Pulmonary Hypertension and Right Heart Failure: Ishlt Monograph Series (Volume 9)

Hypertension

Section I

Pulmonary Hypertension and Right Heart Failure

Introduction

Pulmonary Arterial Hypertension: A Global Disease

Section Editor: Marc Humbert ¹,²,³

Pulmonary arterial hypertension (PAH) is a rare cause of precapillary pulmonary hypertension, affecting 15 to 50 individuals per million inhabitants in the developed and developing countries. It has previously been called an orphan disease, that is, a condition affecting few people and overlooked by the medical profession, the research community and pharmaceutical companies. Although undoubtedly rare, the concept that PAH is overlooked is not to be the case today with more than ten drugs approved worldwide and life-saving surgical options including lung and heart-lung transplantation for refractory disease in eligible patients. There have been a number of important discoveries in recent years that have significantly improved our understanding of the pathomechanisms at play in this devastating disease and helped guide patient management. However, PAH survival and quality of life remain unsatisfactory and we face a major challenge to improve outcomes and ultimately find a cure for PAH based on strong clinical, translational and basic research in that fast growing field of medicine. Since the middle of the twentieth century, major achievements have occurred, as emphasized by the proceedings of the 5th World Pulmonary Hypertension conferences between 1973 and 2013. In parallel, international guidelines have been produced and disseminated supporting better awareness and management of PAH. These guidelines provide robust information on definition, classification, diagnosis and treatment of all forms of pulmonary hypertension.

We have progressed a long way since 1973 when the World Health Organization sponsored the first international meeting on a mysterious condition named primary pulmonary hypertension, corresponding to what we now call idiopathic, heritable and druginduced PAH. Nevertheless the burden of pulmonary vascular diseases and right heart failure is certainly still underestimated worldwide. It is thus very timely to publish an ISHLT monograph on pulmonary hypertension and right heart failure. In this first section, our readers will find important information on definition, classification, genetics, pathophysiology and diagnosis of PAH. We hope that this will be helpful to patients, students, healthcare providers, doctors and surgeons who witness the burden of pulmonary vascular diseases in their daily practice.

Chapter 1

Classification and Epidemiology

Contributors: Richa Agarwal, Thenappan Thenappan, and Mardi-Gomberg Maitland

Updated 2013 Classification and focus from the ISHLT

Pulmonary hypertension (PH) is a complex, progressive disease state defined by increases in pulmonary arterial pressures, pulmonary vascular resistance (PVR) and ultimately right ventricular (RV) failure. Classification schemas in PH, placed to facilitate a common language and clinical approach to these different categories, continue to undergo refinement since the first PH classification was unveiled at the World Symposium on Pulmonary Hypertension (WSPH) in 1973 in Geneva, Switzerland¹. The first WSPH was a response to the alarming rate of pulmonary arterial hypertension (PAH) cases found linked to anorexigen use². To date, five WSPH have been held, reflecting the remarkable progress and paradigm shifts in our understanding of this disease, fueled by impressive scientific and clinical investigations over the past few decades. We are likely to see further evolution of the classification model as we identify better understanding into mechanistic factors, improve clinical trial design to encompass larger, diverse cohorts, and learn from our registries comparing the epidemiology and pathobiology of distinct PH populations.

History and Changes to the Clinical Classifications

The initial PH classification, endorsed by the World Health Organization (WHO) in 1973, was a simple splitting of PH into primary PH or PPH, now referred to as idiopathic pulmonary arterial hypertension (IPAH), and secondary PH for the conditions that were attributed to presence of certain risk factors. This original classification of primary and secondary PH was recognized to be inadequate and did not highlight important differences within these groups. PH is now classified into 5 Groups: Pulmonary arterial hypertension (PAH; Group I) with a number of subgroups; PH from left heart disease (PH-LHD)(Group 2); PH due to lung diseases and/or hypoxia (Group 3); chronic thromboembolic pulmonary hypertension (CTEPH; Group 4); and pulmonary hypertension with unclear multifactorial mechanisms (Group 5), consisting of a group of rare and heterogeneous conditions associated with the development of PH but less extensively studied. Patients may also be described in terms as having PAH or Non-PAH causes, which is useful to differentiate patients with PAH from those with multiple etiologies of PH (i.e. patients who frequently have coexistent diastolic dysfunction, Group 2 PH, and lung disease, Group 3 PH).

Updates From the 5th World Symposium in Pulmonary Hypertension in Nice, France

Hemodynamic Classification of PH

Normal resting mean pulmonary artery pressure (PAP) is 14 ± 3 mmHg with an upper level of normal of 20 mm Hg³. The term borderline PH had been proposed for patients with mean PAP between 21 and 24 mmHg, but this is of uncertain significance and further epidemiology study is needed to determine prognostic impact and if earlier therapeutic interventions are warranted. In patients with scleroderma who have a higher prevalence of PH and worse survival compared with IPAH, a mean PAP between 21 and 24 mmHg puts them at risk for the development of overt PAH within 3 years⁴, ⁵. For this subset of patients and perhaps for those with a family history or hereditary PAH (HPAH), defining tighter cutoffs may aid in screening, earlier diagnosis, and more aggressive monitoring and treatment. During the 5th WSPH in Nice, it was decided to maintain the current definition using a threshold of mean PAP ≥ 25 mmHg. The term borderline PH has not yet been accepted; however, it is recommended that these patients be followed more closely for development of early pulmonary vascular disease and PAH.

The experts helped to create guidelines to distinguish PAH from PH due to left heart disease (PH-LHD). Currently, a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg documented during right heart catheterization (RHC) is used to differentiate between PAH and PH-LHD. Having a normal PAWP does not rule out left heart disease, and provocative maneuvers such as fluid challenge are often performed at time of RHC to unmask diastolic dysfunction. Because patients who have heart failure with preserved ejection fraction (HFpEF) may have a resting PAWP ≤15 mmHg due to diuretic and/or afterload agents, it has been suggested that the PAWP cutoff be lowered to 12 mmHg to better discriminate those with pre-capillary PH from patients with occult left heart disease. At present time, the cutoff for PAWP remains ≤ 15 mmHg and has not been lowered to 12 mmHg.

Additionally, changes surrounding the terminology of passive and reactive PH were proposed at the Nice meeting. The term out of proportion PH being used interchangeably when referring to the reactive PH-LHD patients who experience significant pulmonary vascular remodeling and develop elevated transpulmonary gradients > 12 mmHg (TPG) and pulmonary vascular resistance > 3.0 WU (PVR) is not preferred, in part because of the confusion it creates between those who have an isolated PAH phenotype. The TPG cut-off of 12 mmHg is not physiologically sound for distinguishing pre-from post-capillary PH as it may be influenced by stroke volume and pulmonary artery compliance⁶. Furthermore, this terminology for PH-LHD patients has unclear implications for vasoreactivity (which lacks standardization in the context of LHD), severity of remodeling, and treatment⁷. Thus, to further clarify this group hemodynamically, an elevated diastolic pressure difference (DPD), defined as the diastolic PAP – mean PAWP (which in normal subjects is typically ≤ 5 mmHg) has been proposed for identifying those patients with initially a purely passive PH picture who develop progressive vascular disease independent of changes in PAWP. DPD has emerged as a strong marker of advanced changes in the pulmonary circulation in patients with PH-LHD, and having a DPD ≥ 7mmHg independently predicts a worse outcome in the LHD group, similar to that of patients with PAH⁸. Based on this the 5th WSPH proposed a new hemodynamic definition for PH-LHD: isolated post-capillary (DPG < 7 mm Hg) and combined post-capillary and pre-capillary PH (DPG ≥ 7 mm Hg), although these definitions are provisional and require further validation and clinical studies to confirm the predictive power of the DPD.

Classification

The major changes to the Dana Point clinical classifications from the 2008 4th WSPH are shown in bold in Table 1. For the first time, the proposed classification could be applied to both adult and pediatric patients by adding specific items used for pediatric pulmonary hypertension. Modifications were primarily made to Group 1, with no significant changes to Groups 3 and 4.

Group 1, which includes IPAH and a number of PAH subgroups, has been the main focus of clinical trials and therapeutic interventions. PAH specific therapies are currently only approved for this Group. In the current Nice classification, the subcategory of HPAH has been expanded as new gene mutations have been identified. Both caveolin-1 (CAV1)⁹ and KCNK3¹⁰ are genes that are not related to the transforming growth factor (TGF)- beta super family like the BMPR2, ALK1 and endoglin genes, and suggest different protein signaling pathways leading to the development of PAH.

Five new drugs have been identified as risk factors for the development of PAH, within the subgroup of drug and toxin-induced PAH. These agents are categorized as definite, likely, possible, or unlikely, due to the level of evidence for their causal role in disease development (Table 2). Benfluorex, a fenfluramine derivative used inType 2 diabetic patients with dyslipidemia, has been added as a definite causative exposure after the first case series of PAH associated with benfluorex was reported in 2009 ¹¹. The French National

Table 1: Updated Classification of Pulmonary Hypertension (Nice, France 2013)

Updates to the Dana Point 2008 Classification are in bold.

BMPR = bone morphogenic protein receptor type II; CAV1= caveolin-1; ENG=endoglin; HIV= human immunodeficiency virus

Registry found 85 cases of benfluorex-associated PAH from 1999 to 2011, with median ingestion time of 30 months¹². Mild to moderate mitral and aortic valvular disease, which is known to be associated with fenfluramine use, has also been attributed to benfluorex ¹³. Use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy, especially past 20 weeks gestation, has been clearly linked to a two-fold increase in the risk for persistent PH of the newborn (PPHN)¹⁴, ¹⁵, but at this time, it is not apparent that SSRIs lead to an increased risk for PAH in adults ¹⁶. Dasatinib, a multi-kinase inhibitor (SRC, bcrabl, PDGFR), has been described as a likely contributor for PAH development¹⁷. Newer possible toxic exposures are interferon α and β that may promote release of the potent vasoconstrictor, endothelin-1, from pulmonary vascular endothelial cells. Most of the current data indicates, however, that patients treated with interferon also had additional risk factors for PAH, such as those with hepatitis C and portal hypertension, and thereby these drugs represent only a possible risk association¹⁸. Drugs similar to amphetamines have also been cautioned as possible risk factors for PAH.

Table 2: Updated Risk Factors for Drug- and Toxin-Induced PAH

Updates to the Dana Point 2008 classification are in bold.

Definite= epidemic or large multicenter epidemiologic studies show an association between the drug and PAH

Likely= single center, case-control study or multiple-case series show an association Possible = drugs that have not been studied but have similar mechanisms of action as those in the definite or likely category

Unlikely = epidemiologic studies of the drug show lack of association with PAH

The management of patients with congenital heart diseases (CHD) has improved substantially, but there are now more adults than ever with complex or repaired CHD who are at risk for the development of PAH. Approximately 10% of patients with congenital systemic-to-pulmonary shunts develop PAH¹⁹, with the greatest risk reserved for those who have large ventricular septal defects or arterial shunts which expose the pulmonary vasculature to chronic volume and pressure overload and ultimately promote pulmonary vascular remodeling. Patients who have atrial level shunts (volume-mediated lesions) are at lower risk for developing early PAH. Many patients with CHD develop some degree of PAH, however, and it is recommended that a thorough assessment for PAH be performed in all patients by centers with PAH expertise. In the current classification, both a detailed anatomic and pathologic classification of CHD, and a simple clinical classification emphasizing four distinct CHD phenotypes, are now established (Table 3). Hemodynamic criteria for closing cardiac shunts was also proposed, although this remains a controversial area, and longterm outcomes following left-to-right shunt closure in the setting of an elevated PVR is unknown. Furthermore, it was determined that PH associated with congenital obstructive lesions of the left heart and congenital cardiomyopathies should be categorized with Group 2 PH rather than Group I PAH. Segmental PH, which refers to PH in one or more lobes of one or both lungs, has been designated to Group 5 PH (unclear multifactorial mechanisms).

Other important changes to the clinical classification include moving chronic hemolytic anemia (i.e. sickle cell disease, thalassemia, spherocytosis, and stomatocytosis) from Group I PAH to Group 5 PH, as evidence suggests that the increased risk of PH in these patients is often due to multiple causes and differs from PAH in its pathobiology and response to PAH therapies. Sickle cell disease has been the most extensively studied type of chronic hemolytic anemia, and has both a prominent LHD or post-capillary component²⁰ as well as a pre-capillary component. Pre-capillary PH associated with sickle cell disease differs significantly from PAH in that it lacks the histologic features of typical pulmonary vasculopathy or plexiform lesions, results in less severe PVR elevation than other forms of PAH, and has uncertain therapeutic options²¹-²³. This can occur due to the high output state elevating the pressure but not the overall resistance. Persistent PH of the newborn has been withdrawn from Group 1 PAH and is now designated as a separate subcategory as Group 1".

Table 3: Updated Clinical Classification of PAH Associated with Congenital Heart Disease from Nice 2013

Epidemiology and Survival Data from Major Registries

The NIH Registry

The landmark NIH registry was initiated in 1981²⁴. This multicenter registry collected data prospectively from 1981 to 1985 from 32 centers in the United States. One hundred eighty seven patients with IPAH, HPAH, or anorexigen-associated PAH were included in this registry. PAH was defined as mean PAP ≥ 25 mm Hg at rest or ≥ 30 mm Hg with exercise and PAWP < 12 mm Hg. The mean age at the time of presentation was 36 ± 15 years and majority of them were females. The observed distribution of race was similar to the expected distribution of the US population with 85.4% Caucasians, 12.3% African Americans, and 2.3% Hispanics. The mean time interval between onset of symptoms and diagnosis was 2 years. The most common symptom was dyspnea followed by fatigue and syncope. Patients had severe PAH based on hemodynamics, with a mean PAP of 60± 18 mm Hg, a pulmonary vascular resistance index of 26 ± 14 Wood Units, and a cardiac index (CI) of 2.3 ± 0.9 l/min/ m2. Patients were treated with diuretics, digoxin, and supplemental nasal oxygen and, in a minority of cases, anticoagulation with warfarin. PAH-specific vasodilator therapy was not available except a relatively small number of patients were treated with calcium-channel blockers and/or hydralazine. The estimated median survival in the NIH registry was 2.8 years with a 1-year survival of 68%, 3-year survival of 48%, and a 5-year survival of 34%²⁵. The registry developed a regression equation to predict survival based on the baseline hemodynamics (mean RAP, CI, and mean PAP) at the time of diagnosis. This equation was used in many therapeutic trials to demonstrate improved survival in IPAH or HPAH patients by comparing the observed versus the survival rates predicted by the equation. However, the NIH equation underestimates survival in the current era and is no longer valid²⁶.

Contemporary PAH Registries

Since the NIH registry, there has been remarkable progress in the understanding of the pathogenesis and treatment of PAH in the last two decades. Unlike the NIH registry, in addition to IPAH, HPAH, and anorexigen associated PAH, the current WHO classification of PH includes PH associated with connective tissue disease, congenital heart disease, portal hypertension, and HIV infection under WHO category 1 PAH. Moreover, in the last two decades, the Food and Drug Administration (FDA) has approved eleven drugs for the treatment of PAH²⁷. In view of these changes, several contemporary registries were developed around the world to advance the epidemiological and prognostic data of PAH in the modern era²⁸-³⁵. These contemporary registries differ among each other in various aspects: the time period of enrollment, etiology of PAH patient population enrolled (idiopathic/heritable PAH vs. associated PAH), study design (retrospective vs. prospective), and study cohort (incident cases vs. prevalent cases). Table 4 compares the characteristics of the 11 major PAH registries²⁴, ²⁸-³³, ³⁵-³⁸.

Epidemiology of PAH in the Modern Era

PAH continues to remain an orphan disease with relatively low incidence and prevalence (Table 5A). Nearly half of the patients with PAH in the major PAH registries had IPAH or HPAH and the rest had associated PAH. The most common etiology of associated PAH was connective tissue disease followed by congenital heart disease²⁸, ²⁹, ³⁰. Scleroderma was the most common connective tissue disease associated with PAH. There was a higher prevalence of PAH associated with anorexigen use (9.5 % vs. 3-5.3%) and HIV infection (6.2% vs. 1-2.3%) in the French registry compared to the US based registries³⁹. Unlike the other countries, PAH associated with congenital heart disease was the predominant cause of WHO group 1 PAH in China³⁵.

Table 4: Characteristics of Major PAH registries

§ -COMPERA registry enrolled patients with any WHO group PH. The data presented here is for the incident IPAH cohort only. NIH – national institutes of health, PHC – pulmonary hypertension connections, PAH – pulmonary arterial hypertension, IPAH – idiopathic PAH, and CTEPH – chronic thromboembolic pulmonary hypertension, HPAH – heritable PAH, and APAH – associated PAH.

Data from the contemporary PAH registries suggest that the epidemiology of PAH has changed significantly in the last 3 decades³⁹. The mean age of the patients with IPAH or HPAH enrolled in the contemporary registries from the Western world ranged from 45- 65 years, which is significantly higher when compared to the NIH registry. The reason for the increase in the mean age at the time of presentation is unclear. There are several possible explanations. First, unlike the NIH registry, most of the modern registries enrolled predominantly prevalent cases (~85%) of PAH. Over representation of prevalent cases could have potentially introduced survivor bias. However, even in the incident cases of the French registry and the pulmonary hypertension registry of the United Kingdom and Ireland that studied only treatment-naïve incident IPAH, HPAH, and anorexigen-associated PAH, the median age at the time of enrollment was 50 years (vs. 36 years in the NIH registry), with 13.5% of the total UK and Ireland cohort older than 70 years of age at the time of diagnosis³¹. Second, there is increased awareness of PAH in the western world due to the easy availability of Doppler echocardiography as a PH screening tool and due to the availability of effective PAH-specific therapies. Interestingly, the Chinese IPAH cohort is quite similar to the NIH cohort, arguing that the increased age in the Western cohort may be due to case finding in older patients and not a change in the biological phenotype of PAH³⁷. It is also possible that the increasing age at the time of presentation is perhaps due to misclassification of PH, especially PH associated with heart failure with preserved ejection fraction (HFpEF) being misclassified as PAH due to overreliance on a single measurement of a resting PAWP⁴⁰. These two entities share several clinical characteristics in common⁴¹, and currently the differentiation between these two rests exclusively on the determination of PAWP, which is commonly fraught with errors⁴², ⁴³.

PAH is more common in female than in male. The female to male ratio in the landmark NIH registry was 1.7: 1. This was true in the contemporary registries of PAH as well, although the female to male ratio was significantly higher in the modern US based registries: PHC registry - 3:1, REVEAL registry - 4.8: 1, and the Mayo registry - 3.2: 1³⁹,⁴⁴. The exact reason for the increasing female predominance in the modern US based PAH registries compared with the European registries is unclear. One possible speculation relates it to the increased use of hormone replacement therapy in the United States in the 1980’s and the 1990’s.

The REVEAL registry provided data on the distribution of various ethnicities in PAH. In the REVEAL registry, 72.8% were Caucasians, 12.2 % were African Americans, 8.9% were Hispanics, 3.3 % were Asians or pacific islanders, and 2.8 were others or unknown³⁰. The observed distribution of Caucasians in the REVEAL registry was very similar to the age and sex-adjusted expected distribution of Caucasians in the US population; however, there was overrepresentation of African Americans (12.2% vs. 10.9%) and underrepresentation of Hispanics (8.9% vs. 11.5%), and Asians/pacific islanders (3.3% vs. 4.3%)³⁹. Other contemporary US and non-US based registries lacked data on race.

Unfortunately, despite increasing awareness of PAH, there is still a significant delay between the onset of symptoms and the diagnosis of PAH. The mean interval between onset of symptoms and diagnosis of PAH in the contemporary registries ranged from 18 months to 32 months (vs. 2 years in the NIH registry)³¹, ⁴⁵. In the REVEAL registry, 20% of patients had symptoms > 2 years before diagnosis⁴⁵. Similar to the NIH registry, a majority of the PAH patients enrolled in the contemporary registries also had advanced WHO functional III and IV symptoms (56% to 91%). In contrast to NIH, contemporary registry patients have multiple co-morbities such as systemic hypertension, diabetes, coronary artery disease, and the metabolic syndrome, which may also confuse the underlying diagnosis. The mean six minute walk distance (6MWD) at the time of presentation in the contemporary registries ranged from 292 ± 129 meters to 382 ± 117 meters. On invasive hemodynamic assessment, PAH patients in the contemporary registries had significantly elevated PAP and PVR with moderately reduced CI at the time of presentation (Table 5B), very similar to the NIH registry. Only a minority of patients (4.5–10%) had a positive acute vasodilator response, and among those IPAH was the predominant etiology.

Table 5:

5A: Incidence and Prevalence of PAH in Major Registries

5B: Hemodynamic Characteristics of Patients in Major PAH Registries.

PAH: pulmonary arterial hypertension, RA – right atrial pressure, PA – pulmonary artery, PCWP – pulmonary capillary wedge pressure, PVR – pulmonary vascular resistance, PVRI – pulmonary vascular resistance index, PHC – pulmonary hypertension connections, PAH – pulmonary arterial hypertension, and IPAH – idiopathic PAH.

Contemporary Survival in PAH

Despite significant progress made in the understanding of the pathogenesis and treatment, PAH continues to remain a challenging disease with a high mortality rate. In the contemporary PAH registries, the 1-, 3-, and 5-year survival rates in the total cohort including both prevalent and incident PAH patient cohorts were 85%- 87%, 67%-69%, and 57%- 61%, respectively²⁶,⁴⁶-⁴⁹. The 1-year survival rate in the incident PAH cohort alone was 85-89%.

Survival of patients with IPAH, HPAH, and anorexigen associated PAH has significantly improved when compared to the NIH registry. In the contemporary registries, the 1-, 3-, and 5-year survival rates in both prevalent and incident patients with IPAH, HPAH, and anorexigen-associated PAH were 89-91%, 69-75%, and 65%, respectively (vs. 68%, 48%, and 34%, respectively in the NIH registry)²⁵, ²⁶, ⁴⁶, ⁴⁸, ⁴⁹. The UK and Ireland registry that included only incident IPAH, HPAH, and anorexigen-associated PAH patients also reported similar 1-, 3-, and 5-year survival rates at 93%, 73%, and 61%, respectively³¹.

The improvement in survival in PAH is probably due to a combination of several factors. First, there is increased universal awareness of PAH despite continued late diagnosis. Second, there is likely a greater use of long-term anticoagulation compared with the early years of PAH treatment. Warfarin has been shown to improve survival in retrospective observational studies, especially in patients with IPAH or HPAH⁵⁰, ⁵¹; however, this has not been tested in a randomized control trial. Third, PAH-specific therapies are available. Intravenous epoprostenol improved short-term survival in the pivotal 16-week randomized double-blind control trial⁵². Intravenous epoprostenol, subcutaneous treprostinil, and oral bosentan have improved long-term survival in comparison to either historical controls or to the predicted survival calculated using the NIH survival prediction equation⁵³-⁵⁶. Two metaanalyses that evaluated the effect of PAH-specific therapy on short-term survival suggest a reduction in mortality when all treatment strategies are pooled together, but no individual class of drug produced a statistically significant reduction in mortality⁵⁷, ⁵⁸. Recently, macitentan, a new dual endothelin receptor antagonist, reduced the combined endpoint of morbidity and mortality in an even-driven long-term clinical trial⁵⁹.

Conclusion

Classification and epidemiology of PAH have evolved significantly in the last two decades when compared to the original NIH registry. Contemporary PAH registries have played an important role in redefining the epidemiology of PAH. New genetic mutations and drugs have been identified as putative risk factors for PAH. Although survival of PAH has improved significantly in recent years, it continues to remain a potentially fatal disease with a 1-year mortality ~ 15%.

References

1.     Hatano S, Strasser T. Primary pulmonary hypertension: Report on a WHO Meeting. October 15-17, 1973, Geneva: World Health Organization. 1975

2.     Luthy E. Proceedings: The epidemic of primary pulmonary hypertension in Europe. Pathol microbiol (basel) 1975:246-247

3.     Kovacs G, Berghold A, Scheidl S, Olschewski H. Pulmonary arterial pressure during rest and exercise in healthy subjects: A systematic review. Eur Respir J. 2009;34:888-894

4.     Bae S, Saggar R, Bolster MB, Chung L, Csuka ME, Derk C, Domsic R, Fischer A, Frech T, Goldberg A, Hinchcliff M, Hsu V, Hummers L, Schiopu E, Mayes MD, McLaughlin V, Molitor J, Naz N, Furst DE, Maranian P, Steen V, Khanna D. Baseline characteristics and follow-up in patients with normal haemodynamics versus borderline mean pulmonary arterial pressure in systemic sclerosis: Results from the pharos registry. Annals of the rheumatic diseases. 2012;71:1335-1342

5.     Kovacs G, Maier R, Aberer E, Brodmann M, Scheidl S, Troster N, Hesse C, Salmhofer W, Graninger W, Gruenig E, Rubin LJ, Olschewski H. Borderline pulmonary arterial pressure is associated with decreased exercise capacity in scleroderma. Am J Respir Crit Care Med. 2009;180:881-886

6.     Naeije R, Vachiery JL, Yerly P, Vanderpool R. The transpulmonary pressure gradient for the diagnosis of pulmonary vascular disease. Eur Respir J. 2013;41:217-223

7.     Vachiery JL, Adir Y, Barbera JA, Champion H, Coghlan JG, Cottin V, De Marco T, Galie N, Ghio S, Gibbs JS, Martinez F, Semigran M, Simonneau G, Wells A, Seeger W. Pulmonary hypertension due to left heart diseases. J Am Coll Cardiol. 2013;62:D100- 108

8.     Gerges C, Gerges M, Lang MB, Zhang Y, Jakowitsch J, Probst P, Maurer G, Lang IM. Diastolic pulmonary vascular pressure gradient: A predictor of prognosis in "out-of-proportion" pulmonary hypertension. Chest. 2013;143:758-766

9.     Austin ED, Ma L, LeDuc C, Berman Rosenzweig E, Borczuk A, Phillips JA, 3rd, Palomero T, Sumazin P, Kim HR, Talati MH, West J, Loyd JE, Chung WK. Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circulation. Cardiovascular genetics. 2012;5:336-343

10.     Ma L, Roman-Campos D, Austin ED, Eyries M, Sampson KS, Soubrier F, Germain M, Tregouet DA, Borczuk A, Rosenzweig EB, Girerd B, Montani D, Humbert M, Loyd JE, Kass RS, Chung WK. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med. 2013;369:351-361

11.     Boutet K, Frachon I, Jobic Y, Gut-Gobert C, Leroyer C, Carlhant-Kowalski D, Sitbon O, Simonneau G, Humbert M. Fenfluraminelike cardiovascular side-effects of benfluorex. Eur Respir J. 2009;33:684-688

12.     Savale L, Chaumais MC, Cottin V, Bergot E, Frachon I, Prevot G, Pison C, Dromer C, Poubeau P, Lamblin N, Habib G, Reynaud-Gaubert M, Bourdin A, Sanchez O, Tubert-Bitter P, Jais X, Montani D, Sitbon O, Simonneau G, Humbert M. Pulmonary hypertension associated with benfluorex exposure. Eur Respir J. 2012;40:1164-1172

13.     Frachon I, Etienne Y, Jobic Y, Le Gal G, Humbert M, Leroyer C. Benfluorex and unexplained valvular heart disease: A casecontrol study. PLoS One. 2010;5:e10128

14.     Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, Mitchell AA. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. 2006;354:579-587

15.     Kieler H, Artama M, Engeland A, Ericsson O, Furu K, Gissler M, Nielsen RB, Norgaard M, Stephansson O, Valdimarsdottir U, Zoega H, Haglund B. Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: Population based cohort study from the five nordic countries. Bmj. 2012;344:d8012

16.     Walker AM, Langleben D, Korelitz JJ, Rich S, Rubin LJ, Strom BL, Gonin R, Keast S, Badesch D, Barst RJ, Bourge RC, Channick R, Frost A, Gaine S, McGoon M, McLaughlin V, Murali S, Oudiz RJ, Robbins IM, Tapson V, Abenhaim L, Constantine G. Temporal trends and drug exposures in pulmonary hypertension: An american experience. Am Heart J. 2006;152:521-526

17.     Montani D, Bergot E, Gunther S, Savale L, Bergeron A, Bourdin A, Bouvaist H, Canuet M, Pison C, Macro M, Poubeau P, Girerd B, Natali D, Guignabert C, Perros F, O’Callaghan DS, Jais X, Tubert-Bitter P, Zalcman G, Sitbon O, Simonneau G, Humbert M. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation.125:2128-2137

18.     Savale L, S G, al CMe. Pulmonary arterial hypertension in patients treated with interferon. http://www.ersnetsecure.org/public/prg_congres.abstract?www_i_presentations=63109. 2013

19.     Engelfriet PM, Duffels MG, Moller T, Boersma E, Tijssen JG, Thaulow E, Gatzoulis MA, Mulder BJ. Pulmonary arterial hypertension in adults born with a heart septal defect: The euro heart survey on adult congenital heart disease. Heart. 2007;93:682-687

20.     Fonseca GH, Souza R, Salemi VM, Jardim CV, Gualandro SF. Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease. Eur Respir J. 2012;39:112-118

21.     Manci EA, Culberson DE, Yang YM, Gardner TM, Powell R, Haynes J, Jr., Shah AK, Mankad VN, Investigators of the Cooperative Study of Sickle Cell D. Causes of death in sickle cell disease: An autopsy study. Br J Haematol. 2003;123:359-365

22.     Parent F, Bachir D, Inamo J, Lionnet F, Driss F, Loko G, Habibi A, Bennani S, Savale L, Adnot S, Maitre B, Yaici A, Hajji L, O’Callaghan DS, Clerson P, Girot R, Galacteros F, Simonneau G. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med. 2011;365:44-53

23.     Machado RF, Barst RJ, Yovetich NA, Hassell KL, Kato GJ, Gordeuk VR, Gibbs JS, Little JA, Schraufnagel DE, Krishnamurti L, Girgis RE, Morris CR, Rosenzweig EB, Badesch DB, Lanzkron S, Onyekwere O, Castro OL, Sachdev V, Waclawiw MA, Woolson R, Goldsmith JC, Gladwin MT, walk PI, Patients. Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated trv and low exercise capacity. Blood. 2011;118:855-864

24.     Rich S, Dantzker R, Ayres S, Bergofsky E, Brundage B, Detre K, Fishman A, Goldring R, Groves B, Koerner S, Levy P, Reid L, Vreim C, Williams G. Primary pulmonary hypertension: A national prospective study. Ann Intern Med. 1987;107:216-223

25.     D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, Levy PS, Pietra GG, Reid LM, Reeves JT, Rich S, Vreim CE, Williams GW, Wu M. Survival in patients with primary pulmonary hypertension: Results from a national prospective registry. Ann Intern Med. 1991;115:343-349

26.     Thenappan T, Shah SJ, Rich S, Tian L, Archer SL, Gomberg-Maitland M. Survival in pulmonary arterial hypertension: A reappraisal of the nih risk stratification equation. Eur Respir J. 2010;35:1079-1087

27.     Galie N, Corris PA, Frost A, Girgis RE, Granton J, Jing ZC, Klepetko W, McGoon MD, McLaughlin VV, Preston IR, Rubin LJ, Sandoval J, Seeger W, Keogh A. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62:D60-72

28.     Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Simonneau G. Pulmonary arterial hypertension in france: Results from a national registry. Am J Respir Crit Care Med. 2006;173:1023-1030

29.     Thenappan T, Shah SJ, Rich S, Gomberg-Maitland M. A USA-based registry for pulmonary arterial hypertension: 1982 2006. Eur Respir J. 2007;30:1103-1110

30.     Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, Barst RJ, Benza RL, Liou TG, Turner M, Giles S, Feldkircher K, Miller DP, McGoon MD. Pulmonary arterial hypertension: Baseline characteristics from the reveal registry. Chest. 2010;137:376-387

31.     Ling Y, Johnson MK, Kiely DG, Condliffe R, Elliot CA, Gibbs JS, Howard LS, Pepke-Zaba J, Sheares KK, Corris PA, Fisher AJ, Lordan JL, Gaine S, Coghlan JG, Wort SJ, Gatzoulis MA, Peacock AJ. Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: Results from the pulmonary hypertension registry of the united kingdom and ireland. Am J Respir Crit Care Med. 2012;186:790-796

32.     Escribano-Subias P, Blanco I, Lopez-Meseguer M, Lopez-Guarch CJ, Roman A, Morales P, Castillo-Palma MJ, Segovia J, Gomez-Sanchez MA, Barbera JA. Survival in pulmonary hypertension in spain: Insights from the spanish registry. Eur Respir J. 2012;40:596-603

33.     Hoeper MM, Huscher D, Ghofrani HA, Delcroix M, Distler O, Schweiger C, Grunig E, Staehler G, Rosenkranz S, Halank M, Held M, Grohe C, Lange TJ, Behr J, Klose H, Wilkens H, Filusch A, Germann M, Ewert R, Seyfarth HJ, Olsson KM, Opitz CF, Gaine SP, Vizza CD, Vonk-Noordegraaf A, Kaemmerer H, Gibbs JS, Pittrow D. Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: Results from the compera registry. Int J Cardiol. 2013;168:871-880

34.     Shapiro S, Traiger GL, Turner M, McGoon MD, Wason P, Barst RJ. Sex differences in the diagnosis, treatment, and outcome of patients with pulmonary arterial hypertension enrolled in the registry to evaluate early and long-term pulmonary arterial hypertension disease management. Chest. 2012;141:363-373

35.     Zhang R, Dai LZ, Xie WP, Yu ZX, Wu BX, Pan L, Yuan P, Jiang X, He J, Humbert M, Jing ZC. Survival of chinese patients with pulmonary arterial hypertension in the modern treatment era. Chest. 2011;140:301-309

36.     Peacock AJ, Murphy NF, McMurray JJ, Caballero L, Stewart S. An epidemiological study of pulmonary arterial hypertension. Eur Respir J. 2007;30:1390-1395

37.     Jing ZC, Xu XQ, Han ZY, Wu Y, Deng KW, Wang H, Wang ZW, Cheng XS, Xu B, Hu SS, Hui RT, Yang YJ. Registry and survival study in chinese patients with idiopathic and familial pulmonary arterial hypertension. Chest. 2007;132:373-379

38.     Kane GC, Maradit-Kremers H, Slusser JP, Scott CG, Frantz RP, McGoon MD. Integration of clinical and hemodynamic parameters in the prediction of long-term survival in patients with pulmonary arterial hypertension. Chest. 2011;139:1285-1293

39.     Frost AE, Badesch DB, Barst RJ, Benza RL, Elliott CG, Farber HW, Krichman A, Liou TG, Raskob GE, Wason P, Feldkircher K, Turner M, McGoon MD. The changing picture of patients with pulmonary arterial hypertension in the united states: How reveal differs from historic and non-us contemporary registries. Chest. 2011;139:128-137

40.     Halpern SD, Taichman DB. Misclassification of pulmonary hypertension due to reliance on pulmonary capillary wedge pressure rather than left-ventricular end-diastolic pressure. Chest. 2009

41.     Thenappan T, Shah SJ, Gomberg-Maitland M, Collander B, Vallakati A, Shroff P, Rich S. Clinical characteristics of pulmonary hypertension in patients with heart failure and preserved ejection fraction. Circ Heart Fail. 2011;4:257-265

42.     Ryan JJ, Rich JD, Thiruvoipati T, Swamy R, Kim GH, Rich S. Current practice for determining pulmonary capillary wedge pressure predisposes to serious errors in the classification of patients with pulmonary hypertension. Am Heart J.163:589-594

43.     Kovacs G, Avian A, Pienn M, Naeije R, Olschewski H. Reading pulmonary vascular pressure tracings. How to handle the problems of zero leveling and respiratory swings. Am J Respir Crit Care Med. 2014;190:252-257

44.     McGoon MD, Benza RL, Escribano-Subias P, Jiang X, Miller DP, Peacock AJ, Pepke-Zaba J, Pulido T, Rich S, Rosenkranz S, Suissa S, Humbert M. Pulmonary arterial hypertension: Epidemiology and registries. J Am Coll Cardiol. 2013;62:D51-59

45.     Brown LM, Chen H, Halpern S, Taichman D, McGoon MD, Farber HW, Frost AE, Liou TG, Turner M, Feldkircher K, Miller DP, Elliott CG. Delay in recognition of pulmonary arterial hypertension: Factors identified from the reveal registry. Chest. 2011;140:19-26

46.     Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Cottin V, Degano B, Jais X, Montani D, Souza R, Simonneau G. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation.122:156-163

47.     Humbert M, Sitbon O, Yaici A, Montani D, O’Callaghan DS, Jais X, Parent F, Savale L, Natali D, Gunther S, Chaouat A, Chabot F, Cordier JF, Habib G, Gressin V, Jing ZC, Souza R, Simonneau G. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J.36:549-555

48.     Benza RL, Gomberg-Maitland M, Miller DP, Frost A, Frantz RP, Foreman AJ, Badesch DB, McGoon MD. The reveal registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest.141:354-362

49.     Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, Frost A, Barst RJ, Badesch DB, Elliott CG, Liou TG, McGoon MD. Predicting survival in pulmonary arterial hypertension: Insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management (reveal). Circulation.122:164-172

50.     Rich S, Kaufman E, Levy P. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992;327:76

51.     Olsson KM, Delcroix M, Ghofrani HA, Tiede H, Huscher D, Speich R, Grunig E, Staehler G, Rosenkranz S, Halank M, Held M, Lange TJ, Behr J, Klose H, Claussen M, Ewert R, Opitz CF, Vizza CD, Scelsi L, Vonk-Noordegraaf A, Kaemmerer H, Gibbs JS, Coghlan G, Pepke-Zaba J, Schulz U, Gorenflo M, Pittrow D, Hoeper MM. Anticoagulation and survival in pulmonary arterial hypertension: Results from the compera registry. Circulation. 2013

52.     Barst R, Rubin L, McGoon M, Caldwell E, Long W, Levey P. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med. 1994;121:409-415

53.     McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, Ahearn G. Prognosis of pulmonary arterial hypertension: Accp evidence-based clinical practice guidelines. Chest. 2004;126:78S-92S

54.     McLaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galie N, Rainisio M, Simonneau G, Rubin LJ. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J. 2005;25:244-249

55.     Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve P, Rainisio M, Simonneau G. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: Prognostic factors and survival. J Am Coll Cardiol. 2002;40:780-788

56.     Barst RJ, Galie N, Naeije R, Simonneau G, Jeffs R, Arneson C, Rubin LJ. Long-term outcome in pulmonary arterial hypertension patients treated with treprostinil. Eur Respir J. 2006

57.     Macchia A, Marchioli R, Tognoni G, Scarano M, Marfisi R, Tavazzi L, Rich S. Systematic review of trials using vasodilators in pulmonary arterial hypertension: Why a new approach is needed. Am Heart J.159:245-257

58.     Galie N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009;30:394-403

59.     Pulido T, Adzerikho I, Channick RN, Delcroix M, Galie N, Ghofrani HA, Jansa P, Jing ZC, Le Brun FO, Mehta S, Mittelholzer CM, Perchenet L, Sastry BK, Sitbon O, Souza R, Torbicki A, Zeng X, Rubin LJ, Simonneau G, Investigators S. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809-818

Chapter 2

Genetics and Pathophysiology

Updates with Focus on Translational Approaches

Contributors: James West, Marlene Rabinovitch, Irene M. Lang

Modulators of Pulmonary Vascular Disease

Pulmonary vascular disease occurs in a variety of clinical conditions, with idiopathic pulmonary arterial hypertension (iPAH) being the disease prototype. The histological hallmark is small vessel obliteration by intimal growth (Figure 1). The discussion of genes, regulatory pathways, cell types, and processes in this chapter reflects the paucity of our current understanding of the interplay and relative importance of the individual players.

Figure 1. Examples of grades of pulmonary vascular pathological changes. Representative photomicrographs of lung biopsy tissue after Movat pentachrome staining vessels were graded according to Heath-Edwards and morphometric criteria.

Top. A: Vessel showing a typical grade IA lesion with minimal medial hypertrophy. B: Vessel showing a typical grade IB lesion showing severe medial hypertrophy. C: Vessel showing a typical grade IIIC lesion with extensive neointimal formation. D: Vessel from a typical grade IVC lesion with occlusive neointimal fibrosis and medial atrophy (part of a plexiform complex). Original magnification, X40.

Bottom:. Representative photomicrographs showing immunoperoxidase staining for cellular Fn in graded lung biopsy tissue sections. A: Vessel showing a typical grade UA lesion. B: Vessel showing a typical grade IC lesion. C: Vessel showing a typical grade IIIC lesion. D: Vessel showing a typical grade IVC lesion. Modest to intense periendothelial Fn immunostaining was apparent in grade I lesions (A and B). In higher-grade lesions (C and D), more intense Fn immunostaining was observed in the periendothelial and neointimal cell layers. Original magnification, X 40.

Thrombosis

Thrombosis and hypercoagulability are features of PAH¹, ². Inherited coagulation factors like antithrombin-3, protein C, protein S-deficiencies, factor V, and factor II mutations are not more common³, ⁴ than in the general population. However, markers of thrombin generation, fibrin degradation ⁵ as well as microparticle counts ⁶, levels of plasminogen activator inhibitor-1 (PAI), and structurally abnormal vonWillebrand factor⁷ are increased. Inappropriate tissue factor (TF) expression on the endothelial surface predisposes to in situ thrombosis and supports smooth muscle cell proliferation⁸. While warfarin has failed to show any beneficial effects in animal models of PH⁹, rivaroxaban, an oral direct Factor Xa inhibitor, prevented RV dysfunction and hypertrophy in the monocrotaline model¹⁰. Chronic thromboembolic pulmonary hypertension (CTEPH) represents a particular subset of pre-capillary pulmonary hypertension (PH) that is characterized by misguided thrombus remodeling¹¹ (Figure 2). CTEPH is best distinguished from PAH by a history of venous thromboembolism. Abnormal plasma coagulation factors are not statistically more common than in the normal population¹¹. Lupus anticoagulant and antiphospholipid antibodies occur more commonly in CTEPH⁴. Plasma factor VIII, a protein associated with both primary and recurrent VTE, is elevated¹². No abnormalities of systemic fibrinolysis have been identified. However, imbalances of cell-bound fibrinolysis-associated proteins and dysfunction of the endothelium covering unresolved thrombi have been shown¹¹. Fibrin from patients with CTEPH is more resistant to lysis.¹³

Figure 2. A molecular view of thrombosis.

The left side illustrates platelets, neutrophils and monocytes at the initiation of thrombosis. The right side of the panel describes molecules involved in thrombus resolution. Figure from (Alias & Lang, 2013). © 2014 by the Pulmonary Vascular Research Institute. Reproduced with permission.

Current guidelines recommend treatment of precapillary PH with oral anticoagulants