Elevated hs-CRP level is an important factor predicting the increased CHD risk. It was found that hs-CRP level after a high-fat meal significantly increased in patients with high cardiovascular risk but not in healthy subjects16. The present study showed that CHD patients even after a daily breakfast could also cause non-fasting increase in hs-CRP level, regardless of the conditions of statins using and fasting hs-CRP level. It suggested that the non-fasting increase in hs-CRP level could be related not only to the content of meal17, but also to the underlying diseases of the individuals and the associated cardiovascular risk. More importantly, more than one-third of CHD patients with non-fasting high hs-CRP (i.e., > 3mg/L) came from those without high hs-CRP levels in the fasting state. It indicated that postprandial phase is the key period of atherosclerosis when considering humans are in the postprandial state for most of the day.
Hs-CRP is a kind of hypersensitive detection technology used in clinical laboratory, which can accurately detect low concentration CRP and improve the sensitivity and accuracy of the test. CRP is a nonspecific inflammatory marker secondary to the stimulation of interleukins (IL), including IL-1, IL-6 and IL-17, and the activation of NF-κB plays an important role in regulating CRP production18, 19. CRP can be secreted by many cells, such as artery smooth muscle cells, aortic endothelial cells, inflammatory cells, pyramidal neurons, renal cortical tubular epithelial cells and so on, but it mainly comes from hepatocytes in vivo18, 20–22. Liver connects with gastrointestinal tract directly via portal vein, and is sensitive to food intake. The gastrointestinal tract delivers lipids to liver through the portal vein when western food which is characterized of high sugar and lipid is digested23. Under the stimulation of hyperlipidemia, the liver anti-inflammatory state could be turned to inflammatory state. No matter what the level of fasting hs-CRP is, the two groups of CHD patients with showed significant and similar increase in TG level after a daily meal. Thus, it can be considered that food intake induced the production of hs-CRP from liver.
In addition, diet-induced systemic inflammation accelerates IL production and release in other cells, which might also promote the production of CRP in the non-fasting state. It has been reported that IL-1β increased significantly in metabolic syndrome patients with central obesity after a high-fat meal, accompanied by significant postprandial hypertriglyceridemia which represents the increased number of triglyceride-rich lipoproteins and their remnants24. Chylomicron remnants promoted the expression of IL-1β in monocytes25. Moreover, we found that postprandial triglyceride-rich lipoproteins promoted premature aging of mouse subcutaneous adipose derived mesenchymal stem cells through oxidative stress mechanism, accompanying by IL-1α, IL-6 and other inflammatory factors26. As a key inflammatory factor in the upstream of inflammatory signaling pathway, IL-1β up-regulation or increased release can trigger a cascade of downstream inflammatory factors, including CRP.
In the present study, there was no significant relationship between total AUC of hs-CRP and BMI or total AUC of TG, which may be due to the influence of lipid-lowering drugs. Because a considerable number of enrolled patients with CHD took statins, which could have an impact on the level of hs-CRP. It was reported that statins play an antiinflammation role in hepatocytes via limiting proinflammatory genes expression, such as limiting NF-κB nuclear accumulation and DNA binding27. Additionally, clinical trials also showed the antiinflammatory role of statins13, 28, 29. It was consistent with the finding of the present study that statins using ≥ 1m significantly reduced both fasting and non-fasting hs-CRP in CHD patients.
However, statins using ≥ 1m was not able to completely antagonize the rise of hs-CRP level caused by a daily breakfast, even in those with fasting hs-CRP level ≤ 3mg/L. There was no deliberate diet control in this study. A daily breakfast could be a high-fat meal or not for different patients. Dietary habits could be a factor that reduces the effectiveness of drugs in non-fasting state. The Centers for Disease Control and the American Heart Association defined that hs-CRP level ≤ 3mg/L indicated lower or average cardiovascular events risk while hs-CRP level > 3mg/L indicated higher cardiovascular events risk30. Under the influence of food intake, the non-fasting hs-CRP elevated to a higher level of hs-CRP (> 3mg/L) in approximately 30% patients with a lower level of fasing hs-CRP (≤ 3mg/L). It indicated that about 30% of CHD patients in higher cardiovascular events risk group in the non-fasting state derived from lower or average cardiovascular risk group in the fasting state. Considering that humans are in the postprandial state in the most of a day, thus the detection of fasting hs-CRP level is not enough to reflect the real state of hs-CRP throughout a day. It was confirmed that intermittent fasting was responsible to reducing risk factors of cardiovascular disease, such as LDL-C, TG and fat mass31, 32. However, it was still uncertain whether it will influence the cardiovascular risk deriving from hs-CRP elevation in the non-fasting state.
Elevated hs-CRP act as both inducer and indicator of CHD, patients with CHD showed increased hs-CRP despite LDL-C < 70mg/dL and consequently benefited from antiinflammation therapy33. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) proved that reducing hs-CRP though the IL-1β and downstream IL-6-receptor signaling pathway without reducing LDL-C level significantly lower incidence of recurrent cardiovascular events14. Interestingly, the Cardiovascular Inflammation Reduction Trail (CIRT) using Methotrexate to antiinflammation showed a completely contrary result compared with CANTOS15. According to CANTOS, antiinflammation therapy can independently reduce hs-CRP and cardiovascular events without LDL-C level changed. However, CIRT concluded patients with stable atherosclerosis did not reduce levels of IL-1β, IL-6, or hs-CRP and did not result in fewer cardiovascular events exposure to low-dose methotrexate, a kind of anti-inflammation drug probably reflects adenosine-mediated anti-inflammatory effects. A possible explanation is that the baseline CRP level in CANTOS (4.2mg/L) is significantly higher than in CIRT (1.6mg/L), indicating only patients with high baseline CRP level can benefit from statins anti-inflammation therapy.
Our study result is accord with the result of CANTOS and CIRT studies, statins play a role in non-fasting hs-CRP level decrease in CHD patients with higher fasting hs-CRP level. In our study, in fasting hs-CRP level ≤ 3mg/L group, hs-CRP level elevated significantly in both subgroups regardless of statins duration after meal in 2h and 4h. Interestingly, it is completely different in fasting hs-CRP > 3mg/L group, the hs-CRP level of inpatients with statins using ≥ 1m didn’t elevated significantly after meal, but the inpatients without & < 1m statins using whose hs-CRP level gradually elevated after meal, especially in 4h, and it is significantly higher than hs-CRP level in fasting state. Therefore, we hypothesis statins can reduce non-fasting hs-CRP level when fasting level of hs-CRP > 3mg/L.