Ebook: Pulmonary Arterial Hypertension
Pulmonary hypertension is a fatal lung and heart disease. It is characterized by shortness of breath, fatigue and fainting. It is exacerbated by an increase of the pressure in the lung vasculature through exercise, leading to progressive worsening of hemodynamics, right ventricular hypertrophy, right heart insufficiency and finally right heart failure. This book focuses on pulmonary arterial hypertension, a rare and progressive subgroup of pulmonary hypertension, which is today incurable and terminally fatal. Classification of pulmonary arterial hypertension, its pathology, and strategies for future therapy will be of interest both to those suffering from the disease and those who take care of patients. This volume will also engage physicians and other scientists contributing to an understanding of the pathophysiology of pulmonary arterial hypertension and attempting to extend life of humans with pulmonary arterial hypertension by developing causal and curative therapies.
“The Solvay Pharmaceuticals Conferences: where industry meets academia in a search for novel therapies”
Pulmonary Arterial Hypertension: New Insights
Pulmonary arterial hypertension is diagnosed if the mean pulmonary artery pressure is greater than 25 mmHg at rest or at least 30 mmHg during exercise and is associated with enhanced pulmonary vascular resistance and with a mean pulmonary wedge pressure and left ventricular end diastolic pressure of less than 15 mmHg . Persistent elevation of pulmonary artery pressure and vascular resistance leads to right ventricular failure and death . The pathogenesis of pulmonary arterial hypertension involves several contributing processes: vasoconstriction, smooth muscle and endothelial cell proliferation, and thrombosis.
Calcium channel blockers, anticoagulants, prostacyclin and its analogs, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors dominate therapy of pulmonary arterial hypertension today. However, this therapy does not improve long-term survival and the right heart dysfunction remains the main cause of death of pulmonary arterial hypertension sufferers, despite the implemented therapy.
Disease modification and preventive strategies must be better addressed in order to achieve tangible therapeutic benefits for patients who are at risk for developing or already have pulmonary arterial hypertension. Therefore, the focus of therapy is shifting from treatment of the acutely sick towards disease modifying measures and health management. Such fundamental changes can only be achieved if interest of pharmaceutical industry is shifted towards research in this field.
During the last decade progress in understanding of the role of endothelin receptors in vasoconstriction and proliferation was made, knowledge of mechanisms controlling circulation in the pulmonary artery has expanded, understanding of nitric oxide in the pathogenesis of pulmonary arterial hypertension has matured and new medicines such as bosentan, a dual endothelin A and B receptor antagonist , and sildenafil, a phosphodiesterase type 5 inhibitor, have been introduced .
The emerging therapies of pulmonary arterial hypertension involve 5-hydroxytryptamine transporter blockers, vasoactive intestinal peptide, statins, and voltage-gated potassium channel modulators .
The challenge is to ensure that new findings related to the pathogenesis of pulmonary arterial hypertension are adequately translated into therapies and are driving progress of drug finding by means of systems biology approaches combined with intelligent synthesis of molecules . Increasing understanding of processes responsible for restriction of pulmonary circulation and vascular remodeling provides new basis for modification of the disease early in its course with the aim of improving quality of life of patients marked by significant prolongation of survival.
The current volume contains contributions from the Tenth Solvay Pharmaceuticals Conference on Pulmonary Arterial Hypertension held in Riga (Latvia) December 11–12, 2008.
It has been the aim of these conferences to bring together scientists from academia and from industry in order to stimulate exchange between them in a challenging setting. The focus of the recent conference was placed on the cardiopulmonary disorder “pulmonary artery hypertension”, characterized by multiple unknown aspects which obscure understanding of mechanisms involved in its pathogenesis, ways of its prevention and means limiting its progress, and on the aspects of drug finding and development. New diagnostic procedures and insights into therapy were highlighted including imaging, novel functional diagnostic approaches, disease monitoring, biomarkers and future therapeutics.
W. Cautreels, C. Steinborn, L. Turski
 A. Puri, M.D. McGoon, S.S. Kushwaha. Pulmonary arterial hypertension: current therapeutic strategies. Nat. Clin. Pract. Cardiovasc. Med. 4 (2007) 319–329.
 L.J. Rubin, D.B. Badesch, R.J. Barst et al. Bosentan therapy for pulmonary arterial hypertension. N. Engl. J. Med. 346 (2002) 896–903.
 S. Prasad, J. Wilkinson, M.A. Gatzoulis. Sildenafil in primary pulmonary hypertension. N. Engl. J. Med. 343 (2000) 1342.
 L. Turski. New business models required for today's drug development. Conceptuur 44 (2005) 6–7.
As of February 2010, Solvay Pharmaceuticals is part of Abbott.
Pulmonary arterial hypertension is a severe disease that has been ignored for decades. However, there has been growing interest from respirologists, cardiologists, and thoracic surgeons due to development of new therapies that have improved the outcome and quality of life of patients suffering from pulmonary arterial hypertension. Surgery has a major place among new therapies and consists of either transplanting the lungs in end-stage pulmonary arterial hypertension after failure or escape from pharmacotherapy or curing postembolic pulmonary hypertension by pulmonary endarterectomy. Other procedures, such as endarterectomy of angiosarcomas or Potts anastomoses as a palliative treatment of pulmonary arterial hypertension in children, are less common.
Pulmonary arterial hypertension (PAH), a common complication of systemic sclerosis, is one of the leading causes of mortality in patients with scleroderma. With a prevalence of scleroderma ranging from ~70 to 240 patients/million, and a conservative estimate that about 10% of these patients develop PAH, scleroderma-related PAH (SSc-PAH) is a very frequent etiology of PAH (WHO Group I) throughout the world. However, trials indicate that SSc-PAH patients have a significantly poorer response to therapy compared to other forms of PAH such as idiopathic PAH. This perhaps relates to limited understanding of the pathogenesis of SSc-PAH, lack of adequate specific outcome measures (that factor in components of the cardiovascular response in these patients) and limited knowledge on the phenotypic and genotypic characteristics that underlie development of PAH and disease progression. This review discusses specific features of SSc-PAH and the potential reasons for poor outcomes, currently available and FDA-approved therapy for this syndrome, as well as needed future developments required to alter the overall poor prognosis in this disorder.
Pulmonary hypertension can occur as an isolated disease affecting the lung vessels only, in association with underlying hypoxic lung disorders or due to chronic thromboembolic disease. Regardless of the underlying disease, chronic cor pulmonale is associated with progressive clinical deterioration and a poor prognosis in most cases. The aim of specific therapies for pulmonary hypertension is to reduce pulmonary vascular resistance and thereby improve right ventricular function. Currently three classes of drugs (prostanoids, endothelin receptor antagonists, phosphodiesterase 5 inhibitors) are approved for the treatment of pulmonary arterial hypertension (PAH) in a defined patient population (group I according to the recent WHO classification). However, these medications may also lower pulmonary vascular resistance in patients with associated lung diseases (e.g. chronic obstructive pulmonary disease or lung fibrosis) and significant pulmonary hypertension, for whom these drugs are not yet approved. As non-selective vasodilators may induce gas-exchange disturbances, which preclude their long-term use in these patients, such substances should be avoided in the hypoxemic patient. In this article we provide an update of the current understanding of hypoxia- and non-hypoxia-related pulmonary hypertension, addressing both the pathophysiological understanding of different disease aetiologies as well as the therapeutic options currently available.
Pulmonary arterial hypertension is a vasculoproliferative disorder of the small pulmonary arteries, which is characterized by vasoconstriction and proliferation of the vascular cells in the pulmonary vessel wall. During the last decade, therapeutic options for the treatment of this life-threatening disease have significantly improved. Drugs like prostacyclin, endothelin receptor antagonists and phosphodiesterase 5 inhibitors, which mainly address the increased vascular tone, have been approved for the treatment of pulmonary arterial hypertension and represent the current therapeutic options. The development of a causal treatment targeted on the key events in disease progression (e.g. increased proliferation, migration and resistance to apoptosis of pulmonary vascular cells) aiming a normalization of the pulmonary artery wall structure is the current focus of research. Therefore new non-vasoactive drugs with anti-proliferative properties are investigated, which can not only attenuate (anti-remodeling) but reverse (reverse-remodeling) the disease. These compound classes include growth factor receptor inhibitors (e.g. tyrosine kinase inhibitors), statins, serotonin receptor antagonists and Rho-kinase inhibitors. Preclinical investigations and clinical trials for some of these substances were already initiated addressing safety and efficacy. In summary, further insight into the pathology of pulmonary arterial hypertension is needed to further advance drug development and treatments to improve the management of patients.
Animal models of pulmonary hypertension are used to evaluate new therapies, both their efficacy and the mechanism of their effect. They are also used to explore the biochemical mechanisms at work, with a view to identifying new drug targets. The limiting factor in each case is the extent to which the animal model represents the human condition; in particular, replicates the striking vascular pathology seen in lungs from patients with pulmonary hypertension. A telling observation is that therapies that have had dramatic effects in the animal models used to date have been far less impressive in clinical practice. New animal models have been described with marked intimal vascular lesions. In addition, genetically manipulated mice offer a targeted approach to examining signalling pathways. Comparisons of these models with the human pathology using unbiased genomic, proteomic and metabolomic platforms may reveal common pathogenic pathways and/or identify molecular signatures for personalized medicines. Animal models continue to have a role in the development of drugs for pulmonary hypertension but a clear understanding of their strengths and weaknesses is essential to the intelligent interpretation of data from their use.
The involvement of endothelin-1 (ET-1) in the pathobiology of pulmonary arterial hypertension is well-established and has led to the successful clinical development of endothelin receptor antagonists for patients affected by the disease. Natriuretic peptides, on the other hand, exert a number of effects which in many instances oppose those of ET-1. Thus, natriuretic peptides have a vasodilatory action, especially in the pulmonary arterial vasculature, but they also produce beneficial long-term structural effects in the context of cardiovascular diseases, including pulmonary hypertension, by virtue of their anti-proliferative, anti-inflammatory, and anti-fibrotic properties.
ET-1 is formed from a biologically inactive precursor by endothelin converting enzyme(s) (ECE). Natriuretic peptides are degraded by the neutral endopeptidase (NEP) which is closely related to ECE and shares similar features in its catalytic site. Therefore, both types of enzymes can be targeted by single small drug molecules exhibiting dual ECE/NEP inhibitory activity. Such inhibitors are able to simultaneously prevent the formation of ET-1 (by blocking ECE) and the degradation of natriuretic peptides (by blocking NEP), thus combining two pharmacological principles which are applicable to pulmonary hypertension.
The present chapter reviews the experimental evidence in favor of using this novel therapeutic concept for the treatment of pulmonary arterial hypertension, and possibly also other forms of pulmonary hypertension, and discusses the potential advantages in comparison to existing pharmacological treatments.
Pulmonary vascular disease (PVD) summarizes all congenital or acquired pathologies that affect the pulmonary vasculature. One of these is pulmonary hypertension (PH), which is characterized by a mean pulmonary artery pressure of ≥25 mmHg in rest, or ≥30 mmHg during exercise. This definition applies for adults and children .
Pulmonary hypertension is associated with a variety of diseases with different pathogenesis. A diagnostic classification of PH, based on the different causes, was made in 2003 .
There is some ambiguity about pulmonary hypertension in newborns (PHN). Both primary and secondary PHN are often collectively referred to as persistent pulmonary hypertension of the newborn (PPHN). In the last decades a variety of different terms describing PPHN: persistence of the fetal circulation , persistent transitional circulation  persistence of the fetal cardiopulmonary circulatory pathway , progressive pulmonary hypertension  and persistent pulmonary vascular obstruction . They all describe a failure or delay in the transition from fetal to neonatal circulation, exemplified by the failure of decreasing the PVR after birth and abnormalities in the pulmonary vasculature. Clinically, each form of pulmonary hypertension in the newborn is referred to as PPHN.
In the WHO diagnostic classification of pulmonary hypertension, persistent pulmonary hypertension of the newborn is classified together with pulmonary arterial hypertension (Group I) and pulmonary hypertension that is associated with lung disease and hypoxemia is classified in group III. In this group there is a subgroup for abnormal development, for example in congenital diaphragmatic hernia (CDH).
In this review we will focus on pulmonary hypertension in newborns in relation to therapeutic strategies.
Inhalation of drugs for pulmonary arterial hypertension is a fascinating concept, combining powerful pharmacologic effects of targeted drugs with pulmonary and intrapulmonary selectivity. Such effects are possible because the lung anatomy allows for application of drugs to the small pulmonary arteries by diffusion from alveolar surfaces. All drugs that have been shown to be efficacious in PAH are strong vasodilators, however, they differ very much concerning their vasodilative mechanisms and concerning their physicochemical properties. Prostanoids are particularly strong vasodilators with anti-remodelling properties but their conventional application has two drawbacks: i) they are prone to systemic side-effects and ii) their application necessitates a continuous intravenous or subcutaneous infusion. Inhaled prostanoids avoid these drawbacks and have been shown to be efficacious in randomized controlled trials. Inhaled iloprost (Ventavis®) has been approved in Europe, US, Australia and many other countries, inhaled treprostinil (Tyvaso®) has been approved in the US. Despite this success there is further space for improvement, particularly concerning more convenient and reliable delivery systems via inhalation.