European Journal of Cardiovascular Medicine

The prevalence of coronary artery diseases is progressively increasing over years and ischemic heart disease (IHD) contributes to 12.2% of all deaths worldwide. The increasing incidence of IHD is expected to continue due to the increased prevalence of obesity, diabetes, and metabolic syndrome and population aging and myocardial Infarction is one of the major causes of projected mortality worldwide in 2030.¹

In acute myocardial infarction there is rapid development of myocardial necrosis caused by the decreased oxygen supply to the myocardium. CK-MB, released into blood stream from the injured myocardium is one of the important myocardial markers used in the confirmation of acute myocardial infarction. The post infarct rise of circulating CK-MB  levels reflects extent of injury to the myocardium following MI.² Studies evaluated the independent prognostic value of CK-MB mass in myocardial infarction associated with higher risk of death and major cardiac events on short term and long term follow up.³

The area of myocardium supplied by the affected vessel ceases to function after the myocardial infarction.Survival following acute MI is closely related to the degree of left ventricular systolic function, reflecting the functional state of the surviving myocardium. We measured the left ventricular ejection fraction in patients with myocardial infarction, as the mortality and adverse cardiac events are related inversely to the ejection fraction values, an easily measurable and most reliable prognostic marker.⁴

Myocardial infarction induces a strong up-regulation of cytokines in the injured myocardium within the first few hours to the first day after the infarct.The  release of cytokines like Interleukin-6  is the major inducer of acute phase response which causes the CRP production from liver.⁵C-reactive protein (CRP), an acute-phase reactant is an extremely sensitive marker of systemic inflammation. The CRP level during the acute phase of MI is highly dynamic, with levels beginning to rise within a few hours after onset of symptoms, peaking at 2 to 4 days.⁶Concentrations of CRP usually appear to rise rapidly in proportion to the degree and severity of inflammatory stimuli.The magnitude of CRP levels reflects the extent of myocardial necrosis as it indicates the degree of release of inflammatory cytokines.Inflammatory process play a key role in pathogenesis and determines real damage and ventricular remodelling after infarction.⁷Extent of myocardial injury is the major denominator for long-term prognosis after acute MI.⁸ The post infarct rise of circulating CRP is associated with short-term and long term clinical outcome in patients with acute MI.⁹

The magnitude of serum CRP levels reflects not only the extent of myocardial necrosis but also the inflammatory response of the body to the same. Both of these are important factors that decide the progress of the disease. But CK-MB reflects the quanta of infarcted cells which are leaking the enzyme and its levels fall swiftly with time. The infarction being an event which happened prior to the patient being admitted and beyond clinical intervention. But CRP reflects the ongoing inflammatory response following infarction, which can be modulated by appropriate pharmacological and other means to prevent further worsening of conditions. Since CRP levels stay higher for longer period of time than CK- MB (that dip drastically after 24 hours) it can also be assessed for a longer period of time.

Hence in this study, we study the correlation between the various established prognostic markers like CK-MB & LVEF with serum CRP levels to see if it could be used as an independent and more comprehensive marker which reflects both the magnitude of infarct and the inflammatory response.

55 patients admitted in the coronary unit in the tertiary centre in Kerala with myocardial infarction were serially enrolled from 2011 to 2012.Patients who were diagnosed for acute myocardial infarction for the first time were included in this study as cases.

WHO criteria have classically been used to diagnose MI, a patient is diagnosed with myocardial infarction if two or three of the following criteria¹⁰ are satisfied:

1-Clinical history of ischemic type chest pain lasting for more than 20    minutes

2-Changes in serial ECG tracings

3-Rise and fall of serum cardiac enzymes such as creatine kinase, troponin I, and lactate dehydrogenase isozymes specific for the heart. 

Exclusion criteria: 

The subjects with the following conditions were excluded from the study group. 

• Acute infections or chronic inflammatory diseases or on treatment for any of these conditions in the last 4 weeks.
• Recent trauma 
• Conditions with reduced baseline cardiac activity like previous myocardial infarction cardiomyopathy valvular heart disease and heart failure.
• Postmenopausal hormone usage 
• Conditions with high baseline inflammation or tissue  damage like chronic inflammatory diseases,leukaemia, hepatic or  renal disease, chronic smoking etc.

Investigations done

1. Serum Creatine Kinase- MB: Blood samples were collected from the study group, on the day of admission to estimate serum Creatine Kinase- MB and estimation was done by automated  immunoinhibition method.
2. Serum CRP: Blood samples were collected after 2 days of admission to the hospital for the estimation of serum CRP levels to get close to peak CRP values after infarction. Serum CRP level was estimated by Erba latex turbidimetric immunoassay using fully automated clinical chemistry analyzer EM200.
3. 2-D echocardiography :In all patients ejection fraction measurement was done on the second day of admission by echocardiography. 2-D echocardiography was performed with Nemio-30 device by Toshiba and biplane Simpson rule algorithm

Primary objectives

To study the relationship of serum C-reactive protein (CRP), with CK-MB, the marker of myocardial injury  and Left ventricular ejection fraction.

The data was entered into a personal computer using Microsoft Excel. For the analysis of the data, SPSS was used. Suitable statistical correlation and regression analysis were performed to elucidate the results of the study. P-value of <0.05 was considered significant, and a p-value of > 0.05 was considered not to be significant.

Table1: Distribution of age (in years) in males and females of study population

Table 1 shows the age and gender distribution of participants in the study. Both in male and female category the maximum participants were in the age group of 56-60 years.

Table2: Comparison of CRP, CK-MB and LVEF in males and females

The mean serum CRP level in males was 40.9mg/L. The mean serum CRP level in females was 38.5mg/L

The mean serum CK-MB level was 58.8 IU/L in males and 53.8IU/L in females.

The mean value of the left ventricular ejection fraction was 42% in males and 43.8% in females.

Table 3: Correlation of serum CRP levels with serum CK-MB

There was significant positive correlation between serum CRP level 2 days  after admission and serum CK-MB level. Pearson’s correlation coefficient, r = 0.98 (p<0.001).

Table 4: Correlation of serum CRP levels with left ventricular ejection fraction

There was significant negative correlation between serum CRP level 2 days after admission and left ventricular

(p<0.001).

Figure 1: Scatter diagram showingcorrelation between serum CRP and CK-MB

Figure 2: Scatter diagram showingcorrelation between serum CRP and LVEF

The mean serum CRP value  2 days after admission was 39.65mg/L in our study.Acute myocardial infarction triggers an acute phase response resulting in a rise of circulating CRP levels.We measured Serum CRP concentrations 2 days after admission to get levels close to peak CRP levels, as CRP levels beginning to rise by about 6 hours,and peaking around 48 hours after the myocardial injury.⁶The cytokines released from the infarcted tissue inducesproduction of CRP from liver. The inflammatory process play key role inmyocardial injury and remodelling following myocardial infarction.⁷ Studies in which CRP levels were measured after acute myocardial infarction showed the magnitude of CRP levels reflects the extent of myocardial injury.⁶

Extent of myocardial injury is a major denominator for in hospital and long-term prognosis after AMI in particular mortality during the first 6 months of infarction. In studies by de Beer et al ¹¹Pietila et al  ¹²Anzai T et al ¹³Liuzzo G et al¹⁴,Toss et al¹⁵, D A Morrow et al¹⁶had shown that Post-AMI rise of CRP correlates with extent of infarction and serum high CRP levels  proved to be predictive of worse outcomes like cardiac rupture , arrythmias , reinfarction at hospital and short term and long term follow-ups. Hence serum CRP levels could be used as a comprehensive marker as it reflects the magnitude of both the infarct and the inflammatory response.

Relation of serum CRP with CK-MB levels

The mean serum CK-MB level measured on the first day of admission was 58.8 IU/L in males and 53.8IU/L in females in our study. CK-MB , one of the most important myocardial markers in diagnosis of myocardial infarction.In AMI plasma concentration of CK-MBincreases with in 3 to 6 hours following onset of symptoms of myocardial infarction and reaches peak levels between 16 to 30 hours and returns to normal by 24 to 36 hours.¹⁷Clinical studies have demonstrated a close

relationship between the extent of injury to the myocardium following MI and increased serum CK-MB concentrations.²Similarly, significant correlations have been observed between CK-MB estimated infarct sizing and left ventricular echocardiography.⁴ American College of Cardiology/American Heart Association practice guideline updates in 2002 accepted CK-MB as a marker for risk stratification of acute myocardial infarction patients admitted in hospitals.¹⁸

Researchers in their study^19,20evaluated the independent prognostic value of CK-MB mass in patients with myocardial infarction and identified that it is significantly associated with higher risk of death and major adverse cardiac events at six months follow-up.

Our study showed a significant positive correlation between CK-MB level on the day of admission and CRP level 2 days after admission, Pearson’s correlation coefficient, r=0.98(p-value<0.001).In the present study, as we found a significant positive correlation between  the peak serum CRP levels and CK-MB levels , it is clearly evident that serum CRP levels a marker of inflammation quantitatively related to degree of myocardial damage. Studies by de Beer et al ¹¹Devaki et al²¹and other investigators^8,9,22showed a significant correlation between plasma CRP levels and CK-MB in patients with acute myocardial infarction.So estimation of serum CRP and CK-MB levels, following myocardial infarction give us a better idea about the degree of myocardial damage. Moreover CRP levels can be used to assess the degree of myocardial injury even after 24 hours of onset infarction as a proxy for CK-MB,as its level falls back to normal after 24 hours of infarction. So measurement of CRP in turn helps us to predict the in-hospital outcome of the patients as well as long term prognosis of the disease.

Relation of CRP with left ventricular ejection fraction

The mean value of the left ventricular ejection fraction in our study were 42% in males and 43.9% in females. So in both there is a fall in ejection fraction (<50%).Echocardiography shows the affected left ventricular wall fails to thicken during systole and in fact may be thin, producing systolic bulging of the ischemic segment.Survival following acute MI is closely related to the degree of left ventricular systolic function, reflecting the functional state of the survivingmyocardium.²³ Mortality and reinfarction rates are related inversely to the ejection fraction, an easily measurable and highly reliable prognostic marker.Many investigators have found an important relationship between the two-dimensional echocardiographic extent of acute dysfunction and serious in-hospital AMI complications like death, shock, heart failure, and arrhythmias and long term outcome.^4,23–26

There was significant negative correlation between serum CRP level 2 days after admission and left ventricular ejection fraction. Pearson’s correlation coefficient, r=-0.99 (p<0.001). Studies by Pandian et al ²⁷,Ziaris et al, ²⁸Sanchis et al,²⁹Maria et al ³⁰Maartenet  et al ³¹were also found that high CRP levels were associated with reduced ejection fraction after AMI . In myocardial injury, cytokines like TNF-α and IL-6 can directly reduce myocyte contractility through the immediate reduction of systolic cytosolic [Ca²⁺] via alterations in sarcoplasmic reticulum function.TNF-α can indirectly decrease myocyte contractility through nitric oxide-dependent attenuation of myofilament Ca²⁺  sensitivity.³²Hence inflammation has a role in altering the myocardial contractility also. So CRP an easily measurable biomarker of inflammation after myocardial injury can also give a picture regarding the myocardial function.

So by assessing serum CRP levels and left ventricular ejection fraction together, we can predict the functional state of myocardium which in turn help us to predict the prognosis of the patients.

1. The magnitude of elevation of CRP, the marker of inflammation in circulation correlates with the extent of myocardial injury following infarction showed significant correlation CK-MB.
2. The magnitude of elevation of CRP,  showed a negative correlation with Left ventricular ejection fraction which reflects the systolic functional status of myocardium. 
3. So by estimating CRP we can have a better idea about the extent of myocardial damage as the post infarct inflammatory process has a key role in final infarct area remodelling.
4. A better prediction of the patient’s outcome following an episode myocardial infarction can be done with CRP levels as it remain elevated for 3-4 days after the onset of chest pain at a time when the CK MB, which peaked after about 15 hours, had already returned to normal.
5. CRP is a better prognostic tool as it is a more holistic marker, as the myocardial injury as well as post infarction inflammatory process are reflected in its magnitude.

Acknowledgements

We express our sincere thanks to all participants of the study for their cooperation.

Limitationsof the study

The serial CRP levels and follow up of the patients were not done to assess the progress

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