Angiotensin-Converting Enzyme Gene Polymorphisms and Prognosis in Chronic Thromboembolic Pulmonary Hypertension

Abstract

hronic thromboembolic pulmonary hypertension (CTEPH) due to unresolved pulmonary embolism is a potentially correctable pulmonary hypertension (PH) by pulmonary thromboendarterectomy. [1][2][3] The incidence of this disease has been estimated as 0.1-0.5% in patients surviving acute pulmonary embolism. 1,2 However, it was recently reported that the incidence of this disease is in fact relatively high (3.8% at 2 years after acute pulmonary embolism). 4 In addition, a recent study based on mailed questionnaires in Japan revealed 169 new cases of acute pulmonary embolism and 17 new cases of CTEPH within 2 months, suggesting that the ratio of CTEPH to acute pulmonary thromboembolism (10.1%) might be high in Japan. 5 Without surgery the prognosis of CTEPH is thought to be poor, and the survival rate at 5 years is 30% in patients with mean pulmonary arterial pressure (Ppa) higher than 40 mmHg. 6 The precise mechanism of the progression of PH remains undefined. Although the extent of vascular obstruction is a major determinant, hemodynamic progression may involve recurrent thromboembolism or in situ thrombosis as well as pulmonary vascular remodeling. 2 The renin-angiotensin system plays a fundamental role in the onset and/or progression of a variety of cardiovascular diseases, 7-12 including venous thromboembolism. 13,14 Angiotensin-converting enzyme (ACE) plays an important role in systemic vascular remodeling and also endothelial dysfunction. 12,15,16 As well as its involvement in the development of cardiovascular diseases, the ACE gene has also been considered a candidate for contributing to the development of exercise-induced PH in chronic obstructive pulmonary disease (COPD) patients in Japan. 17 The ACE gene contains a polymorphism based on the presence (insertion, I) or absence (deletion, D) within intron 16 of a 287-basepair nonsense DNA domain, resulting in 3 genotypes (II, DI, DD). 18 The D allele is associated with increased circulating and cellular concentrations of ACE, which could be related to increased cardiovascular risk including venous thromboembolism. 7,12,13,19 In addition, increased expression of ACE has been reported in primary and secondary plexiform PH, 20 and ACE inhibition therapy delays pulmonary vascular neointimal formation. 21 The ACE genotype may contribute to vascular remodeling in distal pulmonary arteries even in CTEPH.We hypothesized that ACE-I/D polymorphism might be related to CTEPH susceptibility, severity of the disease, and its outcome. Methods SubjectsThe patient group comprised 95 consecutive patients with

Survival and Quality of Life for Patients With Peripheral Type Chronic Thromboembolic Pulmonary Hypertension

“…31 In the present series, ACE-ID genotypes were determined in 29 of 32 medically treated patients other than those in the mild disease group. Of 7 patients with II genotype type, no patient died, whereas of 16 with ID or DD genotypes, 6 died.…”

Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat

“…Curiously, mice genetically deficient in ACE exhibit decreased pulmonary vascular remodeling in response to chronic hypoxia but still have elevated pulmonary arterial pressure (42,71). Further evidence of a link between disruption in the normal RAS and PH relates to the associations between polymorphisms in the ACE gene and PH secondary to chronic obstructive pulmonary disease (28), a chronic thromboembolic state (66), or exposure to high altitude (2).…”

Implications of Mutations of Activin Receptor-Like Kinase 1 Gene (<i>ALK1</i>) in Addition to Bone Morphogenetic Protein Receptor II Gene (<i>BMPR2</i>) in Children With Pulmonary Arterial Hypertension

“…21,22 In previous reports, it was also implied that the D allele of ACE was related to pulmonary hypertension by various causes. 23,24 Furthermore, polymorphism in the 894T allele of eNOS and the D allele of ACE could induce rapid progression of high-altitude pulmonary edema because of hypoxic pulmonary vasoconstriction at a high altitude. 25,26 Hence, we investigated if polymorphism of eNOS or ACE in PAH patients could influence the severity of the clinical features.…”