Connective Tissue Disease–associated Pulmonary Arterial Hypertension in the Modern Treatment Era
ABSTRACT Pulmonary arterial hypertension in association with connective tissue disease (CTD-PAH) has historically had a poor prognosis, with a 1-year survival rate among patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) of 45%. However, more therapies have become available.
To investigate the survival and characteristics of all patients diagnosed with CTD-PAH in the U.K. pulmonary hypertension service.
National registry of all incident cases of CTD-PAH diagnosed consecutively between January 2001 and June 2006.
Patients with CTD-PAH (429; 73% SSc-PAH) were diagnosed by a catheter-based approach. One- and 3-year survival rates were 78 and 47% for patients with isolated SSc-PAH. Survival was worse for those with respiratory disease-associated SSc-PAH (3-yr survival, 28%; P = 0.005) whereas survival among patients with exercise-induced SSc-PAH was superior (3-yr survival, 86%; P = < 0.001). Age, sex, mixed venous oxygen saturation, and World Health Organization functional class were independent predictors of survival in isolated SSc-PAH. Nineteen percent of patients with exercise-induced SSc-PAH and 39% of patients with isolated SSc-PAH who were in functional classes I and II had evidence of disease progression. The prevalence of diagnosed SSc-PAH is 2.93 per 1 million. The 3-year survival rate of 75% for those with pulmonary arterial hypertension associated with systemic lupus erythematosus (SLE-PAH) was significantly better than that for patients with SSc-PAH (P = 0.01).
Survival of patients with SSc-PAH in the modern treatment era is better than in historical series. A significant proportion of patients with mild functional impairment or exercise-induced SSc-PAH have evidence of disease progression. Survival of patients with respiratory disease-associated pulmonary hypertension is inferior. SLE-PAH has a better prognosis than SSc-PAH.
- SourceAvailable from: Adrian J Hobbs[Show abstract] [Hide abstract]
ABSTRACT: Background and purposeIdiopathic pulmonary fibrosis (IPF) is a progressive fibro-proliferative disorder refractory to current therapy commonly complicated by the development of pulmonary hypertension (PH); the associated morbidity and mortality are substantial. Natriuretic peptides possess vasodilator and anti-fibrotic actions, and pharmacological augmentation of their bioactivity ameliorates renal and myocardial fibrosis. Herein, we investigated whether natriuretic peptides possess an intrinsic cytoprotective function offsetting the development of pulmonary fibrosis and associated PH, and whether therapeutics targeting natriuretic peptide signalling demonstrate efficacy in this life-threatening disorder.Experimental approachPulmonary haemodynamics, right ventricular function, and markers of lung fibrosis were determined in wild type (WT) and natriuretic peptide receptor (NPR)-A knockout (KO) mice exposed to bleomycin (1mg/kg). Human myofibroblast differentiation was studied in vitro.Key resultsExacerbated cardiac, vascular and fibrotic pathology was observed in NPR-A KO animals, compared to WT mice, exposed to bleomycin. Treatment with a drug combination that raised circulating natriuretic peptide levels (ecadotril) and potentiated natriuretic peptide-dependent signalling (sildenafil) reduced indices of disease progression, whether administered prophylactically or to animals with established lung disease; this positive pharmacodynamic effect was diminished in NPR-A KO mice. Atrial natriuretic peptide and sildenafil synergistically reduced transforming growth factor-β-induced human myofibroblast differentiation, a key driver of remodelling in IPF patients.Conclusions and implicationsThese data highlight an endogenous host-defence capacity of natriuretic peptides in lung fibrosis and PH. An ecadotril/sildenafil combination is effective in reversing the pulmonary haemodynamic aberrations and remodelling that characterize the disease, advocating therapeutic manipulation of natriuretic peptide bioactivity in IPF.British Journal of Pharmacology 03/2014; DOI:10.1111/bph.12694 · 4.99 Impact Factor
- Pulmonary Hypertension - From Bench Research to Clinical Challenges, 12/2011; , ISBN: 978-953-307-835-9
- Archives of cardiovascular diseases 04/2011; 104(4):211-5. DOI:10.1016/j.acvd.2011.01.006 · 1.66 Impact Factor