Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 6  |  Issue : 3  |  Page : 166-173

The relationship between c-reactive protein and cardiovascular events in patients with obstructive and nonobstructive coronary artery disease


National Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Fu Wai Hospital, Beijing 100037, China

Date of Submission18-Jul-2021
Date of Acceptance14-Sep-2021
Date of Web Publication30-Sep-2021

Correspondence Address:
Jian-Jun Li
National Center for Cardiovascular Disease, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Fu Wai Hospital, No 167 BeiLiShi Road, XiCheng District, Beijing 100037
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2470-7511.327240

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  Abstract 


Background and Objectives: Patients with nonobstructive coronary artery disease (NOCAD) have an increased risk of cardiovascular events (CVEs) compared to that in individuals with normal or near-normal coronary arteries (NNCAs) and even a similar risk to that in individuals with obstructive coronary artery disease (OCAD). However, the predictors for a worse outcome in patients with NOCAD are not fully determined. This study aimed to investigate the association of high-sensitive C-reactive protein (hs-CRP) and CVEs in patients with NOCAD. Materials and Methods: In total, 4662 patients with coronary artery angiography were enrolled and followed up for CVE. Patients were classified as having NNCA (<20% stenosis, n = 698, 15.0%), NOCAD (20%–49% stenosis, n = 639, 14.3%), and OCAD (≥50% stenosis, n = 3325, 70.7%) and then further subdivided into three groups based on their baseline hs-CRP level (<1, 1–3, and >3 mg/L). Proportional hazards models were used to assess the risk of CVEs. Results: Over an average 13403 person-year follow-up, 338 patients experienced CVEs. Patients with NOCAD and OCAD had a higher rate of CVE than those with NNCA (P < 0.05). The CVE risk was significantly higher in NOCAD (hazard ratio [HR]: 2.31, 95% confidence interval [CI]: 1.30–4.01, P = 0.004) and OCAD (HR: 3.09, 95% CI: 1.88–5.07, P < 0.001) patients than in NNCA patients. Moreover, elevated hs-CRP levels were associated with an incremental rate of CVE (P < 0.05). Conclusions: Patients with NOCAD had worse outcomes and elevated hs-CRP levels were positively associated with CVEs, which potentially helps assess risk in NOCAD patients.

Keywords: Cardiovascular events; High-sensitive C-reactive protein; Nonobstructive coronary artery disease


How to cite this article:
Zhang HW, Guo YL, Zhu CG, Wu NQ, Gao Y, Dong Q, Sun J, Li JJ. The relationship between c-reactive protein and cardiovascular events in patients with obstructive and nonobstructive coronary artery disease. Cardiol Plus 2021;6:166-73

How to cite this URL:
Zhang HW, Guo YL, Zhu CG, Wu NQ, Gao Y, Dong Q, Sun J, Li JJ. The relationship between c-reactive protein and cardiovascular events in patients with obstructive and nonobstructive coronary artery disease. Cardiol Plus [serial online] 2021 [cited 2021 Nov 27];6:166-73. Available from: https://www.cardiologyplus.org/text.asp?2021/6/3/166/327240




  Introduction Top


Nonobstructive coronary artery disease (NOCAD) is a heterogeneous and prevalent condition of coronary atherosclerosis, occurring in 50%–60% of patients with stable angina and 1%–13% of patients with myocardial infarction (MI) undergoing coronary angiography (CAG).[1],[2],[3],[4] In the recent years, more studies have focused on the pathological and clinical characteristics of patients with NOCAD. However, the cardiovascular outcomes in such patients versus those in ones with obstructive coronary artery disease (OCAD) or normal or near-normal coronary arteries (NNCAs) have not been intensively evaluated.[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15] Previously, several studies have reported the association of NOCAD with an increased risk of cardiovascular events (CVEs).[5],[6],[7],[9] However, a few investigations did not support NOCAD as a condition potentially associated with a high CVE risk.[3],[8],[11] Indeed, the effect of NOCAD on CVEs is currently undetermined, especially in different clinical settings. Furthermore, it is unclear what index or markers are clinically practical and useful if patients with NOCAD have worse clinical outcomes.

High-sensitive C-reactive protein (hs-CRP) is a classic marker of systematic inflammation, clearly demonstrated by many cardiovascular medicine studies.[16],[17],[18],[19],[20],[21] A recent study by Ridker et al. indicated that elevated hs-CRP levels could predict the reduction of CVEs after treatment with proprotein convertase subtilisin-kexin type 9 inhibitors, although this medication did not decrease the hs-CRP concentration among the entire study population.[17] These results caught our attention, as they imply that hs-CRP might potentially help with cardiovascular risk classification of patients with NOCAD.

Recently, a study reported that increased hs-CRP at hospital admission was a marker of worse outcomes in MI patients with NOCAD after a median follow-up of 7 years.[22] To our best knowledge, however, there are still limited data regarding the effect of plasma hs-CRP levels on cardiovascular outcomes in patients with NOCAD. Therefore, we investigated the association of hs-CRP with CVEs in Chinese patients with NOCAD.


  Materials and Methods Top


Study population

From March 2011 to February 2017, 7746 consecutive patients were enrolled owing to angina-like chest pain, a positive treadmill exercise test, or clinically suspected coronary artery disease (CAD). The baseline characteristics and medical history were collected from all patients following the methods of Zhang et al.[23],[24] [Figure 1] presents a detailed study flow. Patients with significant infectious or systematic inflammatory disease, severe liver or renal insufficiency, hematologic disorders, thyroid dysfunction, malignant disease, cardiomyopathies, or myocarditis and patients lost to follow-up were excluded. Finally, 4662 patients who received CAG were analyzed (median follow-up, 34.5 ± 6.2 months [13403 person-years]). The degrees of CAD were defined based on the CAG result, which was performed using standard clinical protocols; all angiograms were interpreted by experienced invasive cardiologists. The patients were divided into NNCA (<20% stenosis in all coronary arteries), NOCAD (20%–49% stenosis in any coronary artery), and OCAD (≥50% stenosis in any coronary artery) groups. The patients were also subdivided based on the hs-CRP cut points recommended by the Centers for Disease Control and Prevention and the American Heart Association (AHA) (hs-CRP: <1, 1–3, >3 mg/L).[25]
Figure 1: The study flowchart.
CAD: Coronary artery disease


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Dyslipidemia was diagnosed by a fasting total cholesterol (TC) level of ≥200 mg/dL, a triglyceride (TG) level of ≥150 mg/dL or a high-density lipoprotein cholesterol (HDL-C) level of <40 mg/dL (for men) or 50 mg/dL (for women), or patients receiving lipid-lowering therapy. Hypertension was defined as repeated blood pressure measurements ≥140/90 mmHg, patients self-reporting hypertension, or patients using anti-hypertensive drugs.

Cardiovascular events

The total outcomes included all-cause mortality, nonfatal MI, stroke, and late coronary revascularization (>90 days). The follow-up visit method was consistent with previous studies.[26],[27] After the initial appointment, all patients were followed up at 6-month intervals via face-to-face interviews or telephone communications by well-trained cardiologists or nurses blinded to the purpose of our study. The follow-up duration was from the enrollment until the last traceable hospital inpatient or outpatient record or telephone interview before August 2018. All available information from patients reporting possible CVEs were collected. A participant's death was reported by their relatives, the general practitioner, or the specialist who treated the participant. Three experienced cardiologists blinded to the study classifications independently evaluated the events.

Laboratory tests

Laboratory data were obtained from venous blood samples taken after a 12-h overnight fast. The lipid profiles were determined by an automatic biochemistry analyzer (Hitachi 7150, Tokyo, Japan). In detail, the low-density lipoprotein cholesterol (LDL-C) concentration was analyzed by a selective solubilization method (LDL-C test kit; Kyowa Medex, Tokyo). The HDL-C concentration was measured by a homogeneous method (Determiner L HDL; Kyowa Medex, Tokyo, Japan). TC, TG, apolipoprotein B, and apolipoprotein A1 levels, were determined by enzymatic methods. hs-CRP concentrations were determined using immunoturbidimetry (Beckmann Assay 360, Bera, Calif., USA).

Ethics statements

The present study complied with the Declaration of Helsinki and was approved by the Hospital Ethical Review Board (Fuwai Hospital and National Center for Cardiovascular Diseases, Beijing, China). Informed written consent was obtained from all patients.

Statistical analysis

Continuous data were presented as means ± standard deviations or medians (interquartile ranges), as appropriate. Normally distributed data were compared using Student's t-test, and nonnormally distributed biomarkers were compared by Wilcoxon's rank-sum test, when appropriate. Categorical data were presented as percentages and compared by the Chi-square test. The linear terms represented comparisons between multiple groups were used P values for trend. The event-free survival rates among subgroups based on the CAD status and hs-CRP level were estimated by the Kaplan–Meier method and compared by log-rank test. P < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS software version 21.0 (SPSS, Inc., Chicago, Illinois, USA).


  Results Top


Baseline characteristics

[Table 1] provides the total population baseline characteristics. Based on the CAG results, 15.0% of patients were classified as having NNCA (<20% stenosis, n = 698), 14.3% as NOCAD (20%–49% stenosis, n = 639), and 70.7% as OCAD (≥50% stenosis, n = 3325). NNCA patients were younger and more likely to be female, and had a lower prevalence of peripheral and cerebrovascular disease, and clinical risk factors than NOCAD and OCAD patients (all P < 0.05). NOCAD patients presented with similar cardiovascular risks, such as hypertension and dyslipidemia, as OCAD patients (P > 0.05).
Table 1: Baseline characteristics stratified by coronary artery severity

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Outcomes

In total, 338 patients (7.3%) experienced new CVEs (all-cause mortality, n = 45; MI, n = 56; stroke, n = 85; late coronary revascularization, n = 152). Patients with NOCAD and OCAD had higher CVE rates than those with NNCA (6.1% vs. 2.6%, P < 0.05 and 8.5% vs. 2.6%, P < 0.05, respectively). The CVE rate in OCAD patients was also higher than that in NOCAD patients (8.5% vs. 6.1%, P < 0.05). Elevated hs-CRP levels were associated with more severe coronary obstruction [median: 1.23 vs. 1.33 vs. 1.52 mg/L, P for trend < 0.05; [Figure 2]A. [Table 2] compares subjects with or without CVEs. The hs-CRP level significantly differed between patients with and without CVEs (median: 2.12 vs. 1.38 mg/L, P < 0.001). Patients with CVEs were older and had a higher rate of diabetes and hypertension [Table 2]; all P < 0.05].
Figure 2: The distribution of hs-CRP concentrations by the degree of coronary obstruction
A, The hs-CRP level distribution of the subgroups (NNCA vs. NOCAD vs. OCAD median: 1.23 vs. 1.33 vs. 1.52 mg/L; P for trend < 0.05). B, hs-CRP level comparisons of the subgroups with or without cardiovascular events (NNCA: 1.22 vs. 1.50 mg/L, P = 0.127; NOCAD: 1.27 vs. 1.62 mg/L, P = 0.010; OCAD: 1.45 vs. 2.19 mg/L, P < 0.001).
NNCA: Normal or near-normal coronary artery, NOCAD: Nonobstructive coronary artery disease, OCAD: Obstructive coronary artery disease, hs-CRP: High-sensitivity C-reactive protein


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Table 2: Baseline characteristic comparisons of participants with or without cardiovascular events

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Overall, 36.1% of patients were classified as low hs-CRP (<1 mg/L, n = 1681), 40.6% as medium hs-CRP (1–3 mg/L, n = 1894), and 23.3% as high hs-CRP (>3 mg/L, n = 1087). [Table 3] presents the baseline characteristics based on the hs-CRP level. Patients with a higher baseline hs-CRP level were significantly associated with traditional cardiovascular risk factors, such as hypertension, diabetes, and dyslipidemia (all P < 0.05). There was also a significantly higher CVE rate as the hs-CRP level increased (P < 0.001). NOCAD and OCAD patients with CVEs had a significantly higher hs-CRP level than those without [P < 0.05; [Figure 2]B.
Table 3: Baseline characteristics stratified by the high-sensitivity C-reactive protein level (mg/L)

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Kaplan–Meier analysis with log-rank test demonstrated that OCAD patients had a significantly lower cumulative event-free survival rate for all endpoint events than NOCAD and NNCA patients [all P < 0.05; [Figure 3]A. Importantly, the CVE rate was significantly higher for NOCAD patients than NNCA patients (P < 0.05). Moreover, when the participants were categorized based on both their hs-CRP and CAD status [Figure 3]B, the hs-CRP<1+NOCAD, hs-CRP 1–3+ NOCAD, and hs-CRP>3+NOCAD groups had significantly lower cumulative event-free survival rates for all endpoint events than those in the NNCA reference group (all P < 0.05). Increased hs-CRP levels were related to worse clinical outcomes in NOCAD and OCAD patients. OCAD patients in the high hs-CRP group had the lowest cumulative event-free survival rate compared with NOCAD patients [P < 0.05, [Figure 3]C].
Figure 3: Kaplan-Meier survival curves of cardiovascular events based on CAD severity and the hs-CRP level
A, The cumulative survival for patients with varying coronary artery severity (P < 0.05). B and C, The cumulative survival for NOCAD patients with different hs-CRP levels compared with OCAD or NNCA patients (all P < 0.05).


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After adjusting for confounders, including age, sex, dyslipidemia, diabetes, hypertension, hemoglobin A1c, TG, TC, LDL-C, lipid-lowering treatment, and family history of CAD, we found a positive relationship with the severity of coronary obstruction [Table 4]. The risk of CVEs elevated with increasing degrees of CAD; the adjusted hazard ratio was 2.31 for NOCAD patients (95% confidence interval: 1.30–4.01, P = 0.004) and 3.09 (95% confidence interval: 1.88–5.07, P < 0.001) for OCAD patients compared with the reference population.
Table 4: The multivariable-adjusted hazard ratios of cardiovascular events in patients with nonobstructive coronary artery disease

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  Discussion Top


This relatively large Chinese cohort study with a 13,403 person-year follow-up found that NOCAD patients had a higher CVE risk than NNCA patients, including all-cause mortality, nonfatal MI, stroke, and late coronary revascularization, and was strongly linked with an increased hs-CRP level.

Several previous studies indicated that NOCAD was associated with an increased risk of CVEs, predominately in patients with MI.[5],[10],[13],[28],[29] Another study reported that NOCAD patients had a low risk of CVEs in a cohort containing non-ST segment elevation MI.[10] Hence, the effect of NOCAD on CVEs is undetermined, especially among various clinical settings.

Recently, the effect of NOCAD has also been investigated in patients with stable CAD. Kissel et al. enrolled NOCAD patients and followed up for a median of 6.5 years,[6] reporting that minimal CAD (stenosis >0% and <50%) presented a similar risk as stable OCAD. Another study including patients with stable angina determined by CAG also showed that patients with NOCAD (defined as 1%–49% stenosis in any epicardial coronary artery) had higher risks of CVEs than subjects without CAD.[7] In contrast, a study conducted by Ouellette et al. suggested that NNCA patients (≤20% stenosis) and NOCAD (21%–49% stenosis) had very low event rates compared to OCAD patients (≥50% stenosis).[8] NOCAD was also associated with an increased CVE risk detected by computed tomography angiography.[7],[9],[30] Therefore, careful consideration of the association between NOCAD and cardiovascular outcomes in different ethnic populations and clinical settings is necessary. Our study investigated the utility of NOCAD (determined by CAG) in a relatively large cohort, and the data indicated that patients with NOCAD had a higher CVE rate than patients with NNCA. After adjusting for confounders in Cox proportional hazards models, the CVE risk increased in patients with NOCAD compared to that in patients with NNCA. This finding provided additional information regarding the association of NOCAD with future risk for CVEs.

Examining potential biomarkers for stratifying NOCAD patients is an interesting topic. Although the exact mechanism has yet to be uncovered, a plausible reason may involve plaque, not only the plaque burden but also plaque stability. It is well known that atherosclerotic plaque stability is determined by multiple factors, and immune and inflammatory pathways play a critical role in the onset of initial lesions, plaque progression, and subsequent complications.[16],[17],[18],[19],[20],[31] Furthermore, a series of studies have demonstrated a significant and independent association between elevated hs-CRP levels and adverse cardiovascular outcomes.[16],[17],[18] A recent study reported that patients with a CRP increase of 2 mg/L or more increased risk of adverse cardiovascular outcomes.[21] Hence, clarifying the prognostic predictors for NOCAD is potentially clinically important for detecting high-risk patients with CAD and improving the outcome of current therapeutic strategies. However, only one recent study attempted to determine the combined effects of an elevated hs-CRP concentration and NOCAD, reporting that an increased hs-CRP concentration at hospital admission was a marker of worse clinical outcomes in NOCAD patients. Their study performed 7 years of follow-up, but the sample size was small (n = 150), and they only enrolled patients with MI.[22]

In our study, based on our larger cohort and 13,403 person-year follow-up, we hypothesized that elevated hs-CRP would help assess CVE risk in patients with NOCAD. Our data indicated that patients with CVEs had a significantly higher hs-CRP level than those without CVEs in the NOCAD and OCAD groups (P < 0.05). The Kaplan–Meier analysis with log-rank test demonstrated that NOCAD patients in the high hs-CRP group had a significantly lower cumulative event-free survival rate from adverse outcomes than patients in the low hs-CRP group (P < 0.05). Since NOCAD has been identified to increase the risk of CVEs, discovering potential markers is of clinical importance. The most notable finding of this study is that hs-CRP may be a marker for predicting NOCAD outcomes. Therefore, our study may help stratify risk stratification in patients with NOCAD.

There are several potential limitations to this study. Inherent to the nature of an observational and prospective study, our findings are subject to several confounding factors, and the baseline level of risk factors may change during follow-up. However, we did adjust for a range of confounding factors to investigate the combined effect of elevated hs-CRP levels on cardiovascular risk. Further, our findings are based on a one-time serum hs-CRP measurement, which may not accurately reflect the status of each participant. Finally, the follow-up duration not might be long enough to make definite conclusions, and a relatively small sample size of NOCAD patients may also be a limitation. Expanded studies may be required to confirm our findings.


  Conclusions Top


NOCAD patients had worse outcomes than NNCA patients. Most importantly, a higher baseline hs-CRP concentration was positively associated with CVEs, suggesting that hs-CRP might be a prognostic biomarker for clinical outcomes in patients with NOCAD.

Declaration of patient consent

The authors certify that they have obtained all appropriate consent from patients. In the forms, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity forms.

Financial support and sponsorship

This study was partly supported by Capital Health Development Fund (201614035) and CAMS Innovation Fund for Medical Sciences (2016-I2M-1-011).

Conflicts of interest

Jian-Jun Li is an Editorial Board member of Cardiology Plus. The article was subject to the journal's standard procedures, with peer review handled independently of the Editorial Board member and their research groups.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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