Associations of pentraxin-3 with cardiovascular events, incident heart failure, and mortality among persons with coronary heart disease: Data from the Heart and Soul Study

doi:10.1016/j.ahj.2011.11.007

American Heart Journal

Volume 163, Issue 2, February 2012, Pages 274-279

https://doi.org/10.1016/j.ahj.2011.11.007 Get rights and content

Background

Pentraxin-3 (PTX3) is an inflammatory marker thought to be more specific to vascular inflammation than C-reactive protein (CRP). Whether PTX3 is independently associated with adverse events among persons with stable coronary heart disease (CHD), independently of CRP, and whether kidney dysfunction influences these associations are not known.

Methods

We evaluated the associations of baseline PTX3 levels with all-cause mortality, cardiovascular (CV) events (myocardial infarction, stroke, or CHD death), and incident heart failure (HF) during 37 months among ambulatory persons with stable CHD participating in the Heart and Soul Study. Cox proportional hazards models were adjusted for age, sex, race, hypertension, diabetes, smoking, and CRP.

Results

Among 986 persons with stable CHD, each 1 unit increase in log PTX3 at baseline was associated with an 80% increased risk of all-cause mortality (hazard ratio [HR] 1.8, 95% CI 1.5-2.1), a 50% increased risk of CV events (HR 1.5, 95% CI, 1.2-1.9), and an 80% greater risk of incident HF (HR 1.8, 95% CI, 1.3-2.5). Further adjustment for estimated glomerular filtration rate (eGFR) attenuated these associations to 1.6 (1.3-1.9) for mortality, 1.3 (1.0-1.6) for CV events and 1.5 (1.1-2.1) for incident HF. Stratification by eGFR >60 mL/min per 1.73m² or <60 mL/min per 1.73m² did not affect these associations (P interaction > .3 for all outcomes).

Conclusions

Among persons with stable CHD, higher PTX3 concentrations were associated with increased risk for all-cause mortality, CV events, and incident HF independently of systemic inflammation. Adjustment for eGFR modestly attenuated these associations, suggesting that future studies of PTX3 should adjust for kidney function.

Section snippets

Participants

As described previously, the Heart and Soul Study is a prospective cohort study initially designed to evaluate the influence of psychosocial factors on CVD events in ambulatory persons with stable CHD.¹⁵ Study participants were recruited from outpatient clinics in the San Francisco Bay Area using ≥1 of the following inclusion criteria: (1) history of myocardial infarction, (2) angiographic evidence of 50% stenosis in ≥1 coronary vessels, (3) evidence of exercise-induced ischemia by treadmill or

Results

Among 986 participants, mean (SD) age was 67 years (11), median (25th, 75th percentiles) of PTX3 was 0.60 ng/mL (0.41, 0.96), and mean (SD) of eGFR was 70.8 (23.0). Persons with higher PTX3 were older, more likely to be of white race, more likely to have a history of chronic HF (CHF), and had lower eGFR, higher LV mass index, and lower ejection fraction by echocardiography. Persons in the highest tertile of PTX3 were less likely to smoke, had lower triglycerides, and had lower levels of CRP and

Discussion

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 CHD.

To our knowledge, we are the first

Acknowledgements

Potential conflicts of interest

None declared.

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Pentraxin 3 regulates tyrosine kinase inhibitor-associated cardiomyocyte contraction and mitochondrial dysfunction via ERK/JNK signalling pathways
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Hepatocellular carcinoma (HCC) patients suffer varying degrees of heart dysfunction after tyrosine kinase inhibitor (TKI) treatment. Interestingly, HCC patients often have higher levels of pentraxin 3 (PTX3), and PTX3 inhibition was found to improve left ventricular dysfunction in animal models.
We sought to assess the therapeutic potential of PTX3 inhibition on TKI-associated cardiotoxicity.
We used a human embryonic stem cell line, RUES2, to generate cardiomyocyte cultures (RUES2-CM) for functional testing. We also assessed heart function and PTX3 expression levels in 16 HCC patients who received TKI treatment, 3 HCC patients who did not receive TKIs, and 7 healthy volunteers.
Significantly higher PTX3 expression was noted in HCC patients with TKI treatment versus those without, and 38% of male and 33% of female patients had QTc prolongation after TKI treatment. Treatment of cardiomyocyte cultures with sorafenib also increased PTX3 expression and induced cytoskeletal remodelling, contraction reduction, sodium current inhibition, and mitochondrial respiratory dysfunction. PTX3 colocalised with CD44 in cardiomyocytes, and cardiomyocyte contraction, mitochondrial respiratory function, and regular cytoskeletal and apoptotic protein expression were restored with PTX3 inhibition. CD44 knockdown confirmed PTX3/CD44 signalling. These results suggest a possible mechanism in which sorafenib treatment increases PTX3 expression, thereby resulting in reduced extracellular signal-regulated kinase (ERK) 1/2 expression that affects cardiomyocyte contraction, while also activating c-Jun N-terminal kinase (JNK) downstream pathways to disrupt mitochondrial respiration and trigger apoptosis.
TKI-induced cardiotoxicity may be partly mediated by the upregulation of PTX3, and thus PTX3 inhibition has potential as a therapeutic strategy.
Pentraxin-3 in coronary artery disease: A meta-analysis
2019, Cytokine
Citation Excerpt :
Particularly, the expression of pentraxin-3 is increased in human atherosclerotic plaques [6]. Several studies [7–12] but not all [13] have shown that increased pentraxin-3 level was associated with an increased risk of all-cause mortality or cardiac death in both clinically stable CAD and ACS. However, studies [9,11,12,14–19] regarding the usefulness of pentraxin-3 level for predicting cardiac events have yielded conflicting results.
Studies on the prognostic significance of circulating pentraxin-3 level in patients with coronary artery disease (CAD) have yielded conflicting results. The aim of this meta-analysis was to evaluate the prognostic value of circulating pentraxin-3 level in CAD patients.
We made a systematic literature search in Pubmed, Embae, CNKI, Wanfang, and VIP database from their inception to January 10, 2019 for prospective cohort studies that investigated the association between pentraxin-3 level and adverse outcomes in patients with CAD. The outcome measures were all-cause mortality, cardiac death, and cardiac events (cardiac death, nonfatal myocardial infarction, heart failure or coronary revascularization). Multivariable-adjusted risk ratio (RR) with 95% confidence intervals (CI) was pooled for the highest versus the lowest pentraxin-3 group to summarize the predictive value.
Nine studies were included, enrolling 5,174 CAD patients. Overall, CAD patients with the highest pentraxin-3 level had an increased risk of all-cause mortality (RR 1.81; 95% CI 1.43–2.28), cardiac death (RR 1.77; 95% CI 1.38–2.26), and cardiac events (RR 1.61; 95% CI 1.16–2.25). However, elevated pentraxin-3 level appeared to not significantly increase the risk of cardiac events (RR 1.63; 95% CI 0.71–3.72) in stable CAD subgroup.
In CAD patients, elevated circulating pentraxin-3 level is possibly an independent predictor of all-cause mortality, cardiac death, and cardiac events. However, interpretation of these findings should be with caution due to the small number of studies analyzed.
Exosomes as intercellular communication messengers for cardiovascular and cerebrovascular diseases
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The cardiovascular system acts like a well-trained orchestra, where exosomes play a role in paracrine and autocrine signaling. Exosomes derived from various cell subtypes, ensure the cell-to-cell communication in the cardiovascular and cerebrovascular systems. These exosomes, found in all biological fluids, are involved in the stimulation of endothelial cell migration, angiogenesis and cardiac/blood vessels repair upon injury in physiological and pathological conditions. This chapter reviews the role of exosomes in a variety of cardiovascular and vascular neurodegenerative diseases. These roles vary from biomarkers to endogenous cargos and therapeutical bioengineered transfer systems. Possible benefits conferred by exosomes in the cardiac regeneration and repair are also discussed.
Pentraxin-3 and coronary artery disease
2018, Experimental Gerontology
Update on the role of Pentraxin 3 in atherosclerosis and cardiovascular diseases
2017, Vascular Pharmacology
Citation Excerpt :
Noteworthy, elevated levels of PTX3, but not high-sensitivity CRP, are significantly and independently correlated with the presence of HF among patients with normal LVEF and even among patients with LV diastolic dysfunction and LVEF [152]. Furthermore, several long-term prospective studies identified PTX3 as significant predictor of CV events including CV/all-cause mortality and worsening HF [129,149,150,153,154,157–160]. Although not constitutively expressed in the central nervous system [161], PTX3 transcription was amplified in acute ischemic stroke (IS) and in chronic conditions like Parkinson's disease and multiple sclerosis [162,163].
Pentraxin 3 (PTX3) is an acute-phase protein that was recently demonstrated to play pleiotropic activities in cardiovascular (CV) diseases. Tumor necrosis factor and interleukins up-regulates PTX3 transcription in different cell types (i.e. endothelial cells, phagocytes, smooth muscle cells, fibroblasts and glial cells) involved in atherogenesis. By interacting with numerous ligands, PTX3 acts as a modulatory molecule of complement system, inflammatory response, angiogenesis, and vascular/tissue remodeling. Experimental data point to a beneficial role of PTX3 in atherosclerotic plaque development and vulnerability. Animal studies indicated a protective role of PTX3 signaling in ischemic/reperfusion injury and failing heart. Clinical studies have so far provided contrasting results, highlighting a debated role of PTX3 as an active mediator of endothelial dysfunction, atherosclerotic plaque vulnerability and worse outcome after ischemic events. Therefore, substantial evidence suggests a dual role of PTX3 as modulator or amplifiers of the innate immune response. The final result of PTX3 activation might be determined by a fine tuning of time, space and environmental signals. The aim of this review is to provide an overview of biological properties of PTX3 in CV diseases and to discuss the ability of PTX3 to act as a crossroad between pro- and anti-inflammatory pathways.
Pentraxin 3 in neonates with and without diagnosis of pulmonary hypertension
2017, Clinical Biochemistry
Pentraxin 3 is a novel biomarker produced by vascular endothelial cells and macrophages. In recent studies involving adults, pentraxin 3 has been introduced as a reliable biomarker in the evaluation of cardiovascular disease and pulmonary hypertension. This study was conducted with an aim to measure the level of pentraxin 3 in neonates with pulmonary hypertension and comparing with normal healthy controls.
In a case-control study, plasma pentraxin 3 levels were evaluated in 3 groups of neonates including neonates with pulmonary arterial hypertension (PAH), neonates with congenital heart disease without pulmonary arterial hypertension (CHD-PAH) and normal healthy neonates.
Plasma pentraxin 3 levels in 72 neonates (21 in PAH, 19 in CHD-PAH, and 32 in control group) were measured. Demographic characteristics had no significant statistical difference among the 3 groups. Pentraxin 3 levels in PAH group was significantly higher than CHD-PAH and control groups (2.12 ± 2.32 vs. 0.58 ± 0.57 and 1.03 ± 1.38 ng/mL, P = 0.008, respectively). No significant correlation was found between concentrations of pentraxin 3 and cardiac ejection fractions between PAH and CHD-PAH (r = 0.009, P = 0.97). However, significant positive correlation was detected between PTX3 concentrations and pulmonary pressures between these two groups (r = 0.499, P = 0.001).
Results from our study showed that pentraxin 3 levels were increased in newborn infants with pulmonary hypertension. Plasma pentraxin 3 could be considered as a novel adjunct diagnostic tool in the evaluation of pulmonary hypertension in combination with echocardiography or as a diagnostic tool when echocardiography is not readily available for confirmation of increased pulmonary pressure.

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Coronary Artery DiseaseAssociations of pentraxin-3 with cardiovascular events, incident heart failure, and mortality among persons with coronary heart disease: Data from the Heart and Soul Study

Background

Methods

Results

Conclusions

Section snippets

Participants

Results

Discussion

Acknowledgements

Atherosclerosis

J Am Coll Cardiol

Am J Kidney Dis

Am J Kidney Dis

J Biol Chem

Prognostic significance of the long pentraxin PTX3 in acute myocardial infarction

Circulation

Associations of pentraxin 3 with cardiovascular disease and all-cause death: the Cardiovascular Health Study

Arterioscler Thromb Vasc Biol

Production of the long pentraxin PTX3 in advanced atherosclerotic plaques

Arterioscler Thromb Vasc Biol

Racial differences in the association of pentraxin-3 with kidney dysfunction: the Multi-Ethnic Study of Atherosclerosis

Nephrol Dial Transplant

Plasma pentraxin 3 in patients with chronic kidney disease: associations with renal function, protein-energy wasting, cardiovascular disease, and mortality

Clin J Am Soc Nephrol

Soluble TWEAK and PTX3 in nondialysis CKD patients: impact on endothelial dysfunction and cardiovascular outcomes

Clin J Am Soc Nephrol

Evidence for increased cardiovascular disease risk in patients with chronic kidney disease

Curr Opin Nephrol Hypertens

Association of cystatin C with mortality, cardiovascular events, and incident heart failure among persons with coronary heart disease: data from the Heart and Soul Study

Circulation

Coronary Artery Disease
Associations of pentraxin-3 with cardiovascular events, incident heart failure, and mortality among persons with coronary heart disease: Data from the Heart and Soul Study