Pancreatitis-associated protein (PAP) is a novel cytokine with putative anti-inflammatory effects. PAP gene expression has been found to be increased in the myocardium of rats with decompensated pressure-overload hypertrophy. A prospective pilot study was performed to test the hypotheses that PAP is elevated in ambulatory patients with heart failure (HF) and that concentrations correlate with the severity of disease. Blood samples were obtained from patients with HF (n = 70) and normal controls (n = 17). Patients with New York Heart Association class III and IV symptoms had a greater mean PAP than patients with class I and II symptoms (35.5 ± 4.0 vs 10.3 ± 1.0 μg/L, p <0.001) and normal controls (35.5 ± 4.0 vs 6.2 ± 0.5 μg/L, p <0.001). Receiver-operating characteristic curves revealed that PAP had similar sensitivity and specificity for HF admission at 6 months as B-type natriuretic peptide and equivalent predictive value for 12-month and 24-month all-cause mortality. On the basis of the receiver-operating characteristic curve analysis, patients were then grouped into those with a serum PAP <24 or ≥24 μg/L. Patients with PAP ≥24 μg/L had significantly worse renal function, greater B-type natriuretic peptide and C-reactive protein levels, higher pulmonary artery systolic pressure, and greater 6- and 24-month all-cause mortality (p <0.05). In conclusion, PAP levels correlate with disease severity in patients with HF and are a marker of cardiorenal syndrome, neurohormonal activation, and elevated filling pressures. PAP is a sensitive and specific marker for increased 6-month HF morbidity and 12- and 24-month all-cause mortality. These results justify the prospective evaluation of PAP as a novel prognostic marker for disease severity in patients with HF.
Pancreatitis-associated peptide (PAP)/Reg 2 is a 16-kDa secretory peptide with structural homology to the C-type lectins, originally discovered in the pancreatic juice of rats with experimental acute pancreatitis. It has subsequently been shown to be expressed in a wide range of tissues in response to external stress or inflammation, for example, by intestinal epithelial cells in inflammatory bowel disease, in the brain tissue of patients with Alzheimer’s disease, and by sensory and motor neurons after peripheral injury. Interestingly, we have observed that PAP gene expression is upregulated in the myocardium of rats with decompensated pressure-overload hypertrophy (unpublished data). Others have highlighted the increased expression of PAP and other Reg-family proteins in rodent models of myocardial disease: a mouse model of myocarditis, a rat model of myocardial infarction, and pressure-overload hypertrophy. Although the precise actions of PAP are still not well understood, it is thought to exert anti-inflammatory effects by induction of the family of suppressor of cytokine signaling molecules. In this study, we aimed to test the hypotheses that circulating PAP levels are increased in patients with heart failure (HF) and that concentrations may correlate with symptoms and/or predict disease severity.
Methods
Subjects were recruited from the HF clinic at the University of Massachusetts Memorial Medical Center. Exclusion criteria for patients with HF included cancer, gastrointestinal disease, end-stage renal disease, and active infection. Normal controls were healthy subjects without hypertension, coronary artery disease, diabetes mellitus, HF, cancer, or gastrointestinal disease. Informed consent was obtained and blood was collected for the measurement of electrolytes, amylase, lipase, highly sensitive C-reactive protein, and B-type natriuretic peptide (BNP) by the University of Massachusetts clinical laboratory. Serum PAP was measured in France by Dynabio S.A. using enzyme-linked immunosorbent assay. Functional status was ascertained at the time of blood draw by patient interview. Clinical information was obtained from the electronic medical record. The protocol was approved by the University of Massachusetts institutional review board.
Log-transformed values of PAP and BNP were used to create receiver-operating characteristic curves for HF-related admissions and all-cause mortality at 6, 12, and 24 months. Normally distributed clinical characteristics were compared using Student’s t tests and Dunn’s post hoc tests. Kruskal-Wallis tests with Dunn’s post hoc tests were used to compare non-Gaussian continuous variables. Categorical values were compared between groups using chi-square tests. Correlation with clinical and laboratory parameters was performed using Spearman’s rank correlation. A p value <0.05 was considered statistically significant. Statistical analysis was performed using GraphPad Prism 5 (GraphPad Software, San Diego, California) and SPSS version 11.0 (SPSS, Inc., Chicago, Illinois).
Results
First, we tested the hypotheses that PAP levels are elevated in patients with HF and correlate with the severity of symptoms. Patients with New York Heart Association (NYHA) class III and IV symptoms had a greater mean PAP level than normal controls (35.5 ± 4.0 vs 6.2 ± 0.5 μg/L, p <0.001) and those with NYHA I and II symptoms (35.5 ± 4.0 vs 10.3 ± 1.0 μg/L, p <0.001) ( Figure 1 ).
We then compared the sensitivity and specificity of PAP with BNP in terms of predicting HF-related admissions and all-cause mortality. PAP and BNP were significant predictors of HF admissions at 6 months ( Table 1 ). Neither was significantly predictive of cumulative HF admissions at 12 or 24 months. In contrast, PAP and BNP were highly predictive of all-cause mortality at 6, 12, and 24 months ( Table 1 , Figure 2 ).
| Outcome | PAP | BNP | ||||
|---|---|---|---|---|---|---|
| AUC | 95% CI | p Value | AUC | 95% CI | p Value | |
| 6-mo mortality | 0.82 ± 0.05 | 0.72–0.92 | <0.05 | 0.82 ± 0.06 | 0.69–0.95 | <0.05 |
| 12-mo mortality | 0.87 ± 0.04 | 0.79–0.96 | <0.01 | 0.85 ± 0.05 | 0.75–0.94 | <0.001 |
| 24-mo mortality | 0.92 ± 0.03 | 0.85–0.99 | <0.001 | 0.91 ± 0.04 | 0.83–0.98 | <0.001 |
| 6-mo HF admissions | 0.73 ± 0.09 | 0.54–0.91 | <0.05 | 0.72 ± 0.08 | 0.57–0.88 | <0.05 |
To determine a diagnostic level of PAP in terms of prognosis, on the basis of the receiver-operating characteristic curve analysis, we chose to classify patients with HF into those with PAP levels <24 or ≥24 μg/L. We then compared clinical, laboratory, and echocardiographic variables between these groups ( Tables 2 and 3 ). Patients with PAP ≥24 μg/L were significantly older, had worse renal function, and had higher BNP, C-reactive protein, and pulmonary artery systolic pressure ( Table 2 ). They also had higher NYHA functional classifications, greater 6- and 24-month mortality, and more frequent moderate to severe mitral and/or tricuspid regurgitation ( Table 3 ).
| Variable | PAP (μg/L) | p Value | |
|---|---|---|---|
| <24 (n = 42) | ≥24 (n = 25) | ||
| Age (yrs) | 61.8 ± 1.8 | 70.5 ± 2.0 | 0.003 |
| Sodium (mEq/L) | 138.8 ± 0.43 | 139.3 ± 0.73 | 0.570 |
| Blood urea nitrogen (mg/dl) | 20.5 ± 1.4 | 44.1 ± 4.9 | <0.001 |
| Creatinine (mg/dl) | 1.0 ± 0.04 | 2.0 ± 0.19 | <0.001 |
| Estimated glomerular filtration rate (ml/min) | 106.9 ± 5.1 | 53.4 ± 6.8 | <0.001 |
| BNP (pg/ml) | 388.6 ± 123.0 | 932.8 ± 150.9 | <0.001 |
| Amylase (μg/L) | 76.2 ± 5.6 | 92.3 ± 9.2 | 0.122 |
| C-reactive protein (mg/L) | 4.8 ± 0.7 | 8.5 ± 1.4 | 0.010 |
| PAP (μ/L) | 11.9 ± 0.8 | 46.5 ± 4.2 | <0.001 |
| Ejection fraction (%) | 32.8 ± 2.5 | 35.0 ± 3.9 | 0.632 |
| Pulmonary artery systolic pressure (mm Hg) | 37.6 ± 2.6 | 52.7 ± 3.3 | <0.001 |
| Variable | PAP | p Value | |
|---|---|---|---|
| <24 (n = 42) | ≥24 (n = 25) | ||
| Men | 31 (73%) | 19 (73%) | 0.947 |
| NYHA functional classes I and II | 20 (76%) | 4 (21%) | <0.001 |
| NYHA functional classes III and IV | 5 (19%) | 15 (78%) | <0.001 |
| 6-mo mortality | 0 (0%) | 4 (16%) | 0.013 |
| 24-mo mortality | 0 (0%) | 4 (22%) | 0.005 |
| Coronary artery disease | 22 (55%) | 15 (60%) | 0.692 |
| Hypertension | 30 (75%) | 20 (80%) | 0.642 |
| Diabetes mellitus | 18 (45%) | 10 (40%) | 0.692 |
| Renal failure (creatinine >1.5 mg/dl) | 9 (22%) | 17 (68%) | <0.001 |
| Chronic obstructive pulmonary disease | 0 (0%) | 3 (12%) | 0.025 |
| Mitral regurgitation (moderate to severe) | 5 (13%) | 9 (36%) | 0.029 |
| Aortic valve disease (moderate to severe) | 2 (5%) | 5 (20%) | 0.075 |
| Tricuspid regurgitation (moderate to severe) | 4 (10%) | 9 (36%) | 0.013 |
| Left ventricular hypertrophy | 8 (22%) | 6 (26%) | 0.734 |
| Preserved ejection fraction | 7 (17%) | 9 (36%) | 0.092 |
| Ischemic cardiomyopathy | 17 (42%) | 12 (48%) | 0.664 |
| Nonischemic cardiomyopathy | 17 (42%) | 4 (16%) | 0.026 |
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