Research progress of CA125 and BDNF in serum of patients with acute myocardial infarction for predicting acute heart failure

1 Introduction

Acute myocardial infarction is the necrosis [1–3] caused by acute and continuous myocardial ischemia-hypoxia induced by the acute occlusion or ectopic embolism of the coronary artery. This mainly manifests as the change in hemodynamics during the ventricular systole or diastole after myocardial infarction, and produces various degrees of heart failure [4] due to the difference in size and part of the myocardial infarction. The physiopathologic mechanism of heart failure is the change in hemodynamics and abnormal activation of neuroendocrine system. This is manifested as the rise in activity of the sympathetic nerve-adrenaline system and renin-angiotensin-aldosterone system, and the activation of various endogenic neuroendocrine hormones and cytokines. The activated neuroendocrine hormone and cytokine can make the body secrete excessive vasoconstrictor substances, and together with stimulating inflammatory reaction, this further aggravates the myocardial infarction and heart failure [5]. The disordered structure of CHF coronary capillaries can stagnate hemodynamics in myocardium and increase resistance to blood flow, whch will subsequently disrupted myocardial microcirculation. This could play a role in the development of CHF [6, 7]. This is the reason why the incidence rate and mortality of acute myocardial infarction combined with acute heart failure continues to increase. Therefore, early prevention strategy is crucial. For example, it’s suggested that aspirin can be used for prevention of cardiovascular disease [8], and a Mediterranean-style diet which is low in fat and high in fiber and protein is also helpful [9, 10]. Adequate exercise is also very important [11].

The novel heart failure markers have increasingly attracted the attention of researchers. Hence, the continuous exploration and mining of novel markers been carried out. Recently, McLean [12] summarized the most valuable biomarkers of heart failure by referring to 114 articles, including brain natriuretic peptide (BNP), N terminal pro b-type natriuretic peptide (NT-proBNP), CA125, interleukin 18 (IL-18), cardiac troponin (cTn), and Urocortin. With the continuous development of medical career, the number of markers have also increased, including Galectins-3 [13], growth differentiation factors-15 [14], procalcitonin [15], ST2 [16], BDNF, etc. Among these, BDNF has been significantly researched in recent years, since this indicator has a higher prediction value for heart failure. WU et al. [17] establish a control experiment and divide the patients into groups, according to the Killip heart function score (patients without acute heart failure, but with level-I heart function, are included in the control group, while patients with combined acute heart failure and level-II-IV heart function were included in the experimental group). The study revealed that the serum level of CA125 and BNDF significantly increases as the illness condition intensifies, and that this is positively correlated to the seriousness of patients with acute myocardial infarction combined with acute heart failure. In other words, the serum level of CA125 or BDNF has certain prediction significance for the occurrence of acute heart failure after acute myocardial infarction. Next, we will have a further understanding of these two biomarkers of heart failure from the mechanism of the increase in serum level and researches in recent years.

2 The mechanism of increase in serum CA125 and BNDF levels

1.1 Carbohydrate Antigen-125 (CA125) is a glycoprotein with high molecular weight, which has a relative molecular mass of 200–1,000. CA125 is generally from the endometrium, peritoneum and ovary [18], and this was first used for the diagnosis of ovarian cancer, pancreatic cancer and lung cancer, with high sensitivity, but poor specificity [19]. The link of CA125 with heart function was first used in patients who underwent heart transplantation abroad. After the heart transplantation, the patient’s disease was controlled. When the hemodynamics becomes stable, the heart function classification degree declined, and the CA125 level also sharply declined after the improvement of heart function. This change is similar to the change in atrial natriuretic peptide and other neuroendocrine hormones. Therefore, researchers have considered that this may be correlated to heart failure [20].

Some studies have indicated [21] that a higher CA125 level is often correlated to the pleura, peripheral edema, acute moderate-severe heart failure, and moderate-severe heart failure. When the pleura, pericardium, or peritoneum suffer from malignant lesions, this would lead to the anomaly of many cytokines and a neuroendocrine system, thereby making the body produce the inflammatory factor, and subsequently stimulate the skin cell secretion of CA125 [22]. Some scholars have considered that the avascular necrosis and apoptosis of myocardial cells due to the myocardial infarction can increase ventricular wall tension, and this would be accompanied by the expression of some cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the ventricular remodeling process. The above cytokines may stimulate the mesothelial cell secretion of CA125 [23]. A study revealed [24] that among patients with myocardial infarction, the increase in CA125 level was parallel to that of the nor adrenal gland. This speculates that this may be caused by the hyperfunction of sympathetic nerve activity due to severe pain.

Among patients with heart failure, the increase in CA125 level may be due to the skin cell secretion of CA125 [25] caused by the venous hyperemia, the activation of pleural mesothelial cells, or the increase of signal peptide under mechanical pressure (capacity overload). Some scholars have considered [26] that among patients with heart failure, myocardial dysfunction and hypertrophy can increase the myocardial elasticity, thereby leading to hemodynamics anomaly, as well as the increase in the release of myocardial cell BNP and the promotion of the synthesis of CA125 in mesothelial cells. CA125 serum level is correlated to right atrial pressure [27] and BNP level [28], which verifies that the hemodynamics anomaly is associated with the increase in CA125 synthesis from the side.

1.2 The brain derived neurotrophic factor (BDNF) belongs to the GDNF family. It is a small protein molecule which is first separated from pig’s brain. This is mainly distributed in the nervous system of the organism, and can promote the growth, differentiation and development of nerve cells, and induce nerve cell death [29]. Subsequently, BDNF is also expressed in lymphocytes, vascular smooth muscle cells, endothelial cells, the spleen, and the heart of the human body, and can intervene with cell growth, differentiation and death [30]. Recently, more and more researches on BDNF have been conducted, in terms of cardiovascular disease. Its synthesis and dysfunction participate in the occurrence and development process [31, 32] of many cardiovascular diseases, such as myocardial infarction, arrhythmia and hypertension.

The present study was more defined to the aspect of BDNF and acute myocardial infarction. A study indicated [33] that BDNF can activate a series of survival signal pathways under a stress state, including vascular endothelial growth factor (VEGF), protein kinase B (Akt), TRPC3/6 channel and activated macrophage, thereby giving play to the role of protecting the ischemic myocardium. The study conducted by Schriewer et al. [34] indicated that the content of malondialdehyde (MDA) in anoxic myocardial cells will increase, and the activity of antioxidative superoxide dismutase (SOD) will decline. After BDNF pretreatment, the content of MDA in the myocardial cells of mouse gradually decreased, and SOD activity gradually picked up, which indicates that BDNF pretreatment can help myocardial cell resist I/R oxidative damage. Tyrosine kinase receptor B (TrkB) is the functional receptor of BDNF. After combining BDNF and TrkB, the receptor would be phosphorylated, and the phosphorylated TrkB can be taken as the signal transmission of the BDNF signal transduction pathway, and activate the related downstream pathways, thereby giving play to various physiological functions. In addition, it can mediate the survival of endothelial cells, promote the migration and proliferation of ischemic cells, and play an important role in the angiogenesis of ischemic tissues [35]. The TrkB inhibitor K252a is a glycosylated alkaloid and tyrosine kinase inhibitor with strong specificity. It inhibits TrkB activation by competing with ATP for the binding site on the tyrosine kinase structure of the TrkB intracellular region, and subsequently interdicts the TrkB phosphorylation induced by BDNF, and intensifies the damage of ischemic myocardial cells, reflecting the role of BDNF in protecting the heart and blood vessel from the side [36]. In addition, Amadio et al. considered that BDNF may affect the stability of the fibrous protein fiber structure and coronary plaque of patients with coronary heart disease. These researchers compared the relationship of restructuring BDNF, with fibrous protein fiber density, the greatest clot hardness and the greatest clot turbidity between patients with coronary heart disease and healthy subjects, and they found that restructuring BDNF can reduce fibrous protein fiber density, the highest clot hardness and the highest clot turbidity, and promote the dissolution of clots. It was speculated that the low-level BDNF was correlated to the thrombosis, and at least part of the reason is mediated by the change in fibrous protein fiber formation [37].

3 Investigating serum CA125 and BNDF levels in acute myocardial infarction and acute heart failure

In recent years, more and more researches have made efforts in investigating CA125, in terms of the heart and blood vessels. In the forward-looking multicenter random test, Julio et al. [38] randomly distributed patients into two groups: CA125 strategy group and SOC. The CA125 strategy decreases CA125 to 35 U/ml by increasing or decreasing the diuretic dose, and forcing the use of statins, while SOC is the standard treatment for patients with heart failure after hospitalization. The test has proven that the CA125 strategy is superior to SOC, in terms of reducing one-year mortality or acute heart failure before hospitalization. In the meta-analysis [39], the PubMed and EMBASE databases were used for the search, and 16 studies (15 cohort studies and one random test) were identified. It was found that the high CA125 level was correlated to acute heart failure symptoms and the heart failure readmission rate, as well as all-cause mortality. CA125 can be used to identify more serious high-risk populations with overload fluid, and can become a useful risk stratification tool. Rheude et al. [40] compared the correlation of CA125 and NT-proBNP with adverse outcomes by investigating 363 patients with trans-catheter aortic valve implantation, and took the all-cause mortality or readmission after heart failure deterioration within one year after the operation. They found that these two plays a certain predictive effect on heart failure deterioration after trans-catheter aortic valve implantation. In addition, upon comparison, the prediction ability of CA125 was stronger. Recent studies have indicated [41, 42] that among patients with acute heart failure, CA125 level also rises, and this increase in level is correlated to the degree of heart function deterioration (New York classification) and the decrease the degree of cardiac ultrasound ejection fraction. The research conducted by Ahmad et al. [43] revealed that compared with normal subjects, the CA125 level of patients with acute myocardial infarction significantly increased, and that this was positively correlated with creatine kinase-MB and troponin. Furthermore, when compared with patients without major adverse cardiac events (MACE), the patients with MACE had higher CA125 levels. That is, patients with higher CA125 levels have higher MACE incidence. Mendez et al. [44] conducted a retrospective analysis of CA125 and NT-proBNP concentrations in 156 patients, who suffered from stable heart failure and admitted by the Heart Failure Outpatient Department within three years, and these patients all received heart failure standard treatment. The Cox regression analysis is used to evaluate the independent association between CA125 or NT-proBNP and mortality, and a comprehensive analysis of the ability of these two to predict the heart failure was performed. It was found that the increase in CA125 level can increase the prediction value of NT-proBNP in patients with heart failure. Durak-Nalbantic et al. [45] discussed the correlation between CA125 level, and ultrasonic cardiogram parameters and BNP level. They found that CA125 level was positively correlated with BNP level, but these had no significant association with ejection fraction and left atrial dimension, and that the CA125 level of patients with decompensated heart failure would significantly increase. Compared with patients without pleural effusion and pericardial effusion, the CA125 level of patients with pleural effusion and pericardial effusion increases more significantly. Therefore, CA125 can be taken as the marker of panhyperemia and volume overload for patients with decompensated heart failure. However, the research that discussed the relationship between CA125 and coronary heart disease revealed that CA125 level is positively correlated with brain natriuretic peptide (pro-BNP), left ventricular end diastolic diameter and left ventricular end systolic diameter, but negatively correlated with left ventricular ejection fraction, and that the CA125 level of patients with heart failure significantly increases [46]. These two studies can reflect the role of the increase in CA125 level, combined with BNP level, in predicting heart failure. However, different results were obtained, in terms of ultrasonic cardiogram, which may be correlated to the conditions and number of included population, and other objective factors in the research.

Cao et al. [47] discussed the role of BDNF in myocardial cell hypertrophy and apoptosis. Angiotensin II was used to form the myocardial cell hypertrophy in new myocardial cells cultured in vitro, and ligature the incomplete aorta abdominalis in the body. The overexpression of recombinant vector pcDNA5-BDNF was transfected to myocardial cells through lipidosome. The immunofluorescence staining method was used to determine the impact of BDNF transfection on the surface area of myocardial cells. According to the test for determining the impact of BDNF overexpression on myocardial cell atrial natriuretic peptides, brain natriuretic peptide, the surface area of myocardial cells, and the apoptosis rate, and compared with myocardial cells without transfection in the control group, the results revealed that the myocardial cell atrial natriuretic peptide, brain natriuretic peptide, surface area of myocardial cells and the apoptosis rate significantly decreased. Hence, it was concluded that BDNF can inhibit the myocardial cell apoptosis induced by angiotensin II. Through investigating the role of micro RNA-195 (miR-195) in ischemic myocardial cell apoptosis and the interaction between BDNF and miR-195, Pengzhou Hang et al. [48] found that BDNF can alleviate the role of miR-195 in promoting myocardial cell apoptosis of the mouse and significantly decrease apoptotic cells, when compared to the control group. This proves that BDNF can reduce the damage of myocardial infarction in mouse and protect myocardial cells. Lee et al. [49] conducted a follow-up of the relationship between BDNF and renalase before and after percutaneous coronary intervention (PCI), and the results revealed that BDNF before and after intervention did not have a significant difference, but this was negatively correlated with the percentage change in the level of renalase. However, a study indicated that renalase level is the predictive factor of myocardial ischemia [49] and cerebral arterial thrombosis [50], which proves the role of BDNF in protecting myocardial cells after acute myocardial infarction reversely.

It was reported [51, 52] that the decline in BDNF level in plasma and serum of patients with heart failure often indicates poorer prognosis. Atsushi et al. [53] conducted a proactive recruitment of patients who are hospitalized due to aggravation of heart failure. They measured the BDNF value of patients when they left the hospital, and measured the peak oxygen intake (peak VO₂) by carrying out a cardiopulmonary exercise test. Although the correlation between these two was not observed, the readmission rate of the low BDNF and low peak VO₂ group within half a year after leaving hospital was far higher than that of the other groups. Hence, it was speculated that the combined BDNF and peak VO₂ can be used to predict early cardiac events. In another large community sample test, it is found that the higher the concentration of BDNF in serum is, the lower the cardiovascular event and death rate are [54].

In summary, the level of CA125 or BDNF in serum has certain prediction significance for the occurrence of acute heart failure after acute myocardial infarction, and this level would constantly increase with disease progression. The combination of these two has higher predictive value in acute heart failure [17]. Early intervention can be carried out through the increase of these two indicators, providing significant benefit in the prognosis of patients with acute myocardial infarction. At present, the level of CA125 and BDNF in serum is used less in clinical tests, and there are no multi-center large-scale clinical research verifying its prediction ability for acute heart failure among patients with acute myocardial infarction. However, the existing research obtained the same results. That is, the level of CA125 and BDNF in serum can be used as a potential test index for the prognosis evaluation of cardiovascular disease and prediction of acute heart failure. However, how to master the relationship between the rise in level of the two and heart failure, and its prognosis accurately still needs further research.

Conflict of interest

The authors declare that they have no competing interests.

Funding

None.