Editorials
Pentraxin 3 – A Link Between Obesity, Inflammation and Vascular Disease? –
2016 Volume 80 Issue 2 Pages 327-328
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2016 Volume 80 Issue 2 Pages 327-328
Obesity is reaching epidemic proportions in Western countries, and is associated with an increased risk of cardiovascular disease (CVD) and mortality.1 Inflammation, oxidative stress and CV alterations, including endothelial dysfunction2 and cardiac remodeling, are responsible for this CVD risk.
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Obesity-induced inflammation involves many cellular types, including immune and inflammatory cells. Pentraxin (PTX) 3 is released by leukocytes and myeloid dendritic cells in response to pro-inflammatory cytokines, or following stimulation with microbial components. PTX3 recognizes and binds many pathogens, facilitating their phagocytosis and clearance. Endothelial cells, smooth muscle cells, fibroblasts, adipocytes, chondrocytes, epithelial cells, and adipose tissue also produce PTX3.
PTX3 may represent a link between obesity, inflammation and CV. However, data on this topic are unclear. PTX3 levels have been equivocally associated with obesity,3,4 and PTX3 is elevated in patients with metabolic syndrome, which is prevalently characterized by visceral adiposity. Another piece of information is provided by Santilli et al5 in this issue of the Journal, who analyze the interplay of obesity, PTX3 and platelet activation. Platelets play a key role in the atherothrombosis, as evidenced by interventional trials with aspirin, which inhibits COX1 preventing formation of the pro-aggregating thromboxane (Tx)A2.6
Obesity is associated with platelet activation; a 10% weight loss reduces oxidative stress and platelet TxA2 formation, suggesting that oxidative stress could promote platelet activation.7 Moreover, NOX2-derived oxidative stress is implicated in platelet activation via formation of isoprostanes.8 PTX3 may represent an alternative mechanism for obesity-related platelet activation. Santilli et al5 explore this hypothesis in a study that included 12 obese patients evaluated at baseline and at 3, 6 and 12 months after laparoscopic gastric banding (LAGB). At 6 and 12 months, PTX3 increased by 178.8% and 214.9% (P<0.0001), respectively, while C-reactive protein decreased by 24% and 29.7% (P<0.0001).
Coincidentally, markers of platelet activation, as assessed by plasma levels of sCD40L (decreased by 64.3% and 58.6%, P=0.002) and urinary 11-dehydro-TXB2 excretion (from 1,443 pre-surgery to 715 and 564 pg/mg creatinine, respectively, P<0.0001) significantly improved.
PTX3 was inversely related to 11-dehydro-TXB2 and sCD40L levels, suggesting that PTX3 could possess antiplatelet efficacy. This finding may provide further insight into the putative anti-atherosclerotic effect of PTX3, as experimental studies have suggested a role for PTX3 as a modulator of vascular disease.9 Thus, PTX3 inhibits fibroblast growth factor 2, and knockout animals for PTX3 show more severe inflammation and atherosclerotic lesion. Unfortunately, there is no evidence yet that PTX3 specifically interacts with platelets and promotes inhibition. As correctly underscored by the authors, the association between PTX3 and platelet activation lowering achieved by weight loss could merely reflect a reduction in the inflammatory process. Moreover, weight loss could ameliorate endothelial dysfunction and, in turn, secretion of PTX3 by endothelial cells, which are the main source of circulating PTX3.
Specific inhibition of PTX3 with ensuing analysis of its clinical effect would be relevant to explore if this protein has an important role in platelet activation and eventually in atherothrombosis.
A crucial point, however, is how to transfer experimental data to human CVD. Most observational clinical studies evaluating the predictive role of PTX3 against CVD in long-term follow-up have reported a direct association between PXT3 and CVD (Table).3,4,10–20
| Study/Author | Population | Main outcome | Results |
|---|---|---|---|
| Cardiovascular Health Study (CHS)3 |
1,583 subjects free from CVEs |
Angina, MI, stroke, CVD death and all- cause death |
A standard deviation increase in PTX3 (189 ng/ml) predicted CVD death and all- cause death but not angina, MI, or stroke |
| Multi-Ethnic Study of Atherosclerosis (MESA)4 |
2,838 subjects free from CVEs |
85-year CVEs and mortality | A standard deviation higher level of PTX3 predicted MI, CVEs but not stroke, CVD mortality, or all-cause death |
| Haibo et al10 | 596 patients with stable CAD | CVEs at 3 years from PCI | High post-PCI PTX3 levels predicted CVEs |
| Tomandlova et al11 | 262 patients with STEMI | 30-day and 1-year mortality | PTX3 at 24 h after STEMI was a predictor of 30-day and 1-year mortality |
| Liu et al12 | 377 patients with CHF | CVEs: cardiac death or re-hospitalization for worsening HF at 3 years |
PTX3 ≥364 ng/ml predicted CVEs |
| Heart and Soul Study13 | 986 patients with stable CAD |
All-cause mortality, CVEs (MI, stroke or CAD death), incident HF at 37 months |
High PTX-3 predicted all-cause mortality, CVEs and incident HF |
| CARE Trial14 | 749 patients with recurrent MI |
Recurrent MI or coronary death during at 5 years |
No significant difference in plasma PTX3 levels between the cases and controls PTX3 did not predict CAD risk (non-fatal MI and fatal CAD) |
| Akgul et al15 | 499 STEMI patients | In-hospital CV mortality and 2-year all- cause mortality |
PTX3 ≥32 ng/ml predicted 2-year all-cause mortality |
| Guo et al16 | 525 NSTEMI patients | 30-day CVEs and mortality | PTX3 ≥30 ng/ml predicted 30-day CVEs and mortality |
| Mjelva et al17 | 871 patients with chest pain and suspected ACS |
MI and mortality at 7 years | PTX3 >588 ng/ml predicted mortality |
| Matsui et al18 | 204 patients with unstable angina/NSTEMI |
6-month cardiac death, re-hospitalization for ACS, or for worsening HF |
PTX3 levels predicted CVEs |
| Latini et al19 | 1,457 patients from the CORONA and 1,233 patients from the GISSI-HF trials |
Baseline and 3-month changes in PTX3 levels correlated with all-cause and CV mortality Median follow-up was 33 in CORONA and 47 months in GISSI-HF |
Baseline elevated PTX3 was associated with all-cause mortality, CV mortality or hospitalization for worsening HF; 3-month changes in PTX3 predicted mortality |
| Eggers et al20 | 401 NSTE-ACS patients from the GUSTO IV study |
1-year mortality | PTX3 did not predict 1-year mortality |
ACS, acute coronary syndrome; CAD, coronary artery disease; CHF, chronic heart failure; CV(E), cardiovascular (event); MI, myocardial infarction; NSTEMI, non-ST-segment elevation MI; PCI, percutaneous coronary intervention; PTX, pentraxin; STEMI, ST-segment elevation MI.
Together these data suggest that increased PTX3 serum levels depict patients with severe inflammatory disease and likely at higher risk of death, but the role in clinically overt atherosclerotic disease progression is difficult to explain, also in the light of experimental data suggesting an inverse relationship between PTX3 and atherosclerotic disease.
In conclusion, there is still uncertainty on how to interpret experimental and clinical data about the role of PTX3 in vascular disease and to explain, more particularly, if PTX3 actually has atheroprotective activity. The increase in PTX3 levels observed in clinical studies may represent a reactive protective mechanism, but there is no study that has explored if modulation of PTX3 levels affects CV events. Further studies are needed to establish if a cause-effect relationship between PTX3 and CV events does exist.
