In this cohort of persons with stable CHD, we found that PTX3 is significantly associated with all-cause mortality, CV events, and incident HF independently of demographics, traditional CVD risk factors and systemic inflammation (CRP). Adjustment for eGFR modestly attenuated these associations. Our findings suggest that this novel marker of vascular inflammation may be an important mechanism involved in vascular injury and repair among persons with stable coronary heart disease.
To our knowledge, we are the first to report an independent association of PTX3 with overall mortality among persons with established and stable CVD, independent of systemic inflammation. PTX3 is produced by multiple cell types (peripheral leukocytes, vascular endothelial cells, smooth muscle cells, to name a few) and is produced in response to both inflammatory stimuli (IL-1, TNF-a, agonists of TLR, LPS) and anti-inflammatory stimuli (IL-10 and HDL).23
The finding that PTX3 is strongly associated with overall mortality in our cohort invites at least two interpretations. Vascular pathology may contribute to the overall risk of death in a cohort of subjects with CVD. Conversely, it is possible that this strong association with overall mortality relates to a non-vascular function of PTX3. The mechanism by which PTX3 is associated with overall mortality requires further study.
Our findings that PTX3 is associated with cardiovascular events and incident heart failure, independent of systemic inflammation are noteworthy. These findings are in accordance with prior reports suggesting that PTX3 may be more strongly associated with adverse outcomes after acute coronary ischemia than CRP and troponin1–2
and that it may be associated with cardiovascular death in an elderly cohort free of CVD.3
The association with incident heart failure is supported by previous findings that PTX3 is elevated in heart failure patients with normal ejection fraction.5
The mechanisms by which PTX3 is associated with cardiovascular outcomes remain unclear. Current investigations suggest that PTX3 may be part of a protective mechanism in vascular repair. PTX3 binds and inactivates FGF-2, an angiogenic growth factor responsible for smooth muscle proliferation involved in atherosclerosis.24–25
Knockout models in mice have been used to demonstrate that atherosclerotic lesions develop faster in PTX3 deficient mice.26
Cardiac ischemia-reperfusion injury was exacerbated in PTX3 knockout mice.27
Taken together, these findings suggest that PTX3 may be elevated in vascular injury as a protective mechanism, much like white blood cells are elevated during infection. Very high levels of PTX3 may indicate a more severe vascular disease state, explaining its ability to detect increased risk for adverse outcomes. Elucidating PTX3 pathways in vascular pathology may lead to a better understanding of risk for secondary events among persons with stable CHD.
Interestingly, the addition of eGFR as an adjustment variable resulted in some attenuation of associations of PTX3 with CV events and incident HF, albeit PTX3 remained statistically significantly associated with these outcomes even after adjustment for eGFR. Several possibilities may explain these findings. One is that vascular injury is a parallel process present in persons with kidney dysfunction and coronary heart disease. Another is that kidney dysfunction is a confounder due to filtration of PTX3 by the kidney. It is less likely that PTX3 is filtered in the glomerulus, given its molecular weight (42kDa), and our group’s findings that the association of PTX3 and eGFR differs by race/ethnicity.6
In the exploratory analysis, the addition of LV mass index and ejection fraction had little effect on cardiovascular outcomes. This would suggest that if PTX3 is related to vascular injury, these echocardiographic measures inadequately measure the effect of this injury in the heart. Future studies are needed to elucidate the mechanisms of these associations.
Strengths of the current study include the large sample size, the extended follow-up time, the comprehensive assessment of risk factors, and the availability of adjudicated outcome classifications. There are also several important limitations. Because the Heart and Soul cohort is recruited primarily from a veteran population and is comprised mainly of white men, our results may not generalize to more heterogeneous populations. Some misclassification may have occurred due to the fact that cardiovascular outcomes were assessed by review of medical records, and incident HF was defined by hospitalization. All participants had prevalent CHD, and results may differ in other settings.
In summary, we found that PTX3 is associated with overall mortality, CV events and incident HF among persons with stable coronary disease. These findings were independent of systemic inflammation, kidney dysfunction and traditional CV risk factors. The addition of eGFR to predictive models provided substantial attenuation, suggesting that future studies of PTX3 should take kidney function into account.