CRP not only related to recurrent CV events, but also to cancer in patients with stable CVD
Data of a prospective cohort suggest that chronic systemic low-grade inflammation, as measured by CRP, plays a role in development of cancer, particularly of the lung, in those with stable CVD.
The relation between systemic inflammation and incident cancer in patients with stable cardiovascular disease: a cohort studyLiterature - Van ’t Klooster CC, Ridker PM, Hjortnaes J, et al. On behalf of the UCC-SMART study group - Eur Heart J, ehz587, https://doi.org/10.1093/eurheartj/ehz587
Introduction and methods
Chronic systemic low-grade inflammation can initiate and accelerate arterial plaque formation and is thereby involved in development of atherosclerotic disease [1]. Low-grade inflammation may also be related to risk of incident cancer, suggest prospective cohort studies. In particular, a higher risk of lung cancer was seen in patients with C-reactive protein (CRP) levels >3 vs. <1 mg/L [2,3]. Moreover, the CANTOS trial showed that patients in the stable phase after myocardial infarction (MI) who were randomized to the interleukin 1β (IL-1β)-inhibitor canakinumab, showed a lower incidence of CVD [4] and total cancer mortality [5].
CRP can serve as a marker of systemic low-grade inflammation, commonly defined as CRP ≤10 mg/L [6]. CRP likely has no causal relationship with cancer, but low-grade inflammation is postulated to be mechanistically linked to cancer development through stimulation of tumor cell survival and proliferation, and promotion of metastatic spread [7,8].
Smoking and abdominal obesity are risk factors for CVD, low-grade inflammation and cancer [9]. It has been described that patients with stable CVD have a higher risk of cancer than the general population [10]. The current study evaluated the relation between systemic low-grade inflammation and the risk of recurrent CVD and incident cancer in patients with stable CVD.
Data of the Utrecht Cardiovascular Cohort - Second Manifestations of ARTerial disease (UCC-SMART) cohort were used, an ongoing prospective cohort study. For the current study, adults with established CVD at baseline between September 1996 and March 2017 were included (N = 8139). Inclusion occurs at least 2 months after the qualifying vascular event. Information on occurrence of recurrent CVD, bleeding events, incident diabetes, and end-stage renal disease was gathered with biannual questionnaires, and complimented with hospital or general practitioner’s data. 7178 Patients with stable vascular disease and CRP ≤10 mg/L were included (median follow-up: 8.3 years, IQR: 4.6-12.3, total of 58568 person-years of follow-up, 1289 recurrent CV events).
Main results
- Crude incidence rates for recurrent CV events were 1.53%, 1.55%, 2.07%, 2.64% and 3.30% across CRP quintiles.
- When comparing the highest CRP quintile with the lowest, the highest showed a higher risk (HR: 1.58, 95%CI: 1.31-1.91). The risk of cancer and/or CVD was 45% higher in the highest vs. the lowest quintile (HR: 1.45, 95%CI: 1.26-1.68).
- 1072 incident malignancies were observed during follow-up, most of which were cancer of the lung (n=226), prostate (n=188) and colon/rectum (n=177).
- The highest CRP quintile showed a higher risk of cancer than the lowest quintile (HR: 1.41, 95%CI: 1.22-1.63). Per 1 mg/L higher CRP, the risk increased by 7% (HR: 1.07, 95%CI: 1.04-1.09).
- Risk of incident lung cancer in the highest CRP quintile was higher than in the lowest (HR: 3.39, 95%CI: 2.03-5.69), and risk of lung cancer increased per 1 mg/L by 16% (HR: 1.16, 95%CI: 1.10-1.22).
- Urinary tract cancer and lymphoid /hematopoietic cancer did not show significantly higher risk in the highest vs lowest CRP quintiles. No relation was seen between CRP level and risk of breast or prostate cancer, or incident colorectal cancer.
- No difference in relation between CRP level and risk of lung cancer was seen for various histopathological subtypes (small cell lung cancer and non-small-cell lung cancers).
Conclusion
These data show that in patients with stable vascular disease plasma CRP concentration is not only related to risk of recurrent CV events, but also to risk of cancer, in particular lung cancer. This finding supports a role for chronic systemic low-grade inflammation as a stimulating factor in cancer development in patients with established vascular disease.
Editorial comment
In their editorial comment, Lancellotti et al. note that the process of cancer initiation and development involves complex tumour-immune cell interplay, which may be due to a deficit in the resolution of inflammation. Van ‘t Klooster et al. have prospectively looked into the relationship between low-grade inflammation and the risk of cancer. The higher incidence of cancer in those with hsCRP levels in the highest quintile as compared with the lowest, was observed in current and former smokers, but not in patients who never smoked. ‘This is the first clinical demonstration that low-grade inflammation in the context of atherosclerosis and smoking is associated with cancer development and recurrent CV events.’
An analysis of the Framingham Heart Study showed that even 25 years after quitting smoking, the risk of cancer remained three-fold higher compared to never-smokiers. The risk did decrease significantly five years after quitting, and continued to decline in time, as compared to continued smoking. Thus, the authors note, it would have been interesting to analyze the association between the lifetime smoking history and hsCRP levels, to further assess whether the relationship between low-grade inflammation and cancer incidence is likely to be promoted by smoking.
hsCRP measurements may help refine risk reduction strategies in selected patient populations, and the current findings ‘might pave the way toward new inflammation-targeted therapies for cancer prevention and/or improved cancer outcomes in the context of CV disease.’
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