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progression and response to therapy appears to differ significantly between the subtypes of PAH.

Once considered a disease of young

women, it is now clear that PAH is diagnosed at all ages, and in both men and women. In young to middle-aged adults the female to male ratio is roughly 2.3:1, but in children the ratio is 1.7:1 and in older adults the gender ratio approaches unity. ● Group 2 consists of PH associated with left heart disease. This pulmonary venous hypertension or post-capillary PH is defined as PH with elevated left ventricular filling pressures.

● Group 3 refers to PH secondary to lung disease or chronic hypoxaemia. The pathogenesis of group III PH may include obliteration of the pulmonary vascular bed as in emphysema or pulmonary fibrosis; and vasoconstriction and vascular remodeling induced by chronic hypoxaemia.

Recommended further reading

1. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004;351:1426–36. An excellent review starting with a succinct description of the pathogenesis of PAH, leading to an in-depth discussion of therapeutic strategies.

2. Proceedings of the 5th World Symposium on Pulmonary Hypertension, Nice, France 2013. J Am Coll Cardiol 2013;62(25 Suppl. D):D1–D126. World symposia on PH have been held every five years since the 2nd symposium in 1998 in Evian, France (the first symposium was held in Geneva in 1973). These meetings have turned into the epicentres of the PH medical and scientific community. The proceedings of the past meeting in Nice in early 2013 are an important resource for those who want to learn the field, as these proceedings cover all the major issues, summarising the state of the art, discussing controversies and creating a roadmap for the next five years.

3. D’Alonzo GE et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991;115:343–9. A landmark paper describing the results of the NIH registry of what was then called Primary Pulmonary Hypertension (now replaced by the term Idiopathic PAH). This registry provided key clinical data about PAH that helped create the framework for many subsequent clinical trials.

4. Lee S et al. Serotonin produces both hyperplasia and hypertrophy of bovine pulmonary artery smooth muscle cells in culture. Am J Physiol 1994;266:46–52. One of several papers showing that pulmonary vasoconstrictors, in this case serotonin, cause proliferation of pulmonary artery cells, thus potentially contributing to the vascular remodeling that is the key event in the pathogenesis of PH. It is thought that the beneficial effect of pulmonary vasodilators demonstrated in PAH is largely due to the effect of these drugs on remodelling.

5. Lane KB et al. Heterozygous germline mutations in a TGFb receptor, BMPR2, are the cause of familial primary pulmonary hypertension. Nat Genet 2000;26:81–4. Deng Z et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000;67:737-44. Thomson JR et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-b family. J Med Genet 2000;37:741–5. Two papers implicating BMP-R-2 gene mutations in the majority of cases of familial PAH. The third paper describes BMP-R-2 mutations in 26% of apparently sporadic cases of PAH.

6. Christman BW et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992;327: 70–5.

A paper showing the involvement of the thromboxane/prostacyclin imbalance in the pathogenesis of PAH, thus leading to trials of prostacyclin, the first specific therapy shown to be beneficial in PAH.

7. Rubin LJ et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol): results of a randomized trial. Ann Intern Med 1990;112:485–91.

The landmark trial showing the efficacy of epoprostenol in PAH. The only trial showing reduced mortality until the current era of long-term, event driven trials.

8. Galiè N et al. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394–403. Realisng that clinical trials powered to detect a mortality benefit are not a realistic goal in a rare disease as is PAH, the authors boldly performed a meta- analysis pooling data from all 22 RCTs of targeted therapies performed to date in PAH. The pooled data suggests that in comparison to placebo, targeted therapies for PAH reduced mortality by 43%.


● Group 4 is chronic thromboembolic pulmonary hypertension (CTEPH), and other pulmonary artery obstructions, according to new guidelines. Strictly speaking, CTEPH is a pulmonary arteriopathy and therefore might belong in group 1. However, CTEPH is in a category of its own, mainly because its

pathophysiology and management algorithm is different from that of group 1 PAH.

● Group 5 PH consists of miscellaneous conditions of largely unknown pathogenesis.

Symptoms and signs This section will focus on PAH, although much of it is relevant to all forms of PH. The objectives of the history and physical examination are: (1) to seek support for the diagnosis of PAH; (2) to seek symptoms and signs of diseases that cause PH such as left heart disease or chronic lung disease; (3) to seek evidence of the various conditions

known to be associated with PAH, such as collagen vascular diseases, HIV, portal hypertension, congenital heart disease and chronic lung disease; and (4) to seek signs of right heart failure that have important prognostic implications. By far the most common presenting symptom of PH is effort dyspnoea. Typically, in PAH, dyspnoea is progressive over weeks or a few months. Indeed dyspnoea over more than about a year is more likely to be due to PH secondary to congenital heart disease, or left heart disease (particularly diastolic heart failure) – or to chronic lung disease. Orthopnoea is suggestive of left heart disease. Angina and syncope are ominous signs in PH, indicating severe right ventricular decompensation. A careful review of systems is crucial. A history of venous thromboembolism should suggest the possibility of CTEPH. A family history of death from ‘heart failure’ at a relatively young age, or of hereditary haemorrhagic telangiectasia, suggest heritable PAH. Chronic liver

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