Pulmonary arterial hypertension (PAH) is a chronic, progressive disease defined by increasing pulmonary vascular resistance and pulmonary arterial pressure, ultimately leading to right heart failure. The life expectancy of patients with PAH who do not receive appropriate treatment is dramatically reduced. Guidelines for the diagnosis and treatment of PAH have been established by the American College of Chest Physicians (ACCP) and the European Society of Cardiology (ESC), and are updated regularly to incorporate new therapeutic options.1,2
Of note, PAH is one out of five classes of pulmonary hypertension according to the World Health Organization (WHO) classification, and includes idiopathic and familial PAH as well as PAH associated with anorexigens, HIV infection, portal hypertension, congenital heart disease, collagen vascular diseases and rare forms of pulmonary capillary or venous involvement.1
Established Therapies for Pulmonary Arterial Hypertension
Basic measures of PAH treatment include oral anticoagulation, oxygen supplementation and birth control. While physical training was thought to be unhelpful for patients with severe PAH, a recent study suggests that specifically adapted training protocols can result in significant improvements in exercise capacity and quality of life of these patients.3 Calcium channel blockers are the long-term treatment of choice in a small subgroup constituting approximately 7% of patients with PAH (the so-called ‘responders’); these patients can be identified by acute vasodilator testing during right heart catheterisation. Beta-blockers and angiotensin-converting enzyme (ACE)-inhibitors do not have a specific role in the treatment of PAH, and their use should be considered very carefully due to possible deleterious effects. Novel specific treatments have been developed in recent years that aim either to restore or to inhibit the effects of the intrinsic mediators prostacyclin, nitric oxide and endothelin-1.4
Prostacyclin – and its more stable analogues iloprost and treprostinil – can be applied as continuous intravenous (treprostinil also subcutaneous) infusion, leading to potent pulmonary and systemic vasodilation and inhibition of platelet aggregation.5,6 In an effort to reduce systemic side effects and catheter-associated risks, direct intrapulmonary drug delivery by inhalation was developed for iloprost7 and is currently being investigated for inhaled treprostinil.8 The inhalation of stable prostanoid derivates, compared with intravenous application, leads to pulmonary selective vasodilatation without clinically relevant tachyphylaxis.9 Inhaled iloprost is approved for PAH and in some countries also for non-operable chronic thromboembolic disease.
Endothelin Receptor Antagonists
Endothelin-1 is a potent vasoconstrictor and a smooth muscle cell mitogen that activates the endothelin receptors A and B. The dual endothelin receptor antagonist (ETRA) bosentan, as well as two selective endothelin receptor-A inhibitors (sitaxsentan and ambrisentan), have exhibited clinical efficacy as oral drugs.10–12 Bosentan and sitaxsentan are approved for the treatment of PAH. Liver toxicity is a potential side effect of this class of drugs and of bosentan; the underlying mechanism of this side effect is thought to be related to a competitive bile salt transporter interaction. Data from the controlled clinical trial with sitaxentan indicated a lower incidence of liver toxicity than was observed in the comparator arm with bosentan.13 Monthly liver function tests are therefore mandatory throughout the duration of the treatment. Relevant increases in serum aminotransferases were not reported for ambrisentan in the controlled clinical trials,14 but were in 2.1% percent of patients monitored afterwards over a mean time of 1.4 years.15
Phosphodiesterase-5 inhibitors (PDE5i) block the degradation of the second messenger of nitric oxide, cyclic guanosine monophosphate (cGMP). Due to high PDE5 expression levels in pulmonary vessels compared with other organs,16 the oral PDE5i sildenafil induces selective pulmonary vasodilatation without undesirable systemic side effects.17,18 Sildenafil is very well tolerated and was the first PDE5i to be approved for use in PAH. Considerable differences between the currently available PDE5i sildenafil, vardenafil and tadalafil were noted in an acute vasodilator trial with regard to the required doses, and selectivity for the pulmonary versus systemic circulation.19 Tadalafil is the second PDE5i to be investigated in a randomised controlled trial in patients with PAH.
Several uncontrolled clinical trials have demonstrated that combinations of two or more of the specific PAH medications may improve and/or stabilise previously unstable patients.20–23 Despite the lack of randomised controlled trials, combination therapies have been suggested by various guidelines for patients failing on initial monotherapies.24–25 Due to the high costs of each individual drug, sequential addition of drugs to an ongoing first-line treatment is currently the preferred approach.26
Data for one- and two-year survival are available for most of the specific PAH treatments, suggesting survival probabilities in the range of 95% and 80%, respectively. From the French PAH registry, it was reported that one-year survival with any of the available first-line treatments is approximately 88%,27 with more than half of the patients in need of additional therapy after two years due to disease progression.28 This indicates that PAH is neither controlled nor cured with the currently available treatment modalities. The growing insight into the pathomechanisms of the disease has led to promising new therapeutic developments, which are described in more detail below.
Phosphodiesterase 1C Inhibition
Over-expression of phosphodiesterase 1C (PDE1c) in the pulmonary resistance vessels of animals with experimentally induced pulmonary hypertension and in patients suffering from PAH was recently demonstrated.29 The PDE1c expression was positively correlated with the severity of the disease. The PDE1c was demonstrated to regulate smooth muscle cell proliferation, and inhibition of PDE1c potently reduced proliferation and vascular remodelling. Interestingly, sildenafil is known to partially inhibit PDE1c in clinically relevant concentrations, potentially explaining some of the previously shown anti-proliferative properties of this compound.30 Thus, PDE1c is an appealing pharmacological target for future therapeutic development in pulmonary vascular diseases.
Rho-kinase represents a common downstream effector of several vasoconstrictor signalling pathways, including those mediated by serotonin, angiotensin and endothelin-1, by controlling the contractile elements of smooth muscle cells. Rho-kinase phosphorylates, and thereby inactivates, myosin light chain phosphatase (MLCP), thus serving as a pro-contractile mediator.31 Systemic or inhaled Rho-kinase inhibitor (RKi) reduced pulmonary hypertension in animal models by promoting vasodilatation and anti-proliferation.32–34 The RKi fasudil exhibited potent pulmonary vasodilatation in humans when administered intravenously.35,36 Controlled clinical trials, potentially utilising an inhalative treatment approach, are anticipated.
Soluble Guanylate Cyclase Activation
The soluble guanylate cyclase (sGC) generates cyclic guanidine monophosphate (cGMP) upon activation by nitric oxide (NO).37 Pulmonary NO production after birth is pivotal for the change from a high to a low vascular resistance organ.38,39 In PAH, nitric oxide synthase expression levels and activity, as well as cGMP levels, are reduced.40 However, exogenous NO does not exert sufficient pulmonary vasodilation in most patients with PAH, which may in part be explained by an impaired sGC function – for example, by enzyme oxidation.41 Newly developed specific sGC activators and stimulators induce potent pulmonary vasodilation and, in some cases, are able to reactivate the inactivated forms of sGC.42,43 The sGC activators/stimulators are currently in clinical development for the treatment of pulmonary vascular disorders.
Vasoactive Intestinal Polypeptide
Vasoactive intestinal polypeptide (VIP) is a 28 amino-acid residue peptide that belongs to the glucagon-growth, hormone-releasing factor superfamily. It has an important role in water and salt secretion in the gut and is a potent vasodilator. Vasoactive intestinal polypeptide can activate both the cAMP and cGMP pathways via specific receptors (VPAC-1 and -2). These receptors are over-expressed in pulmonary arterial vessel walls, and VIP expression is dramatically downregulated in PAH.44 Preliminary data from patients have demonstrated the favourable effects of inhalation of VIP, thus suggesting that further controlled trials are warranted.
Receptor Tyrosine Kinase Inhibition
Several growth factors exert their effects by auto-phosphorylation of intracellular tyrosine residues of their cognate receptors. Small-molecule inhibitors of receptor tyrosine kinases (RTK) have been developed as anti-tumour and anti-angiogenesis treatments. The inhibition of the epidermal growth factor receptor (EGFR) in the monocrotaline rat model of PAH demonstrated beneficial effects.45 Platelet-derived growth factor-BB (PDGF-BB) induced proliferation as well as recruitment of smooth muscle cells during pulmonary vascular remodelling.46,47 Imatinib, apart from its inhibitory effects on the RTK c-it and bcr-abl in chronic myeloid leukaemia, also blocks PDGFreceptor- β.48 In two distinct animal models of PAH, complete rescue of fatally ill animals and nearly complete restoration of normal vascular morphology was demonstrated with imatinib, applied at the time of fully developed vascular remodelling.49
Preliminary clinical experience in PAH patients with progressive disease despite combination therapy showed excellent improvement of pulmonary haemodynamics, exercise capacity and functional class.50–52 A controlled clinical trial assessing the efficacy and safety of imatinib in PAH patients is currently underway.
Germline mutations in the gene encoding the type II bone morphogenetic protein receptor (BMPR-2,) have been observed in patients with familial and idiopathic PAH.53 The BMPR-2 must form heterodimers with a type I receptor (for example, BMPR-1A) to induce signalling, and functional downregulation of BMPR-1A in secondary forms of pulmonary hypertension may mimic the genetic defect of BMPR-2 in patients with iPAH.54 In that report, it was demonstrated that patients with pulmonary hypertension of different aetiologies all exhibit over-expression of angiopoietin-1 (ang-1) in vascular smooth muscle cells, which leads to functional downregulation of BMPR-1A in endothelial cells via tie-2 receptor activation. In addition, ang-1 may induce the production of mitogenic factors for smooth muscle cells such as serotonin.55–57 In line with these reports, ang-1 over-expression by viral gene transfer induced pulmonary hypertension in rats.58 In contrast, cell-based gene transfer of ang-1 reduced the severity of monocrotaline-induced pulmonary hypertension in rats, and this effect was attributed to the angiogenic and endothelial survival signalling effect of ang-1.59 The role of ang-1 in pulmonary hypertension thus remains to be elucidated.
Circulating vascular progenitor cells – endothelial progenitor cells (EPC), circulating fibrocytes – play important roles in angiogenesis and vascular remodelling.60,61 The incorporation of endothelial or smooth muscle cells from bone marrow into adult growing or ageing lungs appears to be negligible.62 Bone marrow-derived cells did not differentiate into endothelial or smooth muscle cells in monocrotaline-induced pulmonary vascular remodelling, whereas significant engraftment was observed in experimental femoral artery neointima formation in the same rats.63 Organ- or lesion-specific mediators may, therefore, be relevant for the recruitment of endothelial- and smooth-muscle progenitors. Moreover, the majority of EPC may not be recruited from bone marrow but from other sources, including the gut and liver.64
Circulating fibrocytes – hybrid cells expressing myeloid and fibroblast markers – may be recruited from the bloodstream to promote tissue remodelling during organ and vascular fibrosis.65,66 These fibrocytes may represent a new target to prevent tissue remodelling, but their precise role in the pathogenesis of PAH remains unclear.
Therapeutic infusion of in vitro cultured and eNOS-transfected EPC increased the survival and reduced the right ventricular pressure and hypertrophy in rats with monocrotaline-induced pulmonary hypertension.67 In mice, bone marrow injection attenuated dehydro-monocrotaline- induced pulmonary hypertension, but aggravated chronic hypoxic pulmonary hypertension.68 An open, placebo-controlled pilot study on the effect of autologous EPC infusion in iPAH has been published recently, and reported an improvement in exercise capacity and haemodynamics.69
Clinical experience has demonstrated that a significant and positive effect of specific drugs in a large patient cohort may not translate into beneficial effects for an individual patient. Tailoring treatments to individual patients should thus take biological differences into account. Considerable effort is currently being made to establish biological screens that are predictive for therapy response or failure in order to better serve individual patients and to identify patients at risk. In this respect, cardiovascular medicine remains behind clinical practice in oncology, in which tailored therapies are becoming more and more state of the art in specific instances. For example, in chronic myelogenous leukaemia (CML), the response to imatinib treatment can be predicted by assessing phosphorylation of bcr-abl tyrosine kinase substrates or the phosphotyrosine content of circulating Cd34+ cells.70,71
Targeting Right Ventricular Hypertrophy
Right ventricular (RV) failure is the ultimate cause of death in PAH. Signs of RV failure are strong negative predictors of survival.72–74 RV function has so far not been addressed as a therapeutic target in PAH. In contrast to the left side, the right ventricle is able to completely reverse ventricular hypertrophy and dilation if RV afterload is normalised.75,76 Moreover, direct effects of sildenafil on myocardial hypertrophy have been demonstrated.77 Sildenafil prevented left ventricular hypertrophy, dilation and failure in a model of aortic banding. Small animal models of RV failure induced by pulmonary artery banding have recently been utilised to investigate this important new therapeutic field.