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Fractional flow reserve (FFR) is a useful modality to assess the functional significance of coronary stenoses. Although adenosine triphosphate (ATP) is generally used as the hyperemic stimulus, we sometimes encounter adverse events like hypotension during FFR measurement. Nicorandil, an ATP-sensitive potassium channel opener, recognized as an epicardial and resistance vessel dilator, has not been fully evaluated as a possible alternative hyperemic agent. The aim of this study was to evaluate the feasibility and safety of intracoronary nicorandil infusion compared to intravenous ATP for FFR measurement in patients with coronary artery disease. A total of 102 patients with 124 intermediate lesions (diameter stenosis >40 and <70% by visual assessment) were enrolled. All vessels underwent FFR measurements with both ATP (150 μg/kg/min) and nicorandil (2.0 mg) stimulus. FFR, hemodynamic values, and periprocedural adverse events between the two groups were evaluated. A strong correlation was observed between FFR with ATP and FFR with nicorandil (r = 0.954, p < 0.001). The agreement between the two sets of measurements was also high, with a mean difference of 0.01 ± 0.03. The mean aortic pressure drop during pharmacological stimulus was significantly larger with ATP compared to nicorandil (9.6 ± 9.6 vs. 5.5 ± 5.8 mmHg, p < 0.001). During FFR measurement, transient atrioventricular block was frequently observed with ATP compared to nicorandil (4.0 vs. 0%, p = 0.024). This study suggests that intracoronary nicorandil infusion is associated with clinical utility and safety compared to ATP as an alternative hyperemic agent for FFR measurement.

Growth hormone (GH) and its mediator, insulin-like growth factor-1 (IGF-1), play a critical role in human growth. In circulation, IGF-1 is found in a ternary complex with IGF binding proteins (IGFBPs) and acid labile subunit (ALS) but little attention has been paid to the regulation of IGF-1 bioavailability. Recently, pregnancy-associated plasma protein-A2 (PAPP-A2) and stanniocalcin-2 (STC2) were identified as novel modulators of IGF-I bioavailability. PAPP-A2 is a protease which cleaves IGFBP-3 and -5, while STC2 inhibits PAPP-A and PAPP-A2 activity. In collaboration with a group in Madrid, we reported the first human cases carrying mutations in the PAPPA2 gene who presented with short stature, elevated total IGF-1, IGFBP-3, IGFBP-5 and ALS, but low free IGF-1. Additionally, the patients demonstrated insulin resistance and below average bone mineral density (BMD). The PAPP-A2 deficient patients were treated with recombinant human IGF-1, resulting in improvements in growth velocity, insulin resistance, and BMD. These findings suggested that the bioactive, free IGF-1 liberated from IGFBPs by PAPP-A2 is important for human growth. Mouse models of PAPP-A2 and STC2 provide further insights into their roles in growth physiology. This review will summarize new insights into PAPP-A2 and STC2 and their role in the GH-IGF axis, thereby highlighting the importance of the regulation of IGF-1 bioavailability in human health and disease.

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Objective Pregnancy-associated plasma protein-A2 (PAPP-A2) is a metalloproteinase that cleaves IGFBP-3 and IGFBP-5. Human mutations in PAPPA2 result in short stature with a low percentage of free IGF-I. Little is known about PAPP-A2 levels and the regulation of free IGF-I throughout childhood. We examined PAPP-A2 and intact IGFBP-3 levels in childhood and explored associations between PAPP-A2, free and total IGF-I, and total and intact IGFBP-3 and their relationship to the percentage of free to total IGF-I and anthropometric factors. Design Cross-sectional study at a single center. Methods PAPP-A2, free IGF-I, and intact IGFBP-3 levels were measured in childhood (3–18 years old) and an evaluation of the relationship between these proteins and anthropometric factors. Results In 838 children, PAPP-A2 consistently decreased throughout childhood. In contrast, free IGF-I increased. A pubertal peak in free IGF-I was present in females but was less evident in males. Intact and total IGFBP-3 increased throughout childhood; however, intact IGFBP-3 had a more marked rise than total IGFBP-3. Percent free IGF-I decreased with no distinct pubertal peak. PAPP-A2 levels positively correlated with the percent free IGF-I (Male, Female; r = 0.18, 0.38; P < 0.001) and negatively with intact IGFBP-3 (Male, Female; r = −0.58, −0.65; P < 0.0001). Conclusions This is the first study to describe serum PAPP-A2 and intact IGFBP-3 in children between 3 and 18 years of age. Our correlative findings suggest that PAPP-A2 is an important regulator of the percent free IGF-I which can be a marker of perturbations in the GH/IGF-I axis.

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