Physiology and Natural History

In patients with pulmonary hypertension associated with congenital heart defects, ultrastructural abnormalities are observed in endothelial cells, which suggest heightened metabolic function. If endothelial production of the von Willebrand factor (vWF) is increased, this may be associated with abnormal interactions with platelets leading to worsening of the pulmonary hypertension. We therefore evaluated vWF in 30 patients with pulmonary hypertension (25 with congenital heart defects) and in 30 individuals with normal pulmonary arterial pressure (12 with congenital heart defects). We measured the antigenic (vWF: Ag) and biologic (VWF: rist) activity of vWF in plasma and assessed endothelial vWF: Ag directly by an immunoperoxidase stain applied to lung biopsy tissue. Because of considerable variance and small size, the group of five patients with pulmonary hypertension and without congenital heart defects were excluded from statistical analyses. Patients with pulmonary hypertension and congenital heart defects had significant higher vWF: Ag levels than individuals with normal pulmonary arterial pressure without congenital heart defects (p < .05), whereas values in those with normal pressure and congenital heart defects were intermediate. In lung biopsy tissue available from 29 patients in this study and from 11 others we previously reported, immunostain of pulmonary arterial endothelium for vWF was intense (suggesting increased production) in 29 of 32 with pulmonary hypertension and congenital heart defects and in only one of eight with normal pulmonary arterial pressure and congenital heart defects (p < .01). Only three patients with congenital heart defects and pulmonary hypertension and increased vWF: Ag, however, had increased vWF: rist. Compatible with this discrepancy was a loss of vWF high-molecular weight forms as determined by both crossed immunoelectrophoresis and multimeric analysis. Our results suggest that increased vWF in most patients with congenital heart defects and pulmonary hypertension is associated with increased production of a biologically deficient molecule lacking high-molecular weight forms. Circulation 76, No. 5, 1043-1052, 1987. IT HAS BEEN SUGGESTED that abnormalities in platelet endothelial interaction may be important in the pathogenesis of pulmonary vascular disease and may contribute to the heightened pulmonary vascular reactivity observed in patients with pulmonary hypertension related to congenital heart defects.*1 We5 as well From the Research Institute and the Departments of Cardiology, Pathology, and Cardiovascular Surgery, The Hospital for Sick Children, the Departments of Pediatrics, Pathology, and Surgery, University of Toronto, and the Department of Pediatrics, McMaster University Medical Center, Hamilton, Ontario. Supported by the Heart and Stroke Foundation of Ontario (grant An-094). Dr. Rabinovitch is a Research Associate of the Heart and Stroke Foundation of Ontario. Dr. Andrew is a Scholar of the Canadian Heart Foundation. Address for correspondence: Marlene Rabinovitch, M.D., Department of Cardiology, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Received Nov. 17, 1986; revision accepted July 2, 1987. Vol. 76, No. 5, November 1987 as others6 7 have reported structural changes in the pulmonary vascular endothelial cells of these patients, which imply increased metabolic function. The von Willebrand Factor (vWF) is a large multimeric plasma glycoprotein produced by endothelial cells,8 which may be important in the adherence of platelets during vascular injury.9 We hypothesized that vWF synthesis would be increased in patients with pulmonary hypertension, in particular the group with associated congenital heart defects. This might contribute to abnormal interactions with platelets, perhaps resulting in increased adherence,' increased release of vasoactive substances3 and smooth muscle mitogens,10 and worsening of the pulmonary hypertension. We therefore measured the circulating components, vWF: Ag and vWF: rist, reflecting antigenic and biologic activity of vWF, analyzed the structure of the molecule by crossed 1043 by gest on A ril 6, 2017 http://ciajournals.org/ D ow nladed from