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BNP and ANP are both natural antagonists of renin angiotensin aldosterone system (RAAS). They also resist the sodium and water retention and hypertension raising effects of vasopressin and sympathetic nerve. BNP, together with ANP, participates in the regulation of blood pressure, blood volume and water salt balance, improves glomerular filtration rate, natriuretic diuresis, dilates blood vessels, reduces systemic vascular resistance and plasma volume, which all play a role in maintaining cardiac function. BNP is different from ANP. ANP is mainly synthesized in the atrium. When the atrium is overloaded or dilated, the secretion increases, and the plasma concentration increases, which mainly reflects the changes of pulmonary vascular pressure. Some other hormones such as antidiuretic hormone and catecholamines can directly stimulate the secretion of ANP. Because ANP precursors are stored in secretory granules, they are decomposed into ANP during secretion, Its rapid regulation is mainly carried out in the amount of hormone secretion; BNP is mainly synthesized in the ventricle and increases when the ventricle is overloaded or dilated; Therefore, it is more sensitive and specific to reflect the changes of ventricular function. Because BNP precursors are not stored in secretory granules, the rapid regulation of BNP synthesis and secretion is carried out at the level of gene expression.
Diagnostic value of BNP in cardiac function
Heart failure is the final stage of many diseases. Heart failure can be divided into acute heart failure (AHF) and chronic heart failure (CHF). CHF is divided into grades I, II, III and IV according to the cardiac function classification of New York Heart Association (NYHA). Grade I cardiac function has no clinical symptoms of heart failure, which can be called left ventricular dysfunction (LVD). The symptoms of acute decompensation of chronic heart failure are similar to those of acute heart failure. The reliability of clinical diagnosis of heart failure is very poor, especially in primary health care institutions. Echocardiography is the most useful and reliable non-invasive method for the diagnosis of cardiac insufficiency. There are 120000 suspected new cases of heart failure in the UK each year. It is difficult to diagnose such a large number of patients by echocardiography. Based on the close relationship between BNP and cardiac function, many researchers have done a lot of work to explore its clinical application. The importance of BNP has been affirmed in the pathophysiological changes and diagnosis of CHF. Mukoyama et al reported that the plasma BNP concentration in patients with CHF was higher than normal and was directly proportional to the severity of heart failure. Comparing the heart and plasma BNP levels between normal group and CHF group, it was found that the ventricular BNP content in normal people was 7.2% of that in atrium and 30% of that in the whole heart, while that in patients with CHF increased to 22% and 52% respectively. The plasma BNP concentration in normal people was about 0.9 ± 0.07fmol/ml, and the BNP / ANP value was about 0.16 ± 0.02, BNP concentration in patients with different degrees of CHF (NYHA grade Ⅰ ~ Ⅳ): grade Ⅰ is about 14.3 ± 1.8fmol/ml; Grade II: About 68.9 ± 37.9 fmol / ml; Grade III: about 155.4 ± 39.1fmol/ml; Grade IV is about 267.3 ± 79.9fmol/ml. In grade III and IV patients, the plasma BNP / ANP values were 1.44 and 1.72 respectively. BNP increased 200 ~ 300 times compared with normal, while ANP was only 20 ~ 30 times. Therefore, it is considered that the increase of ventricular synthesis and secretion of BNP in CHF patients is part of the reason for the increase of plasma BNP, and the severity of heart failure increases. Selvais and others believed that BNP was superior to ANP in the diagnosis of CHF and its severity. They compared the concentrations of ANP and BNP in normal people, patients with coronary heart disease with normal left ventricular ejection fraction (LVEF) and patients with different degrees of CHF. They found that the concentration of BNP (205 ± 143pg / ml) in severe heart failure (NYHA grade III ~ IV) was significantly higher than that in mild heart failure (NYHA ~ II) (51 ± 28pg / ml) (P < 0.001), The ability of BNP to distinguish CHF from normal people and patients with normal LVEF is better than ANP (P < 0.01), the correlation between BNP concentration and LVEF is better than ANP (rbnp = -0.59, ranp = -0.30, P < 0.05), and it is stronger than LVEF (P < 0.05). It is considered that BNP can be used to diagnose outpatients with cardiovascular disease.
At present, the clinical research on BNP mainly focuses on left ventricular dysfunction (LVD), where left ventricular function refers to systolic function. BNP is mainly synthesized and secreted by left ventricular cardiomyocytes in both normal people and patients with LVD. It enters the small vein and flows back to the ventricular septal vein and enters the circulation through the coronary sinus. Its secretion is mainly regulated by the tension of the left ventricular wall. The severity of LVD is positively correlated with its secretion. The level of BNP in peripheral blood can reflect the ventricular secretion rate and the degree of LVD.
At present, moderate and severe LVD can be easily diagnosed according to clinical examination, while mild LVD (NYHA grade I) is difficult to do, but it is very important for the diagnosis of LVD, especially for those patients who return to normal after myocardial infarction. The concentrations of plasma BNP, ANP and other peptide hormones and cGMP measured at rest or 3 minutes after exercise are higher than those in the normal control group, but only BNP has significant statistical significance, Through ROC curve analysis, it was found that the areas under the curve of BNP at rest and after exercise were 0.70 and 0.75 respectively, which was significantly better than ANP and cGMP in distinguishing normal from LVD. BNP was the best marker of natriuretic peptide system for LVD. Huang Yansheng and others reported that the combined detection of BNP and n-anp was more suitable for the diagnosis of LVD. They screened patients with LVD and CHF through radionuclide gated heart blood pool imaging, and selected healthy people with normal cardiac function as control, Results the levels of plasma BNP (98.72 ± 48.96 ng / L) and n-anp (1382.25 ± 549.51 ng / L) in LVD group were significantly higher than those in control group (39.06 ± 18.20 ng / L and 422.06 ± 255.38 ng / L, respectively, P < 0.05 and P > 0.001), but significantly lower than those in CHF group (150.90 ± 83.66 ng / L and 4020.43 ± 2090.95 ng / L, respectively, P < 0.05 and P > 0.001); When plasma BNP > 75.00ng/l, the sensitivity and specificity for the diagnosis of LVD were 91% and 94%; When plasma n-anp > 923.00ng/l, the sensitivity and specificity of diagnosing LVD were 75% and 94%. It was considered that BNP and n-anp could be used to diagnose LVD. BNP > 75.00ng/l and n-anp > 923.00ng/l were suitable as diagnostic indexes.
More and more literatures support the determination of BNP after myocardial infarction (MI). This can not only identify the presence or absence of left ventricular systolic dysfunction, but also may be superior to echocardiography in judging left ventricular remodeling and risk of death. In clinical practice, BNP also helps to distinguish asthma caused by heart failure from asthma caused by other causes. Normal BNP can almost exclude asthma caused by left ventricular dysfunction.
Brain natriuretic peptide, a member of the natriuretic peptide family mainly secreted by the heart, is a polypeptide composed of 32 amino acid residues. It is named because it was first found in the pig brain. It can regulate the self stable balance of blood pressure and blood volume, and has diuretic effect.
Brain natriuretic peptide (BNP), also known as B-type natriuretic peptide and brain natriuretic peptide, is another member of the natriuretic peptide system after atrial natriuretic peptide (ANP). It is named because it was first isolated from the pig brain by Japanese scholar sudoh in 1988. In fact, it mainly comes from the ventricle. BNP has important pathophysiological significance. It can promote sodium excretion and urination, has strong vasodilation, and can resist the vasoconstriction of renin angiotensin aldosterone system (RAAS). Like ANP, BNP is an important endocrine system for human body to resist volume overload and hypertension. Cardiac dysfunction can greatly activate the natriuretic peptide system, and the increase of ventricular load leads to the release of BNP.
Studies suggest that with the increase of Lp-PLA2 level, the risk of coronary heart disease and stroke increases, especially in the elderly and asymptomatic people with atherosclerotic disease. A meta-analysis of 32 prospective studies, including 79036 patients, included patients without vascular disease, stable vascular disease and acute vascular disease for 30 days. The results showed that Lp-PLA2 levels were linearly logarithmically correlated with coronary heart disease and vascular death. After adjusting for routine risk factors, the risk ratios of Lp-PLA2 level to coronary heart disease, ischemic stroke, vascular death and non vascular death were 1.11 (1.07 ~ 1.16), 1.14 (1.02 ~ 1.27), 1.13 (1.05 ~ 1.22) and 1.10 (1.03 ~ 1.18) respectively.
1. Asymptomatic high-risk population: Lp-PLA2 has different value in predicting coronary heart disease for different genders.
The nested case-control analysis of 6000 men with dyslipidemia in the WOSCOPS study showed that after adjusting for known cardiovascular risk factors and other inflammatory indicators, the RR of cardiovascular events in patients with elevated Lp-PLA2 levels was 1.18 (95% CI 1.05 ~ 1.33) [8], and the risk of coronary heart disease in patients with Lp-PLA2 levels in the highest quartile was 2-fold higher. Univariate analysis showed that CRP, leukocyte count, fibrinogen and Lp-PLA2 levels were all associated with the risk of cardiac events, but CRP and leukocyte count were only associated with events at the highest level, while different levels of Lp-PLA2 were associated with cardiac events. However, the WHS study with women as the research object found that the level of Lp-PLA2 was related to LDL-C (r = 0.51), and those receiving estrogen replacement therapy were the lowest. After adjusting for other risk factors, Lp-PLA2 levels did not predict cardiovascular events (coronary heart disease, nonfatal myocardial infarction and stroke), but hs CRP levels were associated with events. This may be related to patients receiving estrogen replacement therapy.
Lp-PLA2 level can predict the risk of coronary heart disease in healthy middle-aged people. 12819 healthy middle-aged people were selected in the ARIC study. After 6 years of follow-up, the levels of Lp-PLA2 and CRP in 608 patients with coronary heart disease events were higher than those in the control group. The hazard ratio of patients with the highest four scores of Lp-PLA2 was 1.78 [95% ci1.33 ~ 2.38]. The levels of Lp-PLA2 and CRP in patients with lower LDL-C levels (< 3.38mmol / L) were associated with coronary heart disease events, and the risk of both rising at the same time was the highest.
Lp-PLA2 is an independent predictor of coronary heart disease risk in the elderly. In the Rancho Bernardo Study, 1077 elderly community residents without a history of coronary heart disease were followed up for 16 years. Compared with the lowest quartile, the hazard ratios of higher Lp-PLA2 levels to predict the risk of coronary heart disease were 1.66, 1.80 and 1.89, respectively (P < 0.05). It is still significant after adjusting CRP and other coronary heart disease risk factors.
Since Lp-PLA2 mainly binds to LDL, lipid regulating drugs have the greatest impact on Lp-PLA2, and statins can significantly reduce the plasma level of Lp-PLA2. The prince study showed that after 12 weeks of fluvastatin treatment, the content of Lp-PLA2 in the treatment group decreased by 22.1% compared with placebo; The change of Lp-PLA2 content was moderately positively correlated with the change of LDL-C level. [11] Fenofibrate can improve HDL related Lp-PLA2. Statin treatment can affect the predictive value of Lp-PLA2. Jupiter study found that Lp-PLA2 level measured before randomized treatment was moderately correlated with LDL-C level. Lp-PLA2 level decreased by 33% and LDL-C decreased by 48.7% in rosuvastatin group. Lp-PLA2 levels were associated with cardiovascular events in patients in the placebo group, while Lp-PLA2 levels in patients in the statin treatment group did not predict the risk of cardiovascular events.
2. Stable coronary heart disease: Lp-PLA2 level can predict the risk of recurrence of cardiovascular events in patients with coronary heart disease.
3766 patients with stable coronary heart disease were enrolled in the peace study. After 4.8 years of follow-up, the incidence of composite cardiovascular events (cardiovascular death, myocardial infarction, coronary revascularization, angina hospitalization or stroke) increased significantly with the increase of Lp-PLA2 level; Lp-PLA2 level is an independent risk factor for non fatal cardiovascular events. In the study of Brilakis et al., the level of Lp-PLA2 in 504 patients undergoing coronary angiography was related to the degree of lesion [12], and the increase of Lp-PLA2 was related to the high incidence of cardiovascular events. Ludwigshafen Risk and cardiovascular health study showed that the level of Lp-PLA2 in 2454 patients with coronary heart disease confirmed by coronary angiography was highly correlated with LDL-C, apoB and non HDL-C levels, but not with hs CRP and fibrinogen. In addition, the level of Lp-PLA2 was correlated with the severity of coronary heart disease and the number of lesions. In patients not treated with statins, Lp-PLA2 levels were clearly associated with the risk of coronary heart disease.
3. Acute coronary syndrome (ACS)
Atherosclerotic plaque rupture is the main mechanism leading to acute thrombotic events, and Lp-PLA2 is an important reason for the increase of plaque vulnerability. The study of a group of patients with carotid endarterectomy showed that the level of Lp-PLA2 in carotid plaque was higher in patients with cardiovascular events. Zhu Yanzhou and others analyzed the histological characteristics of hs CRP, Lp-PLA2 and intravascular ultrasound in patients with ACS, stable coronary heart disease and non coronary heart disease. Results the levels of hs CRP and Lp-PLA2 were positively correlated with the area of atherosclerotic plaque tissue necrosis. [13] It is supported that Lp-PLA2 is an inflammatory marker of vulnerable plaque.
The correlation between Lp-PLA2 level and prognosis in patients with acute ACS is not consistent. The subgroup analysis of prove-it timi22 found that Lp-PLA2 measured 30 days after the acute phase was a prognostic index independent of LDL and CRP. A study of patients with acute myocardial infarction in the community suggests that Lp-PLA2 measured in the acute phase is associated with 1-year mortality, suggesting that Lp-PLA2 may not be affected by acute inflammatory events, but a specific indicator of vascular inflammation.
However, the follow-up analysis of two prospective studies (FRISC Ⅱ and gusto Ⅳ) from patients with acute myocardial infarction showed that although the level of Lp-PLA2 in patients with ACS was higher than that in healthy controls, it had weak correlation with known risk factors and had nothing to do with the recurrence of events in patients with ACS. Similarly, Lp-PLA2 levels measured at baseline in ACS patients enrolled in the miracle study were not associated with the primary endpoint. It was also found that atorvastatin significantly reduced the level of Lp-PLA2, and soluble PLA2 was associated with death.
NOMAS study continuously detected the changes of Lp-PLA2 level before and after myocardial infarction. Different from the rising trend of hs CRP, Lp-PLA2 level gradually decreased after the acute phase (5% per year), from the average 233 ng / ml before infarction to the average 153.9 ng / ml. Lp-PLA2 content was affected by LDL-C level. A Canadian study observed that the content of acute ACS [(143.13 ± 60.88) ng / ml] was significantly higher than that in recovery (12 weeks) [(88.74 ± 39.12) ng / ml], and the content of stable coronary heart disease [(121.72 ± 31.11) ng / ml] was also higher than that in recovery of ACS.
In conclusion, the correlation between Lp-PLA2 level and cardiovascular events in patients with ACS is not consistent, which may be related to the dynamic changes of Lp-PLA2 after ACS events. Other reasons include: different races lead to different Lp-PLA2 gene polymorphisms, different determination time windows, different determination methods, and large differences in baseline Lp-PLA2 levels in different studies.
Lp-PLA2 is one of the subtypes of phospholipase superfamily, also known as platelet activating factor acetylhydrolase, which is secreted by macrophages, T cells and mast cells in vascular intima. Lp-PLA2 expression was up-regulated in atherosclerotic plaque and strongly expressed in macrophages of vulnerable plaque fibrous cap. Lp-PLA2 can hydrolyze oxidized phospholipids in ox LDL to produce lipid pro-inflammatory substances, such as hemolytic lecithin and oxidized free fatty acids, and then produce a variety of atherogenic effects, including endothelial cell death and endothelial dysfunction, and stimulate the production of adhesion factors and cytokines. These substances can further produce self reinforcing circulation through chemotactic inflammatory cells and produce more proinflammatory substances.
Lp-PLA2 released into the blood circulation mainly binds to apolipoprotein (apo) B-rich lipoproteins, with low-density lipoprotein (LDL) accounting for 80%, and the rest binds to high-density lipoprotein (HDL), lipoprotein a [Lp (a)] and very low-density lipoprotein (VLDL). In patients with atherosclerotic diseases, the level of Lp-PLA2 was positively correlated with the level of LDL subfraction.
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