Key Point

bFGF levels are elevated in PAH patients—especially in patients with PPH as opposed to patients with PAH from other etiologies. It is not known whether bFGF levels are a marker or a cause of the disease.

BOSTON—Endothelial and smooth muscle cell proliferation is a recognized component of pulmonary arterial hypertension (PAH). New research shows that plasma and urine basic fibroblast growth factor (bFGF) levels are higher in PAH patients—particularly in those with primary pulmonary hypertension (PPH)—and that elevated bFGF levels are associated with increased disease severity, suggesting that part of the cellular proliferation may be growth factor–mediated.¹

Jacques Benisty, MD, MPH, and colleagues studied bFGF and vascular endothelial growth factor (VEGF) levels in the plasma and urine of 117 PAH patients (ages 10 to 75) and 60 controls. Up-regulation of bFGF may be “one of the molecular mechanisms [contributing] to the vascular cellular growth leading to obstruction in PAH,” explained Dr. Benisty, an Instructor in Surgery at the Children’s Hospital in Boston. Alternatively, “bFGF might be useful as a biomarker.”

bFGF LEVELS ELEVATED

The median urine bFGF level in PAH patients was about double that of controls (2,305 pg/L vs 1,111 pg/L). Plasma levels of bFGF were also significantly elevated in PAH patients (1.9 pg/mL vs 0.5 pg/mL in controls). Both urine and plasma bFGF levels differed according to PAH etiology: PPH patients had the highest levels (2,741 pg/L and 2.1 pg/mL, respectively), followed by patients with PAH from congenital heart disease (2,330 pg/L and 1.7 pg/mL), and from connective tissue disease (1,493 pg/L and 1.0 pg/mL). This finding suggests that there may be different mechanisms underlying PPH and PAH that stem from other causes.

Using the 95th percentile in control subjects as an upper limit of normal, the researchers found that 21% of PAH patients had elevated urine bFGF levels and 51% had elevated plasma bFGF levels. As expected, these elevations were most common in the PPH patients: More than half of them had elevated plasma levels, and 26% had elevated urine levels.

TREATMENT AND PROGNOSIS

Although most patients (61%) were receiving prostacyclin, endothelial blockers, or calcium-channel blockers, 12 patients (all with PPH) were receiving no therapy. Not surprisingly, plasma bFGF levels in the treatment-naïve patients were significantly higher than those of controls (1.91 pg/mL vs 0.5 pg/mL), as were the urine bFGF levels (2,338 pg/L vs 1,111 pg/L). What is surprising is that bFGF and VEGF levels in the nontreated patients were not significantly different from those in patients who were receiving therapy, although plasma VEGF levels were nonsignificantly higher in treatment-naïve patients.

bFGF levels corresponded with illness severity, particularly in PPH patients. In patients with poor functional capacity (World Health Organization [WHO] classes III or IV), median plasma bFGF was 4.2 pg/mL, compared with 0.5 pg/mL among patients in classes I or II. When analyzed by bFGF level threshold, high plasma bFGF levels were associated with a sevenfold increased risk of poor functional capacity in PPH patients. In a subgroup of 14 PPH patients who had elevated plasma bFGF and VEGF levels, pulmonary artery pressures were higher and WHO class was worse than in PPH patients without elevations in both growth factors.

A NEW THERAPEUTIC TARGET?

Both human and animal studies have suggested that the lung is a site of significant production of bFGF, wrote the authors. In fact, they continued, although they may not parallel lung tissue bFGF levels precisely, plasma and urine bFGF levels probably reflect spillover into the circulation.

Dr. Benisty believes that other growth factors, such as matrix metalloproteinase and angiopoietin 1 and 2 may be implicated in PAH as well. Although it is not known whether elevated bFGF levels are merely a marker or a cause of the disease, the authors speculate that bFGF levels might be a new therapeutic target. Dr. Benisty concluded, “We need to look at these growth factors prospectively … to determine their potential usefulness as biomarkers. We also need to do mechanistic studies to determine if they have a causal role in cellular vascular proliferation in PAH.”

—Tamara Gibb

Reference
1. Benisty JI, McLaughlin VV, Landzberg MJ, et al. Elevated basic fibroblast growth factor levels in patients with pulmonary arterial hypertension. Chest. 2004;126:1255-1261.

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