Association of Hs-CRP Levels in Patients with Acute Coronary Syndromes and it’s Correlation with Angiographic Severity of Coronary Artery Stenosis

ABSTRACT IMAGE

INTRODUCTION

A tremendous amount of research has been done in developing biomarkers for the diagnosis and prognostication of atherosclerotic cardiovascular disease (ASCVD) including coronary artery disease (CAD), which is a major contributor to mortality and morbidity worldwide.

Numerous modifiable and non-modifiable risk factors are implicated in contributing to CVD. However, these traditional risk factors may not reliably predict coronary events all the time. Notably, a significant amount of acute coronary syndrome is being seen in patients with normal or borderline lipid profiles. This calls for looking into other markers for risk assessment of ASCVD to identify at-risk populations. As atherosclerosis is an inflammatory process, various markers of inflammation have been proposed for this purpose.^[1] Among them, high-sensitivity C-reactive protein (Hs-CRP) has been the highlight. Hs-CRP may be involved in increasing thrombogenicity and vascular vulnerability through different mechanisms such as increased expression of cell adhesion molecules, endothelial plasminogen activator inhibitor 1, downregulation of endothelial nitric oxide, and altered LDL uptake by macrophages.^[2] This makes Hs-CRP an attractive marker to be assessed in patients presenting with acute coronary events. Although Hs-CRP is being used for risk assessment and primary prevention for ASCVD, information regarding the relationship between levels of Hs-CRP levels in patients presenting with acute coronary syndromes (ACS) and its association with outcomes is scarce. Therefore, our study was undertaken to assess the correlation between the levels of Hs-CRP and the coronary angiographic findings in patients presenting with ACS and its correlation with outcomes.

MATERIALS AND METHODS

We carried out an observational prospective study in patients presenting with ACS, namely, ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI), and unstable angina (UA), who were admitted to cardiology intensive coronary care unit from August 1, 2022, to October 31, 2022. We included all patients who were aged 18 years or older, had confirmed diagnoses of acute coronary syndrome, and gave valid consent. We excluded patients with any overt infection or sepsis, acute or chronic renal failure, acute or chronic liver disease, known collagen vascular disease, febrile disorder (body temperature >37.5°C), or who were unwilling to give consent. Patients who were admitted and were a part of the study were managed by the treating consultant and not the investigator as per standard guidelines. The investigator had no role in deciding the timing and manner of revascularization.

Patients were evaluated and investigated as per standard protocols which included electrocardiogram, chest radiogram, and transthoracic echocardiogram. Echocardiogram was performed using a Phillips iE33 machine. Blood was drawn for parameters such as complete blood count, renal parameters, serum electrolytes, lipid profile, and Hs-Trop I. Apart from these, estimation of serum Hs-CRP was also done at admission. Hs-CRP was quantified by immunoturbidimetric assay measured on Beckman Coulter AU5800.

Values of <1 mg/L were considered normal and values of 1–10 mg/L as elevated. Values >10 mg/L were rejected given the possibility of added sources of inflammation or sepsis. Patients, thereafter, underwent coronary angiogram after consent and were labeled as having single-vessel disease (SVD), double-vessel disease (DVD), triple-vessel disease (TVD), and left main + triple-vessel disease (LM+TVD) based on an angiographic cutoff of ≥50% stenosis. The extent and severity of CAD were assessed using the Gensini score. Echocardiogram was also done before discharge to assess the left ventricular ejection fraction (LVEF). We aimed to take 100 cases; however, valid measurements of Hs-CRP could be made for 80 cases.

RESULTS

A total of 80 patients were enrolled in the study as per inclusion and exclusion criteria among which 58 (72.5%) were male and 22 (27.5%) were female. [Table 1] shows the baseline characteristics of the patients. The average age of enrolled patients was 62 years. Hs-CRP values of <1 mg/L were considered normal and values between 1 and 10 mg/L were considered elevated. Values more than 10 mg/L were not considered due to the possibility of added sources of inflammation or sepsis. Out of 80 cases, eight cases (8.75%) had Hs-CRP in the normal range and 73 cases (91.25%) had Hs-CRP in the elevated range. Among the total subjects, two patients succumbed during their hospital stay. STEMI was the most common diagnosis (57.5%). The most common risk factor was hypertension, present in 72.5% of the study population. Of the number of vessels involved, double-vessel disease was most common (38.8%).

Hs-CRP was elevated in 73 of 80 cases (91.3%). Mean HsCRP values in males were 3.99 mg/L, whereas the mean HsCRP value in females was slightly higher at 4.56 mg/L, but the difference was statistically not significant (P > 0.05). Furthermore, there was no significant difference in mean LDL levels in patients with elevated Hs-CRP (P > 0.05).

[Table 2] shows the distribution of patients by diagnosis and mean Hs-CRP levels in each group. The Hs-CRP level is elevated in all groups with mean values being slightly higher in NSTEMI and STEMI as compared to UA but is not statistically significant (P > 0.05).

[Table 3] shows the distribution of patients by the number of vessels involved and mean Hs-CRP levels in each group. In multiple comparison test, elevation in Hs-CRP between SVD, DVD, and TVD groups is statistically significant (P < 0.01), thereby showing that an increase in Hs-CRP level is associated with an increase in the number of vessels involved, however, between TVD and LM+TVD groups, the elevation was not significant (P = 0.41).

[Table 4] shows the correlation between Hs-CRP and the severity of coronary stenosis as determined by the Gensini score and the LV ejection fraction at discharge. A significant positive correlation was found between Hs-CRP and Gensini score with a correlation coefficient of 0.74 which is highly significant (P < 0.005). The scatter plot [Figure 1] shows a linear correlation. A negative correlation was found between Hs-CRP and LVEF at discharge with a correlation coefficient of −0.39 which is significant (P < 0.005). LVEF at discharge was obtained for 78 of the 80 patients as two patients succumbed during the course of treatment. Furthermore, the correlation between Hs-CRP and Gensini score was present irrespective of sex and was statistically significant. However, although correlation between Hs-CRP and LVEF at discharge was present in males and females, the correlation was found to be statistically insignificant in females (P = 0.45). This could have possibly been attributed to the lesser number of females in our study.

Close

Figure 1:

Linear scatter plot showing correlation between hs-CRP and Gensini score and LVEF. Hs-CRP: High-sensitivity C-reactive protein and LVEF: left ventricular ejection fraction.

Export to PPT

DISCUSSION

It is well established that Hs-CRP is a sensitive marker of systemic inflammation and, therefore, is being used as risk enhancing marker while guiding the initiation of statin therapy for primary prevention of ASCVD. Numerous studies have established the fact that CRP levels are elevated in patients with angiographically diagnosed CAD. Various reasons are speculated for this rise. CRP may not have a direct causative role in atherosclerosis and may be only a marker of inflammation^[3] or it may have a direct role in atherogenesis as evidenced by the following observations: (i) localization of CRP in atherosclerotic lesions, (ii) facilitating LDL uptake by macrophages by binding to the LDL molecules without the need for any enzymatic modification,^[4] and (iii) CRP administration in animal model promotes inflammation.^[5] CRP has also been found to be a key factor in plaque rupture^[6] and that initial and serial measurement of CRP in acute coronary syndrome may help to identify patients with adverse outcomes.^[7] Furthermore, a strong correlation has been found between CRP and the occurrence of future coronary events in patients with chronic stable angina.^[8]

Another possible mechanism underlying the role of CRP in inflammation could be its inverse relationship with vitamin D. It is thought that vitamin D helps in the regulation of inflammatory cytokines and thereby modulates inflammation.^[9] In a large-scale Mendelian randomization analysis, Vitamin D was found to be having a casual effect on CRP meaning that correction of vitamin D could potentially help in abating chronic inflammation which is a major driver for ASCVD.^[10]

We observed that Hs-CRP levels did not vary much with the gender or type of ACS and that it correlates well with the severity of coronary stenosis. It is worthwhile to note that although patients with any of the acute coronary syndromes show an elevation in Hs-CRP, the degree of elevations does not differ significantly between UA, NSTEMI, or STEMI.

In a study by Seyedian et al.,^[11] Hs-CRP levels were significantly higher in patients with unstable angina than those in patients with stable angina. Furthermore, the level of Hs-CRP in patients with unstable angina was associated with the severity of coronary stenosis. In agreement with the above, our study also revealed that the majority of patients with UA had elevated Hs-CRP and that the values correlated with the severity of stenosis in those patients.

Our decision to use the Gensini scoring was based on the fact that not only it scores the lesion according to the absolute angiographic severity but it also takes into account the location of the lesion within the coronary tree. Left main lesions have the maximum score followed by proximal segments of the left anterior descending and left circumflex coronary. The final score therefore also represents the functional significance of the lesions in terms of the at-risk myocardium. Patients with elevated Hs-CRP had higher Gensini scores, thereby signifying a higher disease burden.

Nyandak et al.^[12] noted the presence of a correlation between the severity of coronary stenosis and Hs-CRP levels which are consistent with our study. This supports the fact that inflammation is not only an important trigger for plaque rupture acutely but also acts as a driver of chronic atherosclerosis as evidenced by the occurrence of higher Hs-CRP levels with an increasing burden of coronary atherosclerosis.

Elevated CRP levels were correlated with the severity of CAD in a study by Liu et al.^[13] who found elevated Hs-CRP was an independent predictor of disease burden as evidenced by higher syntax scores in those patients. Although, in our study, the assessment of stenosis was done by the Gensini scoring system, the results were in agreement, with elevated Hs-CRP levels (>1 mg/L) seen in cases with higher Gensini scores. Moreover, patients with CRP levels <1 mg/L had lower stenosis scores.

Attempts have also been made to link Hs-CRP levels with plaque vulnerability by assessing plaque ulceration and inflammation. In a study by Arroyo-Espliguero et al.^[14] who considered Hs-CRP levels in patients with acute and chronic coronary syndromes, levels were notably higher in patients presenting with ACS compared to those of chronic stable angina. Furthermore, the Hs-CRP levels correlated with the number of complex vulnerable plaques in their study. It highlights the importance of Hs-CRP as a marker of atheromatous plaque vulnerability also.

Therefore, Hs-CRP serves as an important marker for disease burden in patients with ASCVD. Another important marker is the fibrinogen-albumin ratio. Assay of both these markers is widely available and inexpensive. With inflammation, fibrinogen being a positive acute phase reactant rises, while albumin a negative acute phase reactant falls. Several studies have shown a relationship between raised fibrinogen and reduced albumin with increased mortality and morbidity in patients with CAD.^[15,16] Combining the two as a ratio has been shown to improve the sensitivity and specificity in predicting the severity of CAD in patients with STEMI.^[17]

CONCLUSION

We conclude that Hs-CRP levels are significantly elevated in patients presenting with ACS. Hs-CRP also correlates well with severity of coronary stenosis and the number of vessels involved. However, the degree of elevation does not vary significantly between UA, NSTEMI and STEMI.