with acute coronary syndromes (ACS).

Section snippets

Study population

Details of the study population have been previously reported [10], [11], [12]. Briefly, in 1996 following research ethics approval, the study cohort consisted of 448 unique patients presenting to the emergency department with chest pain which the triage staff considered likely to be caused by cardiac ischemia. Blood samples (heparin and EDTA anti-coagulated plasma) were obtained at presentation with subsequent collections scheduled based on the reported time of symptom onset [10], [11], [12].

Results

The study cohort is an all-comer ACS emergency department population from an era prior to the use of troponin testing for management of chest pain (i.e., 1996). The median age (IQR) of the cohort was 64 years (51–74) with females being significantly older than males, 67 versus 61 years (p = 0.008), respectively.

The baseline CRP and cTnI results in our study population were obtained early after the onset of symptoms. The median time from the onset of symptoms to ED presentation was 3 h (Table 1).

Discussion

High levels of CRP in ACS patients have been shown to be a good predictor for death but not AMI recurrence [2], [3], [4], [5], [6]. Many studies have evaluated the association between outcomes and CRP concentrations post-AMI, or peak CRP concentrations on outcomes [20]. Few have assessed CRP's role during the early phase prior to any elevation of troponin. Recently, Suleiman et al. [6] reported that in survivors of AMI with elevated CRP between 12 and 24 h after symptom onset, CRP was a marker

Acknowledgments

This work was supported by a grant from the Canadian Institutes of Health Research. The C-reactive protein reagent was contributed for the study by an unrestricted grant from Beckman Coulter Inc.

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CK-MB is one of isoenzymes of the creatine kinase, whose level in serum increases 5–20 times after onset of AMI symptom [14] and reflects the degree of myocardial damage [15]. In addition, the acute phase protein CRP is widely used as an indicator for the cardiovascular diseases associated with inflammation [16]. The normal plasma concentration of CRP is less than 1 μg mL−1 and can rise as high as 1000-fold during the inflammation process [17].
Acute myocardial infarction (AMI) is the leading cause of morbidity and mortality globally. The serum levels of a group of cardiac biomarkers have been regarded as important indicators in the routine diagnosis of AMI. The development of rapid, sensitive, and accurate detection methods of AMI biomarkers is urgently needed for the early diagnosis of AMI. Here, a dynamic and pseudo-homogeneous enzyme-linked immunosorbent assay (ELISA) was reported based on the combined use of bioconjugated magnetic nanochains (MNCs) and gold nanoparticles (AuNPs) probes. The capture antibodies-conjugated MNCs served as dynamic nano-mixers to facilitate liquid mixing and as homogeneously dispersed capturing agents to capture and separate specific targets. The AuNPs probes were prepared by co-immobilization of detection antibodies and horseradish peroxidase (HRP) for signals amplification. The design of bioconjugated MNCs and AuNPs probes significantly increased the assay kinetics and improves the assay sensitivity. This novel ELISA strategy realized accurate detection of a panel of AMI biomarkers within 35 min, leading to considerably improved sensitivities compared to that of conventional ELISA method.
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The high level of CRP reflects an inflammatory response on patient and indicates the poor therapeutic response [34]. In this regard, these findings are consistent with clinical knowledge that higher CRP is related to higher rates of readmission and mortality for HF patients [33,35]. As can be seen in Table 2, the proposed model achieves the best AUC performance in all three cases.
Heart failure (HF) is a serious condition associated with high morbidity and mortality rates. Effective endpoint prediction in patient treatment trajectories provides preventative information about HF prognosis, guides decision making about the type and intensity of care, and enables better understanding of provider performance.
We explored the potential of a large volume of electronic health records (EHRs) for endpoint prediction of HF. Specifically, a suite of patient features observed at the prediction time point were utilized as the auxiliary information during the training of the prediction model.
We extract the latent representation of patient treatment trajectory by equipping a recurrent neural network (RNN) with two learning strategies, namely adversarial learning and multi-task learning. As for the adversarial learning strategy, an adversarial learning scheme is used to differentiate the generated feature vector from the real one, while in the multi-task learning strategy, we consider the prediction of patient feature vector as an auxiliary task other than endpoint prediction. With such learning strategies, the extracted representation of patient treatment trajectory is particularly optimized for predicting HF endpoint, including HF-readmission, all-cause mortality and their combination (i.e., composite endpoint).
We evaluate the proposed approach on a real clinical dataset collected from a Chinese hospital. The experimental dataset contains 2102 HF patient treatment trajectories with 13,545 visits on the hospital. The area under the ROC curve (AUC) achieved by our best model in predicting composite endpoint is 0.744, which is better than that of state-of-the-art models, including the standard Long Short Term Memory (0.727), Gated Recurrent Unit (0.732), RETAIN(0.730). With respect to the prediction of HF-readmission and all-cause mortality, our method also shows better performance than benchmark models.
The experimental results show that the proposed model can achieve competitive performance over state-of-the-art models in terms of endpoint prediction for HF, and reveal some suggestive hypotheses that could be validated by further investigations in the medical domain.
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Heart failure is a systemic condition with increased levels of natriuretic peptides and inflammatory markers.12,13 Therapies targeting these pathways have shown positive prognostic impact in this syndrome.11,17 As described, our cohort represents a severe heart failure population characterized by poor self-reported functional status, reduced exercise capacity and low mean LVEF.
Response to cardiac resynchronization therapy (CRT) can currently be assessed by clinical or echocardiographic criteria, and there is no strong evidence supporting the use of one rather than the other. Reductions in B-type natriuretic peptide (BNP) and C-reactive protein (CRP) have been shown to be associated with CRT response. This study aims to assess variation in BNP and CRP six months after CRT and to correlate this variation with criteria of functional and echocardiographic response.
Patients undergoing CRT were prospectively enrolled between 2011 and 2014. CRT response was defined by echocardiography (15% reduction in left ventricular end-systolic volume) and by cardiopulmonary exercise testing (10% increase in peak oxygen consumption) from baseline to six months after device implantation.
A total of 115 patients were enrolled (68.7% male, mean age 68.6±10.5 years). Echocardiographic response was seen in 51.4% and 59.2% were functional responders. There was no statistical correlation between the two. Functional response was associated with a significantly greater reduction in BNP (-167.6±264.1 vs. -24.9±269.4 pg/ml; p=0.044) and CRP levels (-1.6±4.4 vs. 2.4±9.9 mg/l; p=0.04). Nonetheless, a non-significant reduction in BNP and CRP was observed in echocardiographic responders (BNP -144.7±260.2 vs. -66.1±538.2 pg/ml and CRP -7.1±24.3 vs. 0.8±10.3 mg/l; p>0.05).
An increase in exercise capacity after CRT implantation is associated with improvement in myocardial remodeling and inflammatory biomarkers. This finding highlights the importance of improvement in functional capacity after CRT implantation, not commonly considered a criterion of CRT response.
A avaliação da resposta à terapêutica de ressincronização cardíaca (CRT) assenta em critérios clínicos e ecocardiográficos, sem evidência inequívoca que apoie o uso de uns em relação aos outros. Reduções do péptido natriurético tipo-B (BNP) e da proteína C-reactiva (PCR) associaram-se à resposta à CRT. O objetivo deste estudo é avaliar a variação do BNP e PCR após seis meses de CRT e relacionar essa variação com critérios de resposta funcional e ecocardiográfica.
De 2011 a 2014, doentes com indicação para CRT foram incluídos prospetivamente. A resposta à CRT foi definida por ecocardiograma (redução em 15% no volume telessistólico do ventrículo esquerdo) e por prova cardiorrespiratória (aumento de 10% no consumo de oxigénio máximo), aos seis meses.
Foram incluídos 115 doentes (género masculino: 68,7%, idade média 68,6±10,5 anos); 51,4% apresentaram resposta ecocardiográfica e 59,2% resposta funcional. Não se verificou uma correlação estatisticamente significativa entre esses. Os respondedores funcionais apresentaram reduções estatisticamente significativas de BNP (-167,6±264,1 versus -24,9±269,4; p=0,044) e PCR (-1,6±4,4 versus 2,4±9,9; p=0,04). No grupo de respondedores ecocardiográficos essa redução não atingiu significância estatística [BNP (-144,7±260,2 versus -66,1±538,2) e PCR (-7,1±24,3 versus 0,8±10,3;p>0,05)].
Um aumento da capacidade funcional após implantação de CRT está associado a uma melhoria dos biomarcadores inflamatórios e de remodelagem reversa ventricular. Essa ideia enaltece a importância da melhoria da capacidade funcional após implantação de CRT, pouco considerada como critério de resposta à ressincronização.
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Increasing evidences support that inflammation is involved in the pathogenesis of atherosclerotic diseases [1–3]. C-reactive protein (CRP), one of the important inflammation markers, in addition to being a risk marker, can also act as an important predictive factor for cardiovascular events [4–6]. Recently, it was also demonstrated that CRP could induce the imbalance between tissue factor and tissue factor pathway inhibitor in endothelial cells [7], and treated with highly purified CRP could induce endothelial dysfunction and promote platelet adhesion to endothelial cells [8,9].
Endothelial dysfunction is the basic and original sign of atherogenesis. Some evidences show that C-reactive protein (CRP) and perivascular adipose tissue (PVAT) play a pivotal role in atherosclerosis. However, the effects of CRP on atherosclerosis and the related mechanisms require elucidation.
The levels of basic total cholesterol, low-density lipoprotein cholesterol, triglyceride, CRP, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), nitric oxide (NO) and endothelin-1 (ET-1) were respectively measured in rabbits, endothelium-dependent vasorelaxation function was also evaluated. Animals were randomly divided into two groups: PVAT(−) and PVAT(+) group (removing or keeping pericarotid adipose tissue (PCAT)). Both of the two groups were exposed to a high-fat diet for six-week, and then sustained CRP treatment was performed for a week, at this time point all the above parameters were remeasured. In addition, mRNA and protein expression of TNF-α, IL-6, and macrophage chemoattractant protein-1 (MCP-1) were respectively evaluated by Polymerase Chain Reaction and immunoblotting in PCAT and cultured adipocytes treated by CRP.
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CRP could significantly promote endothelial dysfunction in high-fat diet rabbits especially in PVAT(+) groups, which may be partly mediated by activating inflammatory reaction of adipose tissue.
Gender differences in cardiovascular mortality by C-reactive protein level in the United States: Evidence from the National Health and Nutrition Examination Survey III
2013, American Heart Journal
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We used Cox proportional hazards models to explore gender differences in CRP-associated mortality via the National Health and Nutrition Examination Survey III 1988-1994 linked to the National Death Index with mortality follow-up through 2006. We examined CV mortality as well as all-cause mortality hazards.
The final sample size included a total of 13,878 individuals (7,364 women and 6,514 men) with a median follow up of 18.2 years. All models controlled for race, age, smoking, high-density lipoprotein, hypertension, diabetes mellitus, waist circumference, and total cholesterol. Men with a CRP >3.0 mg/L relative to those with a CRP ≤3.0 mg/L had elevated CV mortality hazards (hazard ratio [HR] 1.79, 95% CI 1.23-2.60) and all-cause mortality hazards (HR 1.57, 95% CI 1.29-1.90). In women, elevated CRP was not significantly associated with either increased CV (HR 1.20, 95% CI 0.90-1.59) or all-cause mortality hazards (HR 1.09, CI 0.93-1.29).
National guidelines from various agencies that make recommendations on the diagnostic and prognostic use of CRP have treated men and women equally. We find that there may be reason to tailor recommendations based upon one's gender.

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Elevated C-reactive protein in acute coronary syndrome presentation is an independent predictor of long-term mortality and heart failure

Abstract

Objectives:

Design and methods:

Results:

Conclusions:

Introduction

Section snippets

Study population

Results

Discussion

Acknowledgments

Clin. Biochem.

J. Am. Coll Cardiol.

J. Am. Coll Cardiol.

Am. Heart J.

Thromb. Res.

Am. Heart J.

Am. J. Cardiol.

J. Am. Coll. Cardiol.

Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease

Circulation

Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease

N. Engl. J. Med.