Thesis
Reference
The unrevealed aspect of the autonomic nervous system in the heart-lung interaction: from lab to bedside
MALASPINAS, Iliona Myrto Irini
Abstract
Cette thèse aborde l'implication du système nerveux autonome dans l'interaction coeur poumon. La première partie se focalise sur le rôle du système nerveux sympathique dans le développement de l'hypertension pulmonaire (HTP). L'inhibition du système sympathique par le carvedilol n'a pas fourni d'évidence quant à la prévention du développement de l'HTP dans deux modèles expérimentaux. En deuxième partie, l'implication du système parasympathique dans la genèse de l'hyperreactivité bronchique dans un modèle expérimental avec inflammation chronique des voies aériennes a été investigué. L'inhibition de ce système nerveux par l'atropine a induit une réactivité bronchique augmentée quand les animaux étaient exposés à l'allergène. En dernière partie, une étude clinique a été effectuée pour explorer l'interaction coeur poumon chez des patients souffrant d'HTP secondaire à une insuffisance mitrale. L'amélioration des résistances des voies aériennes après correction chirurgicale chez ces enfants confirme cette interaction coeur-poumon.
MALASPINAS, Iliona Myrto Irini. The unrevealed aspect of the autonomic nervous system in the heart-lung interaction: from lab to bedside. Thèse de doctorat : Univ.
Genève, 2019, no. Sc. Méd. 36
DOI : 10.13097/archive-ouverte/unige:123504 URN : urn:nbn:ch:unige-1235047
Available at:
http://archive-ouverte.unige.ch/unige:123504
Disclaimer: layout of this document may differ from the published version.
The unrevealed aspect of the autonomic nervous system in heart- lung interaction: from lab to bedside
MD-PhD in medical science, under the supervision of Professor Walid Habre
Iliona Malaspinas
THESIS COMMITTEE : PROFESSOR WALID HABRE, PROFESSOR MAURICE BEGHETTI, PROFESSOR SAM BAYAT
Remerciements:
Au Professeur Walid Habre, mon directeur de thèse pour m’avoir donné l’opportunité de réaliser ce projet et m’avoir introduit au monde difficile et exigeant de la recherche scientifique et pour m’avoir offert un environnement propice à mon apprentissage.
Pour sa bonne humeur et ses encouragements lorsque j’ai rencontré des difficultés.
Pour son encadrement et ses précieux conseils qui m’ont permis de mener ce projet à bien.
Au Professeur Maurice Beghetti, membre de mon comité de thèse et mon mentor dans ma carrière clinique, pour son expertise, pour avoir toujours pris le temps de me relire et répondre à mes questions en un temps record. Pour son soutien tout au long de ces années et ses précieux encouragements qui m’ont permis de toujours avancer.
Au Professeur Sam Bayat pour avoir accepté de faire partie de mon comité de thèse.
Au Professeur Ferenc Petak pour son expertise et son aide.
Aux membres du laboratoire : à Xavier Belin pour ses compétences techniques, sa ponctualité, sa bonne humeur et son respect des animaux qui m’ont permis d’appréhender la complexité de l’expérimentations animales ; à Aurélie Baudat, laborantine, qui m’a permis de réaliser les analyses histologiques et cellulaires avec patience et disponibilité. A Sylvie Roulet pour sa bonne humeur, son organisation et ses cafés indispensables. A Jean-Pierre Giliberto, pour ses blagues et sa disponibilité.
Aux séniors Fanny Bonhomme, Camille Doras, et Morgan Le Guen. A Yves Donati pour son aide et ses précieux conseils.
A la Professeure Anna-Sapfo Malaspinas, qui en plus de son soutien sororal, grâce à sa relecture, ses conseils avisés, ses encouragements et sa bienveillance m’ont donné la force de terminer ce projet.
Aux comités MD-PhD de l’université de Genève qui ont fait preuve de beaucoup de patience pour que je puisse terminer ce projet. Notamment à la Professeure Brenda Kwak et au Professeur Francesco Negro.
Au service de pédiatrie générale des HUG et plus précisément aux Professeures Barazonne et Posfay-Barbe qui m’ont permis de prendre des jours de congés pour pouvoir avancer mon projet.
Au service des soins intensifs pédiatriques des HUG qui grâce à sa flexibilité m’a permis d’avancer ce projet, notamment au Professeur Rimensberger, à Aurélie, Claire, Cristian, Cristina, Diane, Fabienne, Hélène, Alice, Anne-Laure et Serge.
Au soutien inconditionnel de ma famille: Maria, Andreas, Orestis, Anna-Sapfo, Orfeas, Céline, Minas, Ylas et Djack.
A mes précieux amis qui m’ont supportés durant toutes ces longues années : Aïcha, Alice, Ana, Arthur, Christopher, Claire L., Claire R., Coralie, Diane, Francesca, Grégoire, Houda, Iain, Julia, Julien, Laure, Lena, Léonor, Lorraine, Marianthi, Marion, Mélanie, Natacha, Nathalie, Olivia, Pauline, Sarah, Sophie, Taline, Vanessa, Vincent.
A Maya, pour sa fidélité et sa présence.
Table of content
1. INTRODUCTION ... 4
A. AUTONOMIC NERVOUS SYSTEM (ANS) INNERVATION OF VESSELS AND AIRWAYS ... 5
i. Vessels ... 5
ii. Airways ... 7
B. PULMONARY HYPERTENSION (PH) ... 8
i. History ... 8
ii. Definition ... 9
iii. Classification and hemodynamic characteristics ... 10
iv. Pathobiology ... 12
v. Detailed classification ... 15
vi. Treatment ... 18
vii. Sympathetic system and pulmonary hypertension: implication and treatment involved ... 22
viii. Airways in pulmonary hypertension ... 26
C. BRONCHIAL HYPERRESPONSIVENESS (BHR) ... 27
i. Asthma ... 27
ii. Pathobiology of Asthma ... 28
iii. Asthma and autonomic nervous system ... 29
iv. BHR and left heart disease (LFD) ... 30
2. CHAPTER I: SYMPATHETIC INHIBITION BY CARVEDILOL HAS LIMITED EFFECT IN THE DEVELOPMENT OF PULMONARY HYPERTENSION IN TWO EXPERIMENTAL RAT MODELS ... 45
3. CHAPTER II : BLOCKADE OF THE CHOLINERGIC SYSTEM DURING SENSITIZATION ENHANCES LUNG RESPONSIVENESS TO ALLERGEN IN RATS ... 72
4. CHAPTER III: SURGICAL REPAIR OF MITRAL VALVE DISEASE IN CHILDREN: PERIOPERATIVE CHANGES IN RESPIRATORY FUNCTION ... 82
1. Introduction
From a physiological standpoint, the heart and the lung are inseparable organs in all animals. Each change in one will result in an adaptive response in the other one to best ensure their joint task of body oxygenation and CO2 evacuation. For example, because of their location in the thoracic cage, both organs are subjected to pressure regimen during respiration. During inspiration, a negative intrathoracic pressure will result in a decrease in pressure in the right atrium and therefore a better preload of the right ventricle with an increase in cardiac output. Adaptive phenomena are also present in the pulmonary vascular bed and bronchioles. Hypoxia will result in reflex vasoconstriction of arterioles. These different adaptive mechanisms are partially regulated by the autonomic nervous system (ANS). Thus, the ANS is responsible for each organ to maintain adequate homeostasis. If it is true in a healthy organism, we conceive that this will also hold in a diseased organism. While the involvement of the ANS in the regulation of these two organs has been studied, there are still unanswered questions particularly in the presence of bronchial or pulmonary vascular disease. In this work, we first focused on two different pathological conditions to investigate the potential involvement of the ANS. The first condition is related to a disease of the vessels of the lungs, which is pulmonary hypertension (PH). This pathology will be explored in an experimental rat model and this will constitute the main chapter of the current thesis. The second condition concerns the lower airways, which is bronchial hyperreactivity (BHR). Subsequently, the innervations of these components and the potential role of the ANS on the vessels and bronchi will be explored. Finally, we addressed the potential interaction between these two pathologies, by investigating the impact of pulmonary hypertension on BHR.
The first part of the introduction will focus on the description of the innervation of the vessels and the airways. Then, we describe PH and the current advances in its treatment, the implication of the ANS in PH and finally the effect of PH on airways.
Afterwards, we consider asthma disease to describe BHR and the involvement of ANS, and also BHR that is consequence of left heart disease (LHD). More specifically, this thesis is based on the following:
- Characterizing the involvement of the sympathetic nervous system (SNS) in the genesis and modulation of PH in an experimental rat model.
- Investigating the implication of the parasympathetic system in the development of BHR in an experimental allergic model with BHR. (Ref Clinical and Experimental Pharmacology and Physiology)
- Determining the impact of PH on the development of BHR in a clinical condition in children with mitral valve disease. (Ref Journal of Cardiothoracic and Vascular Anesthesia)
A. Autonomic nervous system (ANS) innervation of vessels and airways
i. Vessels
A low-pressure regimen and a low resistance characterize pulmonary circulation.
Pulmonary vascular tone is regulated by different mechanisms, which are different of systemic vascular tone. We will briefly evoke them without going through any details and after focusing on the neuronal control of the vascular pulmonary tone. There are passives mechanisms involved: 1) increase in pulmonary arterial or venous pressure will decrease vascular resistance through two mechanisms: recruitment of closed capillaries and distension of already open vessels and capillaries1. 2) Lung volume : vascular resistance is lower at the functional residual capacity, a diminution or an increase in lung volume will result in an increase of vascular resistance1. 3) Gravity will also contribute to the vascular resistance. Active mechanisms include 1) hypoxic vasoconstriction (HPV) which is characteristic of the pulmonary circulation: the trigger is the alveolar hypoxia and to a lesser degree hypoxemia into mixed venous blood and hypoxemia into bronchial artery. The underlying mechanisms of the vasoconstriction are not completely understood but ion channel activity modification (especially through the K+ and calcium channels) is described1,2. 2) Humoral regulators will directly affect the pulmonary vascular tone whether secreted by the pulmonary endothelium or outside the endothelium. We will not describe them, however we can cite: nitric oxide, endothelin, prostaglandin (they are discussed in the pulmonary hypertension section), thromboxane, angiotensin II, histamine, serotonin, etc1. Finally 3) neural control: through the sympathetic and the parasympathetic
systems that we will discuss in more detail below, and the non adrenergic and non cholinergic systems.
Sympathetic system
The sympathetic nervous system (SNS) innervates the vascular bed of the lung.
Preganglionic neurons originate from T1 to L23 and will innervate the pulmonary vasculature. The density of innervation seems to decrease through the arterial tree2. SNS controls the arteries through various receptors. Initially, the alpha 1 and alpha 2 receptors are activated by noradrenaline and, with a lower affinity, adrenaline, and receptors are bound to a G protein. The resulting complex mediates vasoconstriction.
Another sympathetic receptor found in the vasculature, beta 2, is activated principally by adrenaline, and to a less extent by noradrenaline. Beta 2 is also responsible for vasodilatation. The degree of vasoconstriction is dependent on two variables: the ratio of alpha 1, which is the most important neural receptor for vasoconstriction and beta 2 receptors and the amount of circulating catecholamine.
Two additional receptors — purinergic receptor and Y1, which are activated by ATP and neuropeptide Y respectively — also regulate vasoconstriction when activated2,4. The sympathetic system is activated through a baroreflex mechanism. There are baroreceptors located in the pulmonary artery (similar to those located in the carotid sinus, aortic arch, atria and ventricle4). Stretching of the pulmonary artery will result in increase of the pulmonary vascular pressure as suggested by Juratsch et al. in 1980.
In fact, denervation of the pulmonary artery in dogs results in the suppression of the increase of pulmonary pressure induced by pulmonary distension5. The afferent pathway of this reflex is through the vagus nerve as suggested by the increased activity of the vagus nerve during pulmonary arterial distension in dogs6.
The sympathetic system is also activated in response to hypoxemia. Additionally to the briefly described above HPV, the sympathetic system is activated by the decrease in partial pressure oxygen sensed by the chemoreceptor of the carotid sinus2. The result of the sympathetic system activation is vasoconstriction.
Parasympathetic system
Preganglionic neurons are located in ambigus nuclei and synapse – through vagus nerve myelinated and unmyelinated -in pulmonary arteries and the bifurcation, where the fibers will continue to the pulmonary vasculature. 7,1. There are five different receptors found in the pulmonary circulation M1, M2, M3 and M4-M5, which are less studied. The parasympathetic system exerts a differential effect depending on the muscarinic receptors involved. Stimulation of M3 muscarinic receptors leads to a dilatation of the constricted vessels and to the activation of nitric oxide (NO) synthase with consequent release of NO which is also responsible of vasodilation. Conversely, activation of the isoform M1 and M2 receptors induces vasoconstriction in dilated arterioles8.
ii. Airways
The airways are innervated by the autonomic nervous system. It includes the sympathetic pathway, mediated by norepinephrine, the parasympathetic pathway, involving acetylcholine release, and the non-adrenergic non cholinergic (NANC) system involving afferent sensory fibers and the resulting release of neuropeptides 4,9. Cholinergic nerves, in which acetylcholine acts as a neurotransmitter, play major roles in the airways, determining airway caliber and inducing bronchoconstriction when stimulated10. Cholinergic nerves have their center in the nucleus ambigus and are going through the vagus nerve, having a synapse in a ganglia within the airway, post- ganglionic fibers goes to the airway smooth muscle4. There are two kinds of acetylcholine receptors: nicotinic and muscarinic. In addition to the ganglia, most cell types in the lung present nicotinic receptors11. Receptors are involved in afferent reflexes and may be involved in development of lung cancer through phosphorylation10. Muscarinic receptors are categorized according to their location:
M1, in parasympathetic ganglia; M2, in post ganglionic nerves, where it transduces feedback; and M3, in smooth muscle and submucosal glands, where it induces bronchoconstriction and mucus secretion4. The M2 receptor has been targeted for treatment of bronchoconstriction for chronic obstructive pulmonary disease (COPD).
In fact, anticholinergic agents, such as ipratropium, produce bronchodilatation.
Although there is no evidence of direct sympathetic innervation in the lung12, the physiological effect is achieved by the presence of large numbers of the beta 2
receptor in airway smooth muscle. As a result, airway relaxation depends more on circulating systemic epinephrine than on direct innervation4.
The afferent nerves that represent the NANC play a major role in the release of neuropeptides, which are responsible for neurogenic inflammation13. Myelinated fiber can be distinguished from non-myelinated fiber. The slowly adapting receptor (SAR), found within myelinated fiber is sensitive to pulmonary stretch and is also present in airway smooth muscle. In contrast, rapidly adapting receptors and Aδ are also sensitive to various mediators (i.e., histamine, serotonin) and may produce bronchoconstriction. On the other side, there is a large number of C-fibers in the airways that are unmyelinated and contain neuropeptides (i.e., neurokinin, substance P) and their activation results in bronchoconstriction, reduction of tidal volume, augmentation of respiratory frequency and mucus secretion14.
B. Pulmonary hypertension (PH) i. History
Pulmonary hypertension (PH) is a multifactorial disease with a complex pathophysiology. The disease is characterized by an increase in pulmonary pressure and/or pulmonary vascular resistance (PVR), inducing hypertrophy of the right ventricle leading to right ventricle failure and finally death. The World Health Organization (WHO) formally defined the disease in 1973 (see below), although the disease had been described a century earlier. In 1891, Ernst von Romberg described pulmonary arteriosclerosis, known today as pulmonary arterial hypertension15. Ten years later, a syndrome presenting with dyspnea, cyanosis and polycythemia and associated with arterial sclerosis received the appellation of Ayerza’s disease, named after the Argentinian professor who described it.
In 1951, Dresdale et al. described hemodynamic changes in 39 patients and introduced the term “primary pulmonary hypertension”16. Seven years later, the first classification of histological changes for this condition was established by Heath and Edwards, based on observations of patients with congenital septal defect17. This classification includes 6 stages and addresses muscular hypertrophy, arteriolar muscularization, fibrosis, plexiform lesions and necrotizing arteritis.
In 1965, the well-known appetite suppressant drug Aminorex fumarate was commercialized and subsequently associated with an epidemic of PH. The WHO reacted to this epidemic by gathering experts in Geneva to establish a nomenclature for PH in 1973, where the first classification was published. In 1998, after the second WHO gathering on PH, guidelines for the management of the disease were proposed and the classification was refined. The latter is known as the “Evian classification”
and includes the five categories of pulmonary hypertension that are still in use today.
Regular updates are made to the classification by the Task Force of pulmonary hypertension, and the most recent one was published in 201818. The categories included in the current classification are discussed below.
ii. Definition
PH is defined in terms of the mean pulmonary arterial pressure (mPAP). For healthy adult, the normal value for mPAP is approximately 14±3mmHg. Between 1973 and 2015, a mPAP of ≥25mmHg was considered abnormal19. However, at the last World Symposium on Pulmonary Hypertension (WSPH) in December 2018, the task force on pulmonary hypertension suggested a cut off of 20mmHg 18.
Different mechanisms increase mPAP and different diseases are associated with the condition. Thus, two key measures have to be considered to define PH and to clarify the physiopathology of the disease. The first key measurement is the pulmonary arterial wedge pressure (PAWP). This measurement approximates the left atrial pressure, which allows us to distinguish between pre-capillary and post-capillary pulmonary hypertension. A PAWP of ≤15mmHg indicates pre-capillary pulmonary hypertension, and, correspondingly, a PAWP of >15mmHg indicates post capillary pulmonary hypertension, which is mainly due to left heart disease19. The distinction is important because various mechanisms increase pulmonary pressure, and treatment will correspondingly be different. An increase in pulmonary pressure can be the result of increased resistance of the arterioles, characterized by remodeling. However, increased pulmonary pressure can be the result of transmission of elevated left heart pressure and more precisely of the left atrium20. The second key measurement involves the calculation of the pulmonary vascular resistance (PVR). PVR is obtained by measuring several pressures as well as cardiac output (CO) during catheterization and is defined as (mPAP–PAWP)/CO. High PVR indicates pulmonary vascular
disease (PVD) and a pulmonary arterial resistance of ≥3 Woods Units (WU) is considered PVD18. Since 2018, the definition of pulmonary arterial pressure (PAH) includes mPAP as well as the characterization of the PH. As a consequence, the definition of pre-capillary PH is an mPAP >20mmHg, a PAWP ≤15mmHg and a PVR
≥ 3WU. Post capillary hypertension is defined as a mPAP >20mmHg, a PAWP
>15mmHg and a PVR < 3WU18. Some patients may present both pre- and post- capillary PH.
In the following, we further define the measurement and describe in detail the classification, definition, pathobiology and characteristics of each group.
iii. Classification and hemodynamic characteristics
The classification of PH is based on the pathology, pathophysiology and underlying mechanism of the disease as well as its response to treatment. The latest classification, updated in 201818 is provided in Table 1: Clinical Classification of Pulmonary Hypertension.
Table 1 - Pulmonary hypertensions classification adapted from Simmonneau G, Montani D, Celermaier DS, et al. Hemodynamic definitions and updated clinical classification of pulmonary hypertensions. Eur Resp J 2018
1. Pulmonary arterial hypertension (PAH):
1.1 Idiopathic PAH 1.2 Heritable PAH
1.3 Drug- and toxin-induced PAH 1.4 PAH associated with:
1.4.1 Connective tissue disease 1.4.2 HIV infection
1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis
1.5 PAH long-term responders to calcium channel blockers
1.6 PAH with overt features of venous/capillary pulmonary veno-occlusive disease (PVOD)/
pulmonary capillary haemangiomatosis (PCH) involvement 1.7 Persistent pulmonary hypertension of the newborn syndrome
2. Pulmonary hypertension due to left heart disease (LHD)
2.1 Due to heart failure with preserved left ventricular ejection fraction (LVEF) 2.2 Due to heart failure with reduced LVEF
2.3 Valvular heart disease
2.4 Congenital/acquired cardiovascular conditions leading to post capillary PH
3. Pulmonary hypertension due to lung disease and/or hypoxia
3.1 Obstructive lung disease 3.2 Restrictive lung disease
3.3 Other lung disease with mixed restrictive/obstructive pattern 3.4 Hypoxia without lung disease
3.5 Developmental lung disorders
4. Pulmonary hypertension due to pulmonary artery obstructions
4.1 Chronic thromboembolic pulmonary hypertension 4.2 Other pulmonary artery obstructions:
4.2.1 Sarcoma (high or intermediate grade) or angiosarcoma
4.2.2 Other malignant tumors: renal carcinoma, uterine carcinoma, germ cell tumors of the testis, other tumors
4.2.3 Non-malignant tumors
4.2.4 Arteritis without connective tissue disease 4.2.5 Congenital pulmonary artery stenosis 4.2.6 Parasites, hydatidosis
5. Pulmonary hypertension with unclear/or multifactorial mechanisms
5.1 Hematological disorder, such as chronic hemolytic anemia, myeloproliferative disorders 5.2 Systemic and metabolic disorders, such as sarcoidosis, pulmonary Langerhans
histiocytosis, glycogen storage disease, Gaucher disease
5.3 Others, including fibrosing mediastinitis, chronic renal failure with or without dialysis 5.4 Complex congenital heart disease, including segmental PH; single ventricle, scimitar syndrome
Three types of PH are listed, along with their hemodynamic definition, in Table 2.
Table 2 - Adapted from Simonneau G, Montani D, Celermajer DS, et al. Hemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2018; in press [https://doi.org/ 10.1183/13993003.01913-2018]
iv. Pathobiology
We will first describe briefly the current knowledge about the pathobiology of PH.
PH is characterized by an increase in pulmonary arterial pressure and/or pulmonary vascular resistance, which can lead to right ventricular hypertrophy, right heart failure and death. Multiple pathways have been described for the conditions leading to the remodeling of the arterioles and vasoconstriction associated with PH, which, in turn, results in an increase of vascular resistance. To summarize, mechanical involvement (shear stress) or environmental changes, such as hypoxia, result in endothelial dysfunction, modification of angiogenesis and fibroblast function and inflammation.
Each element involves different signaling pathways and abnormalities, leading to the histological changes of PH.
a) Histology:
Histologically, increased pulmonary resistance is correlated to anatomical changes of the arterioles, capillaries and venules. The large elastic lobar and segmental arteries stiffen. However, the most important changes occur in distal muscular arteries. In
Definition: Hemodynamics Groups
Pre-capillary PH mPAP >20mmHg 1, 3, 4, 5
PAWP ≤15mmHg PVR ≥3 WU
Isolated post-capillary PH mPAP >20mmHg 2, 5 PAWP >15mmHg
PVR <3WU
Combined pre- and post-capillary PH mPAP >20mmHg 2, 5 PAWP >15mmHg
PVR ≥3 WU
distal muscular arteries, lesions typically include hypertrophy of the media layer of the artery, fibrosis of the intima and adventitia layers as well as thrombotic and, at end-stage, plexiform lesions. The pre-capillary pulmonary arteries exhibit obliteration, muscularization and perivascular inflammation and capillaries are also involved. The post-capillary venules also seem to be involved in all groups of PH, but to different degrees in the different groups21.
b) Endothelial dysfunction:
In PAH, the pulmonary endothelium is dysfunctional, losing its ability to regulate pulmonary vascular tone. Through changes in signal transduction, the dysfunction either leads to increased vasoconstriction or the inability to vasodilate small vessels22. Additionally, the pulmonary endothelium losses its ability to regulate in situ coagulation, induces reactive oxygen production, expresses more intercellular adhesion molecules and exhibits altered expression of cytokines. The result of all these changes is an imbalance between angiogenesis and apoptosis21. Consequently, the result of the imbalance is a modification of the arteriolar wall as described in the media, intima and adventis layers. Three well studied endothelial pathways — endothelin (ET), NO and prostacyclin — are of major interest because they are the targets for established PAH treatment.
Patients with PH show an activation of the ET system and ET plasma levels are increased22,23. Activation of ET receptors induces vasoconstriction and vascular remodeling towards proliferation23.
NO bioavailability is decreased in PAH and, as a consequence, the production of cGMP, an important mediator of vasodilation, also decreases24, which subsequently increases vascular tone.
Prostacyclin plays a key role in the endothelium as a strong vasodilator. After binding to membrane and intracellular receptors, an increase of cAMP leads to vasodilation25. Prostacyclin is also important in the regulation of cell proliferation and exhibits antithrombotic activity25. Patients with PH have lower circulating prostacyclin levels than healthy controls26.
The initial changes in endothelial homeostasis observed in PH are also multifactorial.
Two mechanisms — shear stress forces and chronic hypoxia — have been intensively
studied to better understand why this dysfunction appears21. Healthy endothelium responds to shear stress forces with cell elongation, according to blood flow and pressure. In models of PAH or PH, the endothelium of the arterioles losses the ability to adapt21.
Chronic hypoxia also induces endothelial changes and remodeling of the vessels through direct vasoconstriction and muscularization through several molecular pathways.
c) Angiogenesis:
In patients with PAH/PH, rarefaction of pulmonary vasculature is also reported. There is a loss of vessel surface and obliteration of the capillaries. However, the mechanism of this modification is not well understood and requires further study21.
d) Smooth muscle and fibroblast:
In PH, there is a hypertrophy and hyperplasia of the smooth muscle cells and fibroblasts. Hypertrophy and hyperplasia of the smooth cell layer are due to intrinsic dysfunction as well as to environmental signals, notably communicated by endothelial cells27. Changes in intracellular signal transduction in smooth muscle cells lead to hypertrophy. Additionally, paracrine signaling in endothelial cells is also responsible for the growth of the muscular and fibrous layers of the arterioles28.
e) Inflammation:
In patients suffering of PAH/PH, inflammatory cells are found surrounding the small vessels, suggesting a role for inflammation in the pathobiology of PH, an increasing number of studies focus on the relationship between inflammation and/or immune system and PAH/PH. Additionally, it has been demonstrated that inflammatory molecules are increased in patients with PH21,29. However, although changes in the immune systems of PH patients has been demonstrated, the role of immune system in the development of endothelial dysfunction or vascular remodeling requires more study21.
f) Other pathways:
A recent genetic study identified a new channelopathy for the potassium channel subfamily K member 3 (KCNK3) in patients with familial or idiopathic PH in which a mutation results in impairment of KCNK3 function30. The restoration of function in animal models decreases the severity of the disease21. This raises the possible involvement of abnormal membrane function that could lead to abnormal vascular function. Although this mutation seems to be involved in the regulation of the pulmonary vascular tone, the exact mechanisms is still unknown29.
In summary, many different mechanisms lead to the remodeling of pulmonary vasculature, and many these changes can happen in parallel. Ongoing research is attempting to better understand these pathways to find new therapeutic targets that reduce pathogenic remodeling in patients suffering of PAH/PH.
v. Detailed classification
The classification of PH is briefly listed in Table 1. The classes of the disease are described in more detail below.
Group 1: Pulmonary arterial hypertension (PAH)
PAH is defined as mPAP >20mmHg, pre-capillary pressure PAWP ≤15mmHg, and a pulmonary vascular resistance increase of >3 WU. The several subcategories of this condition (see Table 1) share clinical conditions and histological lesions but have different etiologies. If all other causes have been excluded, PAH is considered idiopathic. Several genes have been associated with heritable PAH, including BMPR2, EIF2AK4, TBX4, ATP13A3, GDF2, SOX17, AQP1, ACVRL1, SMAD9, ENG, KCNK3 and CAV1; additionally, SMAD4, SMAD1, KLF2, BMPR1B and KCNA5 may be involved31. Several drugs and toxins are known to induce PAH: aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, toxic rapeseed oil and cocaine18. PAH has also been associated with other conditions listed in Table 1. The last update of the classification included a new category for patients identified during vasoreactivity testing who had long-term indications for calcium channel blockers (CCB)32.
As discussed above the histology of Group 1 is characterized by changes in the pulmonary vascular tree of the lung. In fact, cellular modification has been observed
at every level of the vessels. Stiffening of the main elastic, lobar and segmental arteries might be the result of remodeling of the smaller vessels. Hypertrophy and hyperplasia of the media, fibrosis of the intimal adventitial layer, thrombotic lesions, and plexiform lesions have all been found in PAH21. Changes in the pre-capillary arteries (20–70 µm) include an abnormal muscular layer, obliteration and inflammation. The different mechanisms described above, cause an imbalance between angiogenesis and apoptosis, leading to a reduction in the number of capillaries. All the modifications associated with PAH increase pulmonary resistance, which leads to an increase in pulmonary pressure.
Group 2: PH due to left heart disease (LHD)
PH can be found in patients with LHD, including mitral valve stenosis or insufficiency, aortic stenosis and left heart failure with preserved or decreased ejection fraction. Diagnosis of PH can be challenging for LHD patients with preserved ejection fraction (diastolic dysfunction), as this condition is easily confused with PAH. However, management of the two conditions is different, and it is crucial to correctly identify which condition is presenting.
In LHD, an increase in left atrial pressure results in a passive increase of mPAP.
Additionally, depending of the duration of the disease and individual predisposition, the increase of mPAP can be isolated or associated with pulmonary vascular disease.
To distinguish PH due to LHD and PH, the following two measurements must be made: pulmonary vascular resistance (pathologic if >3WU), and the diastolic pressure difference/gradient (DPG) between dPAP and PAWP, which potentially can be used to identify vascular pulmonary changes33,34. To categorize more precisely the patients, the Task Force added to the definition of post-capillary PH (i.e., mPAP ⩾20 mmHg and PAWP >15 mmHg) the following definitions34 :
a) Isolated post-capillary PH: diastolic pressure difference/gradient DPG <7 mmHg and/or PVR ⩽3 WU
b) Post- and pre-capillary PH: DPG ⩾7 mmHg and/or PVR >3 WU
Note that these definitions are controversial and, consequently, are regularly updated.
Further studies are required to confirm these definitions.
The mechanism affecting the vascular bed is not fully explained. Patients suffering LHD exhibit an increased left heart filling pressure. This abnormal pressure induces venous congestion of the pulmonary venous system, which can lead to reactive and protective vasoconstriction, decreased NO, increased ET expression, and eventually some vascular remodelling35,36. However plexiform lesions as seen in Group 1 are rarely described37,38.
Histological modification of the arteriolar tree has been observed for PH in LHD.
Damage in the post capillary tree, which is partially explained by a destruction of the parenchyma, and an increase in the thickness of the intima in small vessels and venules due to the increase in filling pressure contribute to the severity of PH in LHD.
Additionally, the appearance of interlobular veins is similar to arterioles39. Group 3: PH due to lung disease or hypoxia
COPD is the condition most commonly associated with Group 3 PH. It is reported that 90% of patients with COPD stage IV have a mPAP between 20–35 mmHg, and 1–5% have a mPAP ˃35 mmHg40. Some PH patients with other etiologies also experience bronchopulmonary dysplasia (in children), chronic altitude exposure or other form of congenital lung disease. Recently, the definition of chronic lung disease (CLD) associated with PH has been improved; this is especially important because management depends on the degree of PH. Right heart catheterization is recommended when significant PH is expected in CLD41, and the measurements are used to categorize the severity of PH as follows41:
a) CLD without PH: mPAP <21 mmHg, or mPAP 21–24 mmHg with PVR <3 WU.
b) CLD with PH: mPAP 21–24 mmHg with PVR ⩾3 WU, or mPAP 25–34 mmHg c) CLD with severe PH: mPAP ⩾35 mmHg, or mPAP ⩾25 mmHg with low cardiac
index (e.g., <2.0 L/min/m2)
The mechanisms by which PH develops in lung disease are similar to the mechanisms for PAH. Chronic hypoxia or repeated punctual hypoxia results in vasoconstriction and subsequent remodeling of the arteriolar tree (as discussed above). The loss of lung volume seen in emphysema or COPD, with changes in functional residual capacity (FRC) of the lung, results directly in increased vascular resistance42. Additionally, the association with disturbance of NO synthase and ET-1 pathways are
also described for patients suffering chronic lung disease42. However, plexiform lesions are not encountered in lung of these patients.
Group 4: PH due to pulmonary artery obstruction
The terminology for this group has recently been updated 43. Chronic thromboembolic pulmonary hypertension (CTEPH) is the classic disease for this group. Other diseases associated with this group are listed in Table 1. CTEPH can occur as a complication of acute pulmonary embolism. Data suggests that patients develop CTPEH after an acute embolism in a pooled incidence of 3.4%43. The development of PH in CTEPH is multifactorial and the mechanisms are still under investigation. In summary, CTEPH is characterized by thrombi in the main arteries and subsequent remodeling of the pulmonary vascular tree characterized by compromised angiogenesis, fibrinolysis and impaired endothelial function43. Macroscopically, thrombi found in PH patients are different than thrombi from patients who have had a unique embolism episode.
Thrombi found in CTEPH are yellow and contain more collagen, elastin, inflammatory cells compared to a traditional red blood cell clots with platelets44. Patients with CTEPH have more associated conditions than PAH patients and these include cancer, splenectomy, non O- blood group, prior venous thromboembolism, presence of antibodies to lupus anticoagulant/antiphospholipid, thyroid replacement therapy and abnormal fibrinogen molecules45. Mechanisms involved include platelet dysfunction, which explains the inability to resolve thrombi, abnormalities occurring with fibrinolysis and impaired angiogenesis.
The remodeling of the vessels seen with CTEPH is similar remodeling observed in patients with PAH45: media thickening, intimal fibrosis and plexiform lesions.
Group 5: Pulmonary hypertension with unclear or multifactorial mechanisms
The PH mechanisms in this group are poorly understood. PH types are assigned to this group when the underlying mechanisms are not known or when the PH measurements do not match the definitions of the other groups.
vi. Treatment
Treatment of PH can be considered after the extensive diagnostic work necessary for correct diagnosis19,46 and depends on the pathophysiology and classification of the disease.
Over the last two decades, the efficacy of many drugs for treating PH has been studied and outcomes have generally improved. Available approved treatments focus on three molecular pathways involved in PH (discussed above): prostacyclin, NO and ET. Recently, treatment is frequently based on the stratification of risk of the disease and often includes combination of the different validated treatment46. The algorithm for the stratification risks and the approved treatment are proposed to patients in group 1 PH. We will not discuss the treatment of the other groups. We will discuss briefly the different established treatments.
• Calcium channel blocker treatment
CCBs block the L-type calcium channel, allowing muscle relaxation of the vessels and resulting in vasodilatation. Because vasoconstriction is one of the PH mechanisms, CCBs are used to vasodilate the pulmonary vascular bed. However, this vasodilatation is not specific to the lung vessels. CCB treatment is indicated only for PH patients who are vasoresponders.
Before starting CCB treatment, it is important to evaluate the patient’s response to the medication with pulmonary vasoreactivity during heart catheterization. Briefly, the quick-acting inhaled vasodilator NO47 is administered and the pulmonary pressure is measured to determine the patient’s response47. Vasoresponsivity has been defined by Sitbon et al.47 Studies have demonstrated excellent long-term survival in positive repsonders47,48. It is of importance to highlight that CCB treatment is not relevant for non responders47.
• Endothelin-receptor antagonist treatment
As discussed earlier (Endothelial dysfunction:), the endothelin pathway is abnormally activated in patients suffering from PH: ET-1 is increased during PAH and is responsible for vasoconstriction and vascular remodeling. ET receptor ETa is expressed in smooth vessel of the arteries within the myocardium and is responsible for pulmonary vasocostrcition and the resulting mitotic effect27. A second receptor, ETb, is more ubiquitous and is also found in endothelial cells, smooth muscle cells of the arteries, glial cells and glomerular endothelium. Depending on the subtype of receptors, ETb activation provokes vasoconstriction or vasodilation as well as an
antiproliferative effect27. Different ET-receptor antagonists are available for each receptor.
Three molecules have been developed and approved as ET-receptor antagonists for the treatment of PH: ambrisentan, bosentan and macitentan.
Ambrisentan is a selective antagonist of ETa, and, in theory, its use allows the ETb receptor to counterbalance the vasoconstriction effect of ETa. Two randomized control trials studied PAH patients: ARIES 1 and 2 (Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter)49. The studies demonstrated that treatment with ambrisentan improved hemodynamics and exercise capacity. No significant biological adverse effect was observed for ambrisentan, and, notably no increase in transaminase was detected compared to the first developed endothelin-receptor antagonist Bosentan49.
Bosentan, the first drug developed in this category, acts as an antagonist for both receptors. As a result, resistance in both pulmonary and systemic circulation is reduced25. Histological studies revealed that bosentan decreases wall thickness of the arterioles in animal models50,51. The use of Bosentan as an effective treatment for PAH has been validated by six randomized control trials (RCTs) (Study-351, BREATHE-1, BREATHE-2, BREATHE-5, EARLY and COMPASS 2). Clinically, patients receiving treatment experienced improvement in several criteria, including total distance walked in 6 minutes (6-minute walk distance), WHO functional classes, hemodynamic parameters, and echocardiographic measurement as well as a delay in the worsening in symptoms19,52,53,54,55,56,57. However, the treatment can alter the hepatic function, and monitoring with monthly blood test is necessary.
Macitentan also acts as an antagonist for both ET receptors. SERAPHIN, a RCT study of macitentan treatment of PAH patients, demonstrated a reduction of composite event morbidity and mortality and also a slight increase in 6-minute walk distance58. Another recent RCT, the MAESTRO study, included patients suffering Eisenmenger syndrome, demonstrated no significant difference in the patient groups given the drug and a placebo59. The advantage of macitentan treatment has no demonstrated effect on hepatic function; however, anemia was observed in 4.3% of case.
• Phosphodiesterase type 5 inhibitor treatment
NO increases cGMP, which is responsible for vasodilation and antiproliferation.
Patients with PH exhibit decreased NO availability, resulting in vasoconstriction and proliferation. Attempts to identify molecules that increase the bioavailability of NO and that modify the NO–cGMP pathway identified the phosphodiesterase type 5 (PDE5) enzyme, which activates the degradation of cGMP. Additionally, inhibition of PDE5 increases cellular cGMP levels, resulting in vasodiltation25. Three drugs – sildenafil, tadalafil and verdanafil – are commonly used to inhibit PDE5.
A randomized controlled trial (SUPER1) demonstrated and validated the use of Sildenafil. With other studies, the use of PDE5 inhibitor has demonstrated an improvement of total distance walked in 6 minutes, decreased dyspnea and measurably decreased pulmonary arterial pressure60,61,62.
• Soluble guanylate cyclase stimulator treatment
The soluble guanylate cyclase (sGC) enzyme converts GTP to cGMP. Stimulating this enzyme increases the bioavailability of cGMP. In synergy with NO, sGC decreases cell proliferation and acts as an anti-aggregant. The treatment used is Riociguat, which acts as a stimulator of sGC. This treatment was validated with randomized controlled trial, which demonstrate the efficacy of riociguat63.
• Prostacyclin treatment
Prostacyclin increases cAMP and as a result cAMP vasodilates the arteries.
Additionally, prostacyclin has anti-proliferative and antithrombotic properties.
Because prostacyclin is decreased in PH patients, treatment-restoring prostacyclin was sought. Although effective drugs were identified, treatment usually involves continuous intravenous or subcutaneous administration 64. However, recently a prostacyclin receptor agonist has been approved for oral treatment.
• Combination treatment
As mentioned earlier, much research in recent years has been dedicated to optimizing available therapy.
The algorithm proposed is intended for patients diagnosed with PAH only: the algorithm should not be used with patients of other PH groups. Several risks scales are available to classify the mortality risk for PAH patients, stratifying the mortality
risk for one year into low, medium or high risk. The most current recommendation of the task force in pulmonary hypertension is based on a stratification proposed in 201519, which takes the following into account: signs of right heart failure, progression of symptoms observed, frequency of syncope, WHO functional class, cardiopulmonary exercise results, NT-Pro-BNP plasma level, echocardiography, heart MRI and hemodynamics measurements. Based on these data, the amount of risk determines the therapeutic strategy 46. Three recent publications have described and validated this decision making process65,66,67 Only patients considered at low risk, newly diagnosed and without treatment are candidates for monotherapy (usually a choice of PDE5 inhibitor or ET antagonist). Combined therapy is usually administered to patients with intermediate risk. Patients with high risk are immediate candidates for iv administration of prostacyclin and are evaluated for lung transplantation46. However, there is increased tendency to start combination therapy for most patients. A follow up 3–6 months after initial treatment is mandatory to evaluate the response to the treatment and/or the progression of disease. After this follow up, patients at intermediate or high risk are usually treated with additional drugs or considered for lung transplantation.
• Transplantation
Transplantation remains the last option for patients with pulmonary hypertension.
There are specific criteria to determine if a patient is eligible for pulmonary
transplantation and, as it is out of the scope of this document, transplantation will not be discussed.
vii. Sympathetic system and pulmonary hypertension: implication and treatment involved
As discussed earlier in section 1.B.vii, since the SNS, even if not the major contributor to the vascular tone, is nevertheless involved in maintaining vascular tone, there is considerable interest in determining the role of the SNS in PH, particularly following inhibition, either with the use of beta-blockers or by denervation of the pulmonary artery.
Recently, studies suggest an increased activity in patients suffering of PH. The sympathetic activity was measured by microneurography with the muscle sympathetic nerve activity in patients suffering of established PH. 17 patients were included (14 with IPAH and 3 induced by drugs). The study demonstrated that patients suffering of PH have an increase of sympathetic nerve activity compared to the control group68. Mak S. et al, demonstrate an increase of cardiac sympathetic activity thanks to radioactive noradrenalin, which were comparable to left heart insufficiency. The study was conducted in patients suffering of PH (10 with IPAH and 5 associated with connective tissue disease)69. It has been demonstrated, that over-activation of alpha 1 receptors leads to proliferation and growth of smooth muscle70.The study was performed in knocked out mice for receptor alpha 1B and 1D, and in mice with PH induced by hypoxia. The wall thickness of the arterioles were less increased than the once of the control group70.
In the early 80s, C.E. Juratch et al. demonstrated that stretching the baroreceptors in the pulmonary artery induced pulmonary hypertension. The increase in mPAP was abolished when the pulmonary artery was denervated (surgically and chemically)5. Subsequently, other research groups studied the effects of denervation of the pulmonary artery in PH. Ling Zu et al. used a dog model with monocrotaline-induced PH and denervated the pulmonary artery percutaneous. Hemodynamic measurement confirmed that mPAP decreased with denervation and that resistance also decreased compared to animals given a sham treatment. Additionally, remodeling of the pulmonary artery was also prevented in dogs with denervation. Interestingly, the velocity of conduction of the sympathetic nerve was abnormal in dogs with PAH. The velocity normalized after the denervation71. This result was replicated in a similar animal model study where it was shown that denervation is also associated with a down regulation of the renin angiotensin aldosterone system72. A very recent study in rats explored denervation in models of PH induced either with monocrotaline or sugen/hypoxia. The study demonstrated improvement in hemodynamic data with a decrease of mPAP, normalization of right ventricular ejection and a histological evidence of decreased right ventricular hypertrophy and a decrease in muscularization of the arterioles. Additionally, an examination of the distribution of the nervous receptors after the procedure indicated a decrease of neurohumoral of receptors in arterioles receptors and an increased in the ventricle receptors73.
S.L Cheng et al. reported a clinical study involving percutaneous PA denervation.
Thirteen patients were subjected to the denervation protocol and eight patients who refused the treatment were included as the control group. Patients undergoing the treatment had a diminution in mPAP, vascular resistance compared to the control group that lasted for the 3 months after the procedure. Significant improvements were seen in their 6-minute walk distance and the WHO classification of dyspnea. These improvements also lasted 3 months. Additionally, during the follow up, no complication of the denervation procedure was observed74. A subsequent study included a total of 66 patients with Group 1, 2 or 3 PH, and measurements were repeated at 6 months and 1 year after treatment. They reported a sustainable decrease of mPAP, an improvement in symptomatology with a longer 6-minute walk distances75. In the recent PADN-5 Study, the effect of pulmonary denervation was studied in patients suffering combined pre- and post-capillary pulmonary hypertension associated with left heart failure and compared to sildenafil treatment and sham surgery. Their results demonstrate that, 6 months after the procedure, patients had improved 6-minute walk distance and hemodynamic data (diminution of mPAP, diastolic and systolic function improvement)76.
In summary, sympathetic system activity seems increased in patients suffering of PAH, adrenergic receptors are involved in the increase of wall thickness of the arterioles in PH, and the denervation decreases the severity of the disease. If the increase in activity of SNS is a result or a consequence of PH it is not established.
However, SNS seems involved and could be a target for the treatment of PH.
In light of these results, inhibitors of the SNS are of great interest for developing new therapies. SNS inhibitors were used in PH-induced animal models. Many sympatholytic compounds were used, including carvedilol, a non-selective alpha-beta blocker. In a hypoxemic hypobaric model, carvedilol reduce the increase of systolic right ventricular pressure, reducing the wall thickness of the arteries. The treatment also diminishes right heart hypertrophy77. In another model, in which PH was established with SU5416 and hypoxia or monocrotaline (MCT), carvedilol treatment lead to an improvement of right heart function without influencing the right heart pressure and to a decrease in the right heart hypertrophy. The use of carvedilol decreased the mortality of the rats78. Blocking specifically the beta-receptor with bisoprolol in a MCT rat model, S. Frances et al, demonstrated an improvement of
right heart contractility but with no improvement of systolic right ventricle pressure.
Under treatment of bisoprolol, right heart hypertrophy was diminished in rats79. In a 2006 clinical study, S. Provencher and al, investigated the use of beta-blockers in patients suffering porto-pulmonary hypertension. The results suggest a deleterious effect of beta-blockers due to a worsening in exercise tolerance and pulmonary hemodynamics. The study included ten patients receiving beta-blockers and measurements were made 2 months after withdrawal of the treatment, comparing results before and after80. Currently, the avoidance of beta-blockers is recommended due to the side effect of negative inotropy. However, because animal studies show improvement in right heart function and remodeling, some clinical studies are addressing this issue. C. Moretti et al. studied patients with PH receiving beta- blockers for systemic hypertension. The study concerned exclusively PAH with different etiology (idiopathic, associate to connective tissue disease, HIV, porto- pulmonary PH, congenital heart disease, pulmonary embolism). In their study, the follow up period was 2 years, with evaluation every 6 months. Ninety-one patients were enrolled: ten receiving beta-blockers and 84 individuals in the control group. No increase in negative outcomes was observed; note, however, that the 6-minute walk was not included. Heart catheterization did not show a reduction in mPAP; however, echocardiography data suggested improvement of right heart function, with amelioration of tricuspid annular plan systolic excursion (TAPSE) and decreased right ventricular (RV) diameter81. Other research groups using a similar design with 94 patients concluded no danger for the use of beta blockers in PH, but reported no improvement in either of the diseases studied82. A recent clinical randomized controlled trial, performed with carvedilol demonstrated the safe use of beta-blockers.
It shows no difference in 6min walk, but a better heart rate recovery at the end of the walk and a decrease in heart metabolism (lower glycolytic rate) 83.
Taken together, these studies suggest that the nervous system seems activated in patients with PH, even if clinical studies didn’t show beneficial effects in patients suffering of PAH. However the real implication for the development of the disease remains unclear.
Since, we aimed to study the involvement of the sympathetic nervous system in the genesis of PH.
viii. Airways in pulmonary hypertension
Considering the close interactions between the heart and lung and the interdependence between the corresponding pulmonary vessels and the airways, seems reasonable to assume that the effect of PH on the vessels could impact the airways and vice-versa.
Correspondingly, examination of lung function is often considered in clinical practice for PH to discriminate between the involvement of the vessels or of the airways.
The presence and the severity of lung function alterations can vary depending on the PH category and is assessed by spirometer, lung function with total lung capacity and forced vital capacity, and by the carbon monoxide diffusing capacity (DLCO).
In Group 1 PAH, conflicting results have been published for lung capacity, with some authors reporting a decrease in total lung capacity84 and others reporting no change85. Interestingly, the studies in which total lung capacity is not reduced report a reduction in vital capacity85. The underlying pathophysiological mechanism changing the total lung capacity remains unclear, although it has been suggested that enlargement of the arterioles exerts a potential direct anatomical influence that compresses the airways, leading to subsequent decrease in the distensibility of the lungs84. To date, there is also evidence that bronchial obstruction is associated with PAH85,86. Two hypotheses to explain bronchial obstruction have been published. An anatomic mechanism associated with the enlargement of vessels might directly affect the bronchioles84. Alternatively, the inflammation encountered in PAH could affect also the airways84,86. Both of the proposed mechanisms could result in ventilation–perfusion mismatch and alterations in alveolocapillary diffusion and potentially lead to hypoxemia.
Observations of patients with congenital heart disease and PAH confirmed that the major changes in lung function were due primarily to bronchial obstruction86,87. Total lung capacity and forced vital capacity are both reduced in Group 2 PH84. Several mechanisms in this group contribute to altered lung function. Firstly, the presence of a cardiomegaly may contribute by directly restricting lung volume84. Secondly, the edema resulting from venous congestion also contributes to the restricted mechanics of the lungs88. Finally, increased airway resistance is present without actual bronchial obstruction88. As in Group 1 PAH, DLCO is also reduced in PH associated with left heart disease. This pathophysiology is explained by edema-
altered diffusion as well as chronic venous compression, which may lead to remodeling of the alveolocapillary membrane. The effects of chronic venous compression have been confirmed by studies with heart-transplant patients for whom there was still evidence for alterations in the diffusion capacity despite improvement in DLCO 88.
Finally, when PH results from the presence of a chronic lung disease (Group 3), it has been a challenge to identify the mechanism that results in PH. Nevertheless, it has been demonstrated that patients with PAH associated to chronic lung disease exhibit lower DLCO than in patients suffering exclusively from chronic lung disease88.
C. Bronchial hyperresponsiveness (BHR)
Bronchial hyperesponsiveness (BHR) is the physiological consequence of chronic lung inflammation. Considering the high incidence of chronic pulmonary diseases with consequently the development of BHR, exploring this pathophysiological consequence was of great interest to address the challenges raised by its treatment.
We considered first asthma disease to describe BHR before focusing in the second part on BHR encountered in left heart disease.
i. Asthma
Asthma is a chronic lung disease, which affects all ages but starts commonly in the first 5 years following birth89. According to the World Health Organization (WHO), asthma concerns 235 million people, and in 2015 the average mortality was about 383 000 people wordlwide90. Definition of asthma has evolved and the last update is from the Global Initiative for Asthma (GINA) in 2018: “asthma is a heterogeneous disease, usually described by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze shortness of breath, chest tightness and cough, together with variable expiratory airflow limitation”91. The airflow limitation is due to bronchial hyperesponsiveness which is a result of airway inflammation89. The etiology that precipitates the bronchoconstriction is variable and multiple triggers have been identified: the most common triggers are allergens, cold air, cigarettes or physical activity92. To establish the diagnosis, physicians rely on the history of
variable respiratory symptoms (wheezing, cough, shortness of breath or chest tightness) and confirmed with variable expiratory airflow limitation (improvement or amelioration). Airflow limitation is assessed by spirometer and/or with peak expiratory flow (less accurate). Usually to point out the lung function variability, lung function is measured either in different medical visits, at home with PEF daily or in different conditions like: before and after bronchodilators, before and after exercise or with bronchial provocation tests91. Spirometer measurements are considered as pathologic when we observe airway obstruction by the forced expiratory volume in one second (FEV1) over the forced vital capacity (FVC) < 0.75 in adults. The variability is defined as a change of FEV1 between 10-12% and/or change of 200ml from baseline increased or decreased depending of the test91. The pathobiology of asthma is complex and the underlying mechanisms include bronchoconstriction, airway inflammation and airway remodeling. Pathways leading to this phenotype are multiple and are being widely investigated. We will briefly focus on the pathobiology of asthma and discuss the involvement of the nervous system in the development of the disease.
ii. Pathobiology of Asthma Airway inflammation:
It has been demonstrated that the lung of patients with asthma are swollen. Acute and chronic inflammation is responsible for bronchial hyperresponsiveness. The commonest pathway that leads to inflammation is the acute response to an allergen.
This allergen enters into the bronchial tree. The early phase consists on the implication of antibodies IgE, which recognize the allergen and activate the receptor FcεRI, found in different immune cells (basophil, mast cells and epithelial cell).
These cells will release variable inflammatory mediators that will result in bronchoconstriction and also vasodilation and mucus secretion89. The late phase involves additional neutrophils, eosinophil and T Lymphocytes, which will also express inflammatory mediators and will contribute to the chronic recruitment of inflammatory cells. Clinically, bronchoconstriction will occur in the acute phase and gradually, a state of bronchial hyperesponsiveness will be reached93. The chronic phase of inflammation seems to be the result of T2 lymphocyte (Th2) activation. Th2 cells, through different cytokines will generate a cascade of reaction. Th2 will maintain activation of lymphocytes B Cell excreting IgE. IgE in return will activate
