GENETICS OF PRIMARY PULMONARY HYPERTENSION

Pulmonary arterial hypertension (PAH) is an uncommon disorder of the pulmonary vasculature characterized by remodeling of the smallest pulmonary arteries, leading to a progressive increase in pulmonary vascular resistance. Various forms of PAH exist, including familial (FPAH) and idiopathic (IPAH) forms and associated conditions. FPAH transmits as an autosomal dominant trait that exhibits genetic anticipation but also markedly reduced penetrance (20%). The primary genetic defect of FPAH, identifiable in more than 70% of cases of FPAH, is a mutation in the gene encoding bone morphogenetic protein receptor type 2 (BMPR2), a member of the transforming growth factor β superfamily. The true prevalence of BMPR2 mutations in IPAH is unknown, with reports ranging from 10% to 40% of patients. The cause of the variable phenotypic expression of PAH among carriers of mutated BMPR2 genes and patients is unclear, and likely related to environmental and genetic modifiers of disease not yet fully elucidated. Although BMPR2-related pathways seem to be pivotal, many other mediator pathways participate in the pathogenesis of different forms of PAH and are being actively investigated, both independently and in combination. As understanding of the molecular basis of this devastating disease improves, opportunities for earlier diagnosis, additional therapeutic regimens, and perhaps disease prevention will emerge.

Despite advances in drug therapy, severe sustained pulmonary arterial hypertension can be a fatal disease. When medical therapy is exhausted, transplantation may be an option. The most common approaches are heart-lung transplantation or double-lung transplantation, with repair of the cardiac defect if necessary. Single-lung transplantation optimises the use of scarce donors but leads to particular management problems. Heterotopic cardiac transplantation has occasionally been employed in subjects with pulmonary vascular disease secondary to cardiac disease. Timing of transplantation is a difficult decision and depends largely on the aetiology of pulmonary arterial hypertension and the rate of decline. Outcomes following transplantation are steadily improving but remain poorer than for other solid organ transplants, mainly because of the high incidence of post-transplant bronchiolitis obliterans syndrome.

Primary graft failure (PGF) is a devastating acute lung injury syndrome following lung transplantation. We sought to identify donor, recipient, and operative risk factors for its development.

We conducted a cohort study of 255 consecutive lung transplant procedures performed between October 1991 and July 2000. We defined PGF as follows: (1) diffuse alveolar opacities exclusively involving allograft(s) and developing within 72 h of transplant, (2) a ratio of Pao₂ to fraction of inspired oxygen < 200 beyond 48 h postoperatively, and (3) no other secondary cause of graft dysfunction identified. Risk factors were assessed individually and adjusted for confounding using multivariable logistic regression models.

Tertiary-care academic medical center.

The overall incidence was 11.8% (95% confidence interval [CI], 7.9 to 15.9). Following multivariable analysis, the risk factors independently associated with development of PGF were as follows: a recipient diagnosis of primary pulmonary hypertension (PPH; adjusted odds ratio [OR], 4.52; 95% CI, 1.29 to 15.9; p = 0.018), donor female gender (adjusted OR, 4.11; 95% CI, 1.17 to 14.4; p = 0.027), donor African-American race (adjusted OR, 5.56; 95% CI, 1.57 to 19.8; p = 0.008), and donor age < 21 years (adjusted OR, 4.06; 95% CI, 1.34 to 12.3; p = 0.013) and > 45 years (adjusted OR, 6.79; 95% CI, 1.61 to 28.5; p = 0.009).

Recipient diagnosis of PPH, donor African-American race, donor female gender, and donor age are independently and strongly associated with development of PGF.

Pulmonary involvement is common in patients with portal hypertension and can manifest in diverse manners. Changes in pulmonary arterial resistance, manifesting either as the hepatopulmonary syndrome or portopulmonary hypertension (PPHTN), have been increasingly recognized in these patients in recent years. This review summarizes the clinicopathologic features, diagnostic criteria, as well as the latest concepts in the pathogenesis and management of PPHTN, which is defined as an elevated pulmonary artery pressure in the setting of an increased pulmonary vascular resistance and a normal wedge pressure in a patient with portal hypertension.

The 1998 World Health Organization Pulmonary Hypertension Meeting in Evian, France, marked a fundamental shift in our understanding of this disease entity with the adoption of an aetiology-based classification system and descriptive reporting protocols. The five new categories incorporate a broad array of diseases included within their respective categories on the basis of shared clinical, pathological, therapeutic and prognostic features.

Since 1998, further insights into the pathogenesis have been gained through studies of subsets of the related diseases causing pulmonary arterial hypertension with implication of chemical mediators causing dysfunction of both medial smooth muscle cells and endothelial cells. The genetic candidate involved in both familial and 25% of sporadic cases of arterial pulmonary hypertension is the bone morphogenic protein on chromosome 2. Such findings have also had an effect on histological assessment and grading schemes.