Update on the Treatment of Pulmonary Arterial Hypertension

Abstract

In the last decades, important advances have been made in the treatment of pulmonary arterial hypertension (PAH), a severe, progressive, incurable, and potentially fatal disease. For an adequate therapy, correct hemodynamic diagnosis and etiology classification are fundamental. Many etiologies – rheumatic disease, portal hypertension, congenital heart diseases, schistosomiasis – require specific measures, in addition to drug therapy for PAH. The specific therapy for PAH is based on medications that act on three pathophysiological pathways – prostacyclin, endothelin, and nitric oxide pathways. These drugs have multiple presentations (oral, intravenous, subcutaneous, and inhaled) and have changed the history of PAH. This review presents an overview of drug therapy strategies and different forms and peculiarities of PAH.

Pulmonary Arterial Hypertension; Pulmonary Hypertension; Diagnosis; Therapeutics

Resumo

Muitos avanços ocorreram nas últimas décadas na terapêutica da hipertensão arterial pulmonar (HAP), uma doença grave, progressiva, incurável e potencialmente fatal. Para seu tratamento adequado, são fundamentais o diagnóstico hemodinâmico e a classificação de sua etiologia, em que várias delas (colagenoses, hipertensão portal, cardiopatia congênitas, esquistossomose) requerem medidas específicas, além do tratamento farmacológico característico para HAP. O tratamento com fármacos-alvo para HAP baseia-se em produtos farmacêuticos que interferem em três vias fisiopatológicas moleculares: da prostaciclina, da endotelina e do óxido nítrico. Tais fármacos apresentam múltiplas apresentações (oral, endovenosa, subcutânea e inalatória) e mudaram a história da HAP. Essas medicações e suas estratégias de uso, assim como particularidades das diferentes formas de HAP, são o foco desta revisão.

Hipertensão arterial pulmonar; Hipertensão Pulmonar; Diagnóstico; Terapêutica

Introduction

Pulmonary arterial hypertension (PAH) is a clinical condition that leads to remodeling obliteration of the pulmonary vascular bed, ultimately resulting in increased vascular resistance.¹ This causes an increase in systemic pressure and right ventricular overload, which progresses to a gradual ventircular failure, which is the main cause of the symptoms associated with the disease.²

PAH is a rare and severe condition that affects 2-5 million patients per million adults per year,³ with a median survival of 2.8 years in the absence of specific treatment.⁴ However, since the 90’s, a number of medications with multiple presentations (oral, intravenous, subcutaneous and inhaled) have been developed and drastically changed the PAH course and the quality of life of these patients.⁶

Data from the French Pulmonary Hypertension Network registry showed that, after introduction of specific therapy, patients’ survival increased to 82.9% in one year and 58.2% in three years, corresponding to an estimated improvement of at least 15% as compared with the predicted survival in case of no access to pharmacological treatment.⁷ The type of these medications and their strategy use, as well as the different forms of PAH are the focus of this review.

Definitions

Pulmonary hypertension (PH) is defined as an increase of mean pulmonary arterial pressure (MPAP) greater than 20 mmHg.⁸ Although a threshold of 25 mmHg had been classically used in PH definition,⁹ evidence from recent studies has supported that lower levels are already associated with a worse prognosis.¹⁰ A concomitant pulmonary artery occlusion pressure (PAOP) equal to or lower than 15 mmHg characterizes the pre-capillary PH; in this situation, vascular disease is predominantly in the arterial territory. A PAOP higher than 15 mmHg determines the presence of post-capillary PH, suggesting changes in the left heart chamber ( Figure 1 ). Based on this definition, it seems clear that right cardiac catheterization is fundamental for an adequate characterization of PH.¹¹

Figure 1
– Definitions of hemodynamic changes of pulmonary vascular system and its correlation with pulmonary hypertension classification groups. PH: pulmonary hypertension; PAH: pulmonary arterial hypertension; MPAP: mean pulmonary arterial pressure; PAOP: pulmonary artery occlusion pressure; PVR: pulmonary vascular resistance; W: Woods, mmHg: millimeter of mercury.

It is worth pointing out that, while current criteria for PAH definition include pulmonary vascular resistance (PVR) values greater than 3.0 W, recent data have indicated that PVR values greater than 2.2 W already have an impact on patients’ survival and a response to medical treatment.¹² Thus, it is possible that future definitions of PAH will include PVR values greater than 2.2 W in addition to the criterion for MPAP greater than 20 mmHg.

Classification

Based on hemodynamic definitions, and also considering pathophysiological, clinical and therapeutical features of different etiologies of PH, the cases of this disease can be classified into five groups.⁸ , ¹³ Group I, patients with predominant pulmonary arterial disease, in the absence of pulmonary or thromboembolic disease (focus of this revision); group II, patients with PH caused by left heart disease and elevation in hydrostatic pressure from the left atrium.¹⁴ Group III includes patients with PH associated with chronic pulmonary disease, caused by loss of pulmonary vascular bed and hypoxic vasoconstriction.¹⁵ Group IV includes patients with pulmonary hypertension due to chronic pulmonary embolism, and has a distinct clinical management, beyond the scope of this text. Recommendations for the diagnosis and treatment of patients with pulmonary hypertension due to chronic pulmonary embolism can be found in other publications.16 Group V includes patients with rarer diseases, involving multiple mechanisms.⁸ The different etiologies of PH and their classifications are described in Table 1 . Of note, although out of the scope of this review, the diagnostic process for a correct classification of PH cases is extensive and comprehensive, allowing the provision of appropriate treatment strategies to the predominant pathophysiological mechanisms of pulmonary vascular pressure elevation.¹⁷

Table 1
– Classification of pulmonary hypertension etiologies by groups (modified from reference 5)

1. Pulmonary arterial hypertension (PAH)
1.1 Idiopathic PAH
1.2 Heritable PAH
1.3 Drug- or 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 diseases
1.4.5 Schistosomiasis
1.5 Calcium channel blocker responders
1.6 Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis
1.7 Persistent pulmonary hypertension of the newborn
2. Pulmonary hypertension (PH) due to left heart disease
2.1 Heart failure with preserved ejection fraction
2.2 Heart failure with reduced ejection fraction
2.3 Valvular heart disease
2.4 Congenital or acquired heart diseases leading to post-capillary pulmonary hypertension
3. Pulmonary hypertension due to pulmonary disease and/or hypoxia
3.1 Obstructive lung disease
3.2 Restrictive lung disease
3.3 Other lung diseases with mixed obstructive/restrictive pattern
3.4 Hypoxia without structural lung disease
3.5 Developmental lung diseases
4. Pulmonary hypertension due to pulmonary artery obstruction
4.1 Pulmonary hypertension due to chronic pulmonary thromboembolism
4.2 Other pulmonary artery obstructions
5. Pulmonary hypertension with multifactorial and/or unknown mechanisms
5.1 Hematological diseases: chronic hemolytic anemia, myeloproliferative disorders
5.2 Systemic and metabolic diseases: pulmonary Langerhans cell histiocytosis, Gaucher’s disease, glycogen storage disease, neurofibromatosis and sarcoidosis
5.3 Others: fibrosing mediastinitis, chronic renal failure, with or without hemodialysis
5.4 Complex congenital heart diseases

• PH: pulmonary hypertension; PAH: pulmonary arterial hypertension; HIV: human immunodeficiency virus.

Treatment of PAH

General measures

After the diagnosis of PAH is confirmed, general measures aiming at minimizing the consequences of the disease should be implemented. In this context, three important measures should be considered: to prevent pregnancy (which is associated with a worsening of hemodynamic status due to cardiac output increase, leading to elevated maternal-fetal mortality),¹⁸ immunization against influenza and pneumococcal disease,⁹ and psychosocial support to PAH patients.¹⁹ Other measures include the use of diuretics, supplemental oxygen, and avoidance of strenuous exercise. Supervised physical exercises, as part of a rehabilitation program, may be recommended²⁰ after introduction of specific pharmacological therapy.

Studies in the 80s²¹ suggested a beneficial effect of anticoagulation based on the occurrence of in situ thrombosis reported in studies on lung biopsies in PAH patients. However, subsequent data²² have indicated a beneficial effect of anticoagulation only in patients with idiopathic PAH, heritable PAH or PAH associated with the use of anorectic drugs. Since then, indication for anticoagulation has been made based on a case-by-case risk and benefit analysis.²³

Vasoreactivity testing

For patients with idiopathic, heritable, or drug-induced PAH, vasoreactivity test should be performed during diagnostic right heart catheterization. Inhaled nitric oxide (NO) at a dose of 10-20 ppm for 10 minutes is recognized as the gold-standard method to assess pulmonary vasoreactivity in patients with PAH. A positive vasoreactivity test is a fall of at least 10 mmHg in MPAP, fall to an absolute MPAP less than 40 mmHg, and unchanged cardiac output.² Vasoreactivity testing aims to identify a subgroup of patients in whom the increase in vascular tone is the main mechanism of the genesis of PAH, rather than vascular remodeling.²⁴

Patients with PAH that show a positive response to the vasoreactivity test should receive treatment with calcium channel blocker (CCB), preferably long-acting CCB at the highest tolerable dose.²⁵ Administration of 10 mg amlodipine once a day, 30 mg nifedipine twice a day, and 60 mg diltiazem three times a day has been recommended. Patients who do not show improvements in functional class (to I/II) or in hemodynamic function should receive specific medications for PAH. Although nearly 12.6% of patients diagnosed with idiopathic PAH show an acute response to vasodilation, half of these patients do not show good clinical response to CCB at one year of follow-up.²⁶ Patients who have not undergone vasoreactivity test should not be treated with CCB.²³

Specific treatment

Treatment pathways

The main anatomical and physiological feature in PAH is pulmonary vascular remodeling, with development of intimal and medial thickening.²⁷ Vasoconstriction also plays a role in the development of the disease, because of the increase of vascular tone and proliferation of smooth muscle cells (SMC) in arterioles.²⁵ Three pathophysiological pathways related to molecular mechanisms involved in these histological findings have been identified and been used as pharmacological targets for the treatment of PAH – the prostacyclin (PGI₂), pathway, the endothelin pathway, and the NO pathway.²⁸

The prostacyclin pathway

PGI₂, a derivative of arachidonic acids, acts on transmembrane receptors of multiple tissues involved in many biological activities.²⁹ In the pulmonary circulation, by stimulation of the IP receptor, PGI₂induces relaxation of SMC in pulmonary arterioles leading to vasodilation, and inhibits their proliferation by stimulation of cyclic AMP synthesis.³⁰ On the other hand, another molecule of the PGI₂pathway, the thromboxane A2 (TXA2), counterbalances the PGI₂effects, causing vasoconstriction and increase of platelet aggregation. In PAH, the levels of PGI₂and the enzymatic activity of prostacyclin synthase are reduced, and the balance is shifted towards TXA2.³¹ Therefore, one of the strategies for the treatment of PAH is the direct action on IP receptor, by administration of prostacyclin (epoprostenol)³² or of a structural analog of TXA2 (e.g. treprostinil, beraprost and iloprost).³³ , ³⁴ Other drugs with different structures can also act on the IP receptor, like the selexipag.³⁵

The endothelin pathway

Endothelin-1 (ET-1) is the most potent natural vasoconstrictor of the biological systems.³⁶ ET-1 levels are elevated in both pulmonary vascular endothelium and in the blood of patients with PAH.³⁷ ET-1 exerts its physiological effect via two receptors, endothelin A receptor (ETA) and endothelin B receptor (ETB). Bosentan³⁸ and macitentan³⁹ are two endothelin receptor antagonists that non-selectively block ETA and ETB, and ambrisentan⁴⁰ exhibits a higher affinity for ETA. These three drugs have been shown to be effective in the treatment of PAH.

The nitric oxide pathway

NO is a potent endogenous vasodilator that acts in the SMC by stimulation of guanylyl cyclase (GC) and synthesis of cyclic GMP.⁴¹ Patients with PAH have reduced low levels of serum and tissue NO.⁴² The phosphodiesterase type 5 (PDE-5) is an enzyme responsible for degradation of cyclic GMP. Inhibition of PDE-5 leads to an increase in cyclic GMP levels and consequent relaxation of SMC and vasodilatation.⁴³ Sildenafil, tadalafil and vardenafil are the PDE-5 inhibitors currently available.

Targeting another part of the NO pathway, riociguat, a GC stimulant, potentializes GC activity independently from NO.⁴⁴ GC, stimulated by riociguat, potentializes the conversion of GTP into cyclic GMP and promotes vasodilation. Riociguat can be used for treatment of both PAH⁴⁵ and chronic thromboembolic pulmonary hypertension.⁴⁶ The drugs commercially available for the treatment of PAH in Brazil are listed in Table 2 .

Table 2
– Authorized drugs for the treatment of pulmonary arterial hypertension, available in Brazil

Drugs	Posology	Administration route	Common side effects	Pathway	Reference
Iloprost	2,5-5 mcg 6-9x day	Inhaled	Cough Local irritation	PGI2	34
Selexipag	200-1600 mcg 2x day	Oral	Headache Diarrhea	PGI2	35
Ambrisentan	5-10 mg 1 x day	Oral	Anemia Edema	ET1	40
Bosentan	62,5-125 mg 2x day	Oral	Anemia Hepatotoxicity	ET1	38
Macitentan	10 mg 1x day	Oral	Anemia Hepatotoxicity Edema	ET1	39
Sildenafil	20-80 mg 3x day	Oral	Headache	NO	43
Riociguat	0,5-2,5 mg 3x day	Oral	Headache Hypotension	NO	45

• ₂

Strategies of treatment

Over recent years, there has been a marked change in the use strategies of different drugs available, with trends towards earlier treatment and combination of different drug pathways/classes.

The combination of drugs is based on the potential synergy between these drugs acting simultaneously in different pathophysiological pathways. As compared with monotherapy, the addition of a second drug (sequential combined therapy) has shown to be beneficial for different combinations of drugs.³⁵ , ³⁹ , ⁴⁷ These findings were corroborated by a meta-analysis of 14 studies on sequential combined therapy, showing a reduction in clinical worsening compared with monotherapy.⁴⁸

In a different approach, a large clinical trial evaluated the use of ambrisentan plus tadalafil since the diagnosis of PAH.⁴⁷ This drug combination caused a 50% reduction in the combined endpoint of clinical worsening when compared with the use of any of the other drugs alone, with no significant differences in side effects.

Although there are no studies directly comparing initial versus sequential combination therapies, evidence has suggested that initial combined therapy is well tolerated and beneficial even in patients classified as low risk.⁴⁷ Thus, the current recommendation is to consider combined oral therapy since diagnosis as detailed in Figure 2 .

Figure 2
– Treatment algorithm and risk stratification in the follow-up of pulmonary arterial hypertension proposed by a work group on pulmonary circulation (Heart Institute [INCOR], University of Sao Paulo). CCB: calcium-channel blockers; FC: functional class; 6MWD: six-minute walk distance; BNP: brain natriuretic peptide; MRI: magnetic resonance imaging; ECHO: echocardiography; CPT: cardiopulmonary test; ERA: endothelin receptor antagonists; PDE5i: phosphodiesterase type 5 (PDE-5).

However, a minority of patients could still benefit from monotherapy strategy. Patients with portal hypertension, HIV, complex congenital heart disease, veno-occlusive disease, idiopathic PAH, and those with high likelihood of left heart failure and preserved ejection fraction can begin treatment with one drug class. Besides, long-term clinically stable patients in monotherapy may not need combination therapy.²³

The potential of combination of three drugs since diagnosis has also been evaluated. A French retrospective study evaluated the efficacy of a triple combination therapy (epoprostenol, bosentan and sildenafil) in the initial treatment of severe PAH, and showed an improvement in NYHA functional class, exercise performance, and hemodynamic parameters. The study also showed longer survival of patients under triple therapy compared with that expected by the French historical registry, suggesting a long-term benefit of this approach.⁴⁹

Nevertheless, for less severe patients, there is no evidence supporting the efficacy of initial triple therapy. A recent study evaluated the efficacy and safety of initial triple oral therapy with selexipag, macitentan and tadalafil versus initial double oral therapy with macitentan and tadalafil in 247 newly diagnosed PAH patients.50 No difference was found in terms of improvement of PVR, six-minute walk distance and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Also, adverse effects were more common in the initial triple therapy group.

Triple combination therapy for the treatment of PAH patients seems efficient. The addition of selexipag as a third agent in patients receiving endothelin receptor antagonist and PDE-5 inhibitor was associated with less hospitalizations and events of disease progression.51 The beneficial effects were more pronounced in patients with World Health Organization functional class II.

Another potential strategy is the substitution of drugs targeting the same biochemical pathway. However, although promising, this strategy still lacks robust scientific evidence and should not be performed routinely.⁵²

Risk stratification and clinical follow-up

Assessing the risk of progression of PAH is essential to guide treatment. Strategies for mortality risk stratification evaluating the combination of multiple markers ( Table 3 ), both at diagnosis and during treatment, have shown effective in predicting the clinical course of the disease.⁵³ - ⁵⁵

Table 3
– Prognostic factors in pulmonary arterial hypertension (adapted from reference 8)

Prognostic determinants	One-year mortality (estimated)
	Low risk < 5%	Intermediate risk 5-10%	High risk > 10%
Clinical signs of right ventricular failure	Absent	Absent	Present
Progression of symptoms	None	Slow	Fast
Syncope	None	Occasionally*	Repeatedly **
WHO FC	I, II	III	IV
6M-WD	> 440 m	165-440 m	< 165 m
Cardiopulmonary exercise test	Peak VO2> 15 mL/min/Kg (>65% predicted ) VE/VCO2slope < 36	Peak VO211–15 mL/min/Kg (35-65% predicted) VE/VCO2slope 36–44.9	Peak VO2< 11mL/min/Kg (<35% predicted) VE/VCO2≥ 45
NT-proBNP plasma levels	BNP < 50 ng/l NT-proBNP < 300 ng/mL	BNP 50–300 ng/l NT-proBNP 300–1,400 ng/L	BNP > 300 ng/L NT-proBNP > 1,400 ng/L
Imaging tests (ECHO, chest magnetic resonance)	Right atrial area < 18 cm2 Absence of pericardial effusion	Right atrial area 18–26 cm2 Absent or minimal pericardial effusion	Right atrial area > 26 cm2 Presence of pericardial effusion
Hemodynamic parameters	Right atrial pressure < 8 mmHg CI ≥ 2.5 L/min/m2 ScvO2> 65%	Right atrial pressure 8–14 mmHg CI 2.0–2.4 L/min/m2 ScvO260–65%	Right atrial pressure > 14 mmHg CI < 2.0 L/min/m2 ScvO2 < 60%

• ₂

There are several methods to assess the risk of progression of PAH. One of them is to assign a score (from 1 to 3) to each variable, according to the range risk group (low, intermediate, or high, respectively). The overall risk is estimated by dividing the sum of all points by the number of variables. The nearest whole number classifies the risk as low (1), intermediate (2) or high (3) risk.⁵⁵ A simpler approach aims to identify only patients at low risk, by using the combination of the following parameters: brain natriuretic peptide (BNP) levels < 50 pg/mL, six-minute walk distance > 440m and functional class of II.⁵³ A third approach, derived from the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management Registry) risk score calculator, includes up to 12 variables and has been recently updated.⁵⁶

Although a more comprehensive approach can be superior to a more simplified evaluation, the low availability of the different tests limits their application. Thus, risk stratification, here suggested, is based on what is considered the minimum requirements for an adequate clinical management of patients with PAH, by a combination of functional class, six-minute walk test and BNP for identification of patients at “low risk” and “not low risk” ( Figure 2 ). According to their availability, tests like magnetic resonance, echocardiography and cardiopulmonary stress test should be encouraged due to their potential adjuvant role.²³ , ⁵⁷ The main objective of PAH treatment is to achieve or maintain a low risk of disease progression using the strategies and risk stratification above discussed.

Particularities of different types of PAH

PAH associated with connective tissue disease

PAH is a known complication of connective tissue disease (CTD). The main CTDs associated with PAH are systemic sclerosis (SS), systemic erythematosus lupus (SEL), and mixed CTD (MCTD), and in a lesser degree, dermatomyositis, and Sjögren syndrome.⁵⁸ In Brazil, PAH associated with CTD represents nearly 25%⁵⁹ of PAH cases. The primary disease associated with PAH is SS in western countries, and SEL in Asian,⁶⁰ - ⁶² and the prevalence of PAH in SS and SEL patients is around 10%,⁶³ and 4%, respectively.⁶⁴

The presence of antiphospholipid, anti-RNP and anti-Ro antibodies is predictive of PAH in SEL patients.⁶⁵ In patients with SS, the presence of long-term disease, telangiectasias, anti-centromere antibody positivity and reduction in the diffusing capacity for carbon monoxide (DLCO) are the main factors related to PAH.⁶⁶

SS is characterized by an association between vasculopathy and tissue fibrosis.⁶⁷ Clinically, SS is marked by a high prevalence of interstitial pulmonary disease (up to 50% of patients),⁶⁸ and cardiac involvement (50-80% of patients), frequently leading to diastolic dysfunction.⁶⁹ Therefore, in these patients, PH may be a result of either a pulmonary vascular disease alone or a combination of different pathophysiological mechanisms related to PH in groups II and III.⁶⁸ Besides, these patients are at increased risk of pulmonary thromboembolism and associated veno-occlusive disease, which may even worsens patients’ prognosis.⁶⁸ It is imperative to determine the preponderant mechanism to guide treatment of these patients.

In SS patients, annual screening for PH is recommended, even in asymptomatic patients.⁷⁰ Screening models including risk factors, DLCO and BNP seem to be more sensitive than echocardiography alone.⁷¹ In SEL, due to the low prevalence of PH, the screening for this condition is not recommended as a routine practice, and echocardiography should be performed only for symptomatic patients ( Table 4 ).

Table 4
Risk factors and screening for pulmonary hypertension in patients with connective tissue disease

	Risk factors	Screening
SS	Long term disease Telangiectasias Anti-centromere Reduced DLCO or FVC/DLCO>1.6	-Annually in asymptomatic patients Echocardiogram ± biomarkers/ PFT or DETECT algorithm BNP/NTproBNP and PFT ± ECHO
LES	Serositis Antibodies: Antiphospholipid, RNP and Ro	In symptomatic patients only

• SS: systemic sclerosis; SEL: systemic erythematosus lupus; PFT: pulmonary function test; DLCO: diffusing capacity for carbon monoxide; forced vital capacity (FVC); BNP: brain natriuretic peptide; NT-proBNP: N-terminal pro-brain natriuretic peptide.

Table 5
Treatment of pulmonary arterial hypertension associated with connective tissue

	Immunosuppression (IS)	Specific therapy
SS	Not recommended	According to risk stratification
SEL functional class I/II	CCP and GCT for six months	If PH continues after IS
SEL functional class III/IV	CCP and GCT plus specific therapy	Associated with IS, according to risk stratification
MCTD functional class I/II	CCP and GCT for six months	If PH continues after IS
MCTD functional class III/IV	CCP and GCT plus specific therapy	Associated with IS, according to risk stratification

• IS: immunosuppression; SS: systemic sclerosis; SEL: systemic erythematosus lupus; MCTD: mixed connective tissue disease; CCP: cyclophosphamide; GCT: glucocorticoid; PH: pulmonary hypertension.

In case of clinical suspicion, the diagnostic flow is the same, aiming at differentiating the diagnosis of PAH (group I) from other forms of PH. Vasoreactivity testing is not applied for patients with DTC, as at least 1% of them have a sustained response.

For patients with inflammatory diseases, such as SEL and DMTC-PAH, immunosuppression is an alternative approach before specific therapy is initiated. In patients with functional class I and II, it is recommended to start treatment with cyclophosphamide (CCP) and glucocorticoid (GCT), whereas in those with functional class III and IV, a combination of CCP, GCT with specific therapy is recommended, due to a lower chance of response to immunosuppression, with reassessment after six months of CCP ( 5).⁵⁸ , ⁷² In patients with SS, there is no evidence of improvement with immunosuppression.⁷³

PAH associated with HIV

The association between human immunodeficiency virus (HIV) and PAH was first described in 1987.⁷⁴ Today, the estimated prevalence of PAH in HIV patients is 0.5%,⁷⁵ and HIV infection is an important etiology of PAH in referral centers. In a Brazilian registry, 4.5% of PAH patients had HIV diagnosed.⁵⁹

The pathophysiological mechanisms involved in the association between HIV and PAH are not fully understood. From a histological point of view, concentric laminar intimal fibrosis, medial hypertrophy, and plexiform lesions were found in up to 78% of patients, which resembles the changes observed in patients with PAH.⁷⁶

The presence of PAH worsens the prognosis of HIV patients. CD4 counts lower than 200 cells/µL and a cardiac output lower than 2.8 L/min per m2 are independent predictors of survival.⁷⁷ Then, antiretroviral therapy (ART) is recommended for all patients with HIV, regardless of CD4 count, viral load,⁷⁸ or concomitant PAH.

With respect to the NO pathway, there are no controlled studies with sildenafil evaluating therapy response in patients with HIV and PAH. Positive results regarding exercise performance, functional class, and hemodynamic parameters were obtained from case studies.⁷⁹ Caution is advised because of the interaction with ART, particularly with protease inhibitors.⁸⁰ Also, there are no studies with riociguat, despite recent publication showing good safety and tolerability of riociguat and ART combination regimens.⁸¹

Among the endothelin receptor antagonists, bosentan was evaluated for the treatment of 59 HIV patients with PAH in a prospective study.⁸² There was an improvement in six-minute walk distance, symptoms and hemodynamic status. In pivotal studies on ambrisentan⁴⁰ and macitentan,³⁹ 17 and 10 HIV patients with PAH were included, respectively, and no interactions with ART were observed.⁷⁸

Small case series evaluated prostanoids for treatment of HIV-PAH patients. Treatment with epoprostenol resulted in improvement of hemodynamics,⁸³ and iloprost improved functional lass and six-minute walk test in four patients.⁸⁴ In a pivotal trial, selexipag was administered to 10 HIV patients.³⁵ In a study evaluating potential interactions between ART and selexipag, no interaction was detected, and adaptations of the selexipag dose were not required in a study with healthy subjects treated with a single dose of 400 µg selexipag in combination with multiple doses of lopinavir/ritonavir (400/100 mg) twice daily.⁸⁵

Portopulmonary hypertension

Portopulmonary hypertension (PPH) refers to a form of PAH that is associated with portal hypertension. Portal hypertension leads to the formation of portosystemic shunts and increased pulmonary blood flow, which results in endothelial remodeling and dysfunction, with elevations in ET-1 production and pulmonary vascular pressure.⁸⁶

It is estimated that 10.6% of PAH patients have PPH,⁸⁷ and in a review⁸⁸ of 1,205 consecutive liver transplant patients, the incidence of pulmonary hypertension 8.5% of liver transplant candidates. PPH is not associated with the etiology of portal hypertension nor with the severity of lung disease.⁸⁹

Clinical presentation of PPH is similar to other forms of PAH, and the most common symptom in PPH patients is dyspnea. In PAH, the presence of ascites may be indicative of PPH.⁹⁰ For diagnosis of this condition, right catheterization can be made to confirm PAH, as described before, and portal hypertension can be confirmed by a hepatic venous pressure gradient greater than 4 mmHg.⁹¹

The treatment of PPH was evaluated by small studies, that demonstrated beneficial effects of three classes of drugs. Hepatotoxicity of endothelin receptor antagonists may not be a major problem in continuously monitored patients.⁹² The largest study conducted with PPH patients showed hemodynamic improvements after 12 weeks of macitentan, with no hepatic side effects.⁹³ Some well-established drugs for the treatment of portal hypertension, including beta-blockers, should not be administered in PPH, due to worsening of hemodynamic status and exercise capacity.⁹⁴

It is worth pointing out the role of PPH in liver transplant candidates. PPH is a marker of a worse prognosis in the perioperative period, and MPAP values lower than 35 mmHg indicated a lower risk of death in liver transplant recipients.⁹¹ Therefore, a screening echocardiogram to detect PAH is mandatory for patients in the liver transplant waiting list and for patients with portal hypertension presenting with (even mild) dyspnea.⁹⁵

Schistosomiasis

Schistosomiasis (Sch) is an endemic parasitic disease in Brazil, associated with poverty and poor sanitation. It is caused by trematode worms of the genus Schistosoma, and its transmission has been documented in more than 70 countries. Although the hepatosplenic form is the most common manifestation of chronic Sch,⁹⁶ one of the most severe and limiting manifestations of the disease are related to impairment of the pulmonary circulation in the presence of PAH (Sch-PAH).

Nearly 5% of patients with the hepatosplenic form of Sch have PAH.⁹⁶ Thus, considering the high prevalence of schistosomiasis worldwide, Sch-PAH is potentially one of the most prevalent PAH, especially in developing countries.⁹⁷ A recent registry showed that Sch-PAH can represent about 20% of the incident cases of PAH.⁵⁹

The diagnosis of Sch-PAH requires invasive confirmation of PAH (see “definition” session) and confirmation of hepatosplenic Sch, with presence of ultrasound changes compatible with the disease (e.g., periportal fibrosis) plus one of the following epidemiological factors: 1) patients from endemic areas; OR 2) previous treatment for Sch; OR 3) detection of Schistosoma eggs in stool samples or rectal biopsies.⁹⁸

Although Sch-PAH usually have a better clinical course than idiopathic PAH, even in the absence of specific therapy, it does not mean that the disease poses no risk. Sch-PAH mortality can reach 15% in three years.⁹⁹ Cases of PAH with pronounced dilatation of pulmonary arteries should suggest Sch-PAH, especially in areas where Sch is highly prevalent.¹⁰⁰

Treatment of Sch-PAH is similar to the other forms of PAH. Cases series have demonstrated clinical and hemodynamic benefits,¹⁰¹ in addition to longer survival with specific therapy.⁹⁷ Thus, also for Sch-PAH, it is recommended to follow the therapeutic algorithm as proposed in Figure 2 . Anticoagulation should be avoided due to the risk of upper gastrointestinal bleeding. All patients should receive at least one cycle of anti-parasite treatment, since it is not known whether the persistence of infection can contribute to progression of pulmonary vascular dysfunction.⁹⁷

Congenital heart disease

PAH is a relatively common condition in patients with congenital heart diseases (CHDs), affecting 5-10% of this group.¹⁰² CHDs can cause pulmonary hyperflow, inducing endothelial remodeling and consequent PVR, which is histologically indistinguishable from other forms of PAH. Thus, most cases of CHD-PAH are classified as group I. In this group, when PVR exceeds the systemic vascular resistance, the direction of the shunt reverses, which characterizes the Eisenmenger syndrome.¹⁰³ Patients with this syndrome have severe hypoxemia, and hematological changes (erythrocytosis and low platelet count). Also, these patients may have hemoptysis, stroke, brain abscess in addition to a higher incidence of sudden death.⁹

The treatment of CHD-PAH should follow the guidelines previously established for other forms of group I. Therapeutic phlebotomy can be considered for Eisenmenger syndrome patients who present hyperviscosity symptoms (usually hematocrit levels above 65%).⁹ As in other forms of PAH, anticoagulation is controversial in Eisenmenger syndrome,¹⁰⁴ and should be weighed case by case. Likewise, the benefit of supplemental oxygen in patients with Eisenmenger syndrome and hypoxemia is questionable,¹⁰⁵ and indication should be tailored to the patient’s needs.

With respect to the specific therapy for CHD-PAH, the only validated drug treatment was bosentan, which improved the six-minute walk test and decreased PVR after 16 weeks of treatment in functional class III patients.¹⁰⁶ Smaller series have shown beneficial effects with PDE-5 inhibitors and prostanoids.⁹

Some CHDs, including patent ductus arteriosus, sinus venosus atrial septal defect, or anomalous pulmonary venous drainage can be unnoticed in PAH patients, who would be considered as idiopathic PAH. However, in the context of PAH, the diagnosis of a CHD in the context may indicate the need for surgical repair of the defect, according to PCR at diagnosis¹⁰⁷ and the clinical course. This evaluation should be performed in centers with expertise in this condition for a proper referral (or not) for surgery. The mere possibility of correction reinforces the necessity of actively investigating the presence of CHD. In patients undergoing diagnostic evaluation, this can include echocardiography with microbubbles for examination of intracardiac and extracardiac shunts.

In addition, some complex, rarer CHDs, are classified as group V, i.e., of uncertain or multifactorial mechanisms.⁸ In these cases, due to the absence of prospective studies, the pharmacological or surgical approach (including heart-lung transplantation) should be individually performed.

Special situations

Pulmonary hypertension and pregnancy

Physiological changes in pregnancy, including increase in blood volume and cardiac output,¹⁰⁸ , ¹⁰⁹ are generally not well tolerated in PAH patients. Thus, pregnancy is associated with high morbidity and mortality rates, varying from 30 to 56%.¹⁸

Thus, because of the high lethality of PAH in pregnancy, it is recommended the use of two contraceptive methods, although there is no consensus on the best method. Barrier methods are considered safe, although their efficacy is directly related to a correct use.¹⁰⁸ Hormonal methods of birth control, as those containing progestin only, are effective; combination with estrogen should be avoided due to the increased risk in thromboembolic events.¹⁰⁹ Intrauterine devices may be used, but vasovagal reactions may occur at their insertion.¹¹⁰

When pregnancy is confirmed, the patient should be informed about potential risks. In extreme cases, therapeutic interruption of gestation may be considered,¹⁰⁹ preferably before 22 weeks of gestational age.¹¹¹ In a recent European registry of PH and pregnancy,¹¹² therapeutic abortion was performed in 4% of cases, whereas perinatal mortality in idiopathic PAH was performed in 43% of the cases. Although there is no consensus about the safest birthing method, cesarean section at 32-36 weeks’ gestation, without general anesthesia, has been the preferable method.¹¹¹ , ¹¹³ Preeclampsia or eclampsia, preterm birth, fetal death, postpartum bleeding were the most common complications in pregnant women with PH.¹¹⁴

Specific therapy should be adapted to pregnant women with PAH who do not accept pregnancy termination and insist on continuing with their pregnancy. Case series have demonstrated the efficacy of sildenafil and prostacyclin analogues in pregnancy.¹⁸ , ¹¹³ , ¹¹⁵ However, endothelin receptor antagonists should be avoided due to their potential teratogenic effect.¹¹⁶

Angina and PAH

Angina is reported by 15.8¹¹⁷ -29.0%%⁹ of patients with PAH and may result by an imbalance between myocardial oxygen supply and demand in the right ventricle, with no change in the flow of epicardial coronary arteries. The increase in ventricular wall tension leads to a decrease in the coronary flow reserve, which, associated with greater ventricular work and oxygen consumption, and myocardial hypertrophy, results in ischemia. However, another consequence of PAH is vascular remodeling, with increased pulmonary artery diameter.

Dilated pulmonary artery may induce inferior displacement of the left main coronary artery (LMCA), which become in close contact with the left aortic sinus ( Figure 3 ). This compression may cause LMCA stenosis.¹¹⁸ A prevalence of up to 40% of LMCA occlusion caused by external compression has been described in PAH patients with angina.¹¹⁷ The main predictor of LMCA compression was a pulmonary artery diameter > 40 mm, followed by a pulmonary artery to ascending aorta diameter ratio ≥1.5.¹¹⁷

Figure 3
– A) Computed tomography angiography showing inferior displacement of the left main coronary artery caused by an aneurysm of the pulmonary artery and left coronary ostial stenosis. B) coronary cineangiography of the same patient, showing occlusion of the left main coronary artery ostium.

The prognostic impact of LMCA compression is still uncertain. Therapeutic management of this condition if similar to that performed in LMCA lesion caused by atherosclerosis: myocardial revascularization, with the percutaneous approach being the safest and most attractive modality for these patients.¹¹⁹ Data from an Italian study demonstrated good results with this approach. In a mean follow-up of 4.5 years of 53 patients who underwent angioplasty, 19 patients (37.3%) died, with no case of infarction or stent thrombosis, and five patients required a new angioplasty.¹²⁰

LMCA compression should be considered in all patients with PH and angina, with initial investigation by computed tomography angiography. Patients with a high clinical probability of extrinsic compression of the LMCA (e.g., patients with large pulmonary artery aneurysm and angina), referred for right catheterization, should be submitted to coronary cineangiography, even without coronary computed tomography angiography. With the increase in survival of PAH patients, atherosclerotic comorbidity should also be considered, with control of traditional cardiovascular risk factors.

Supraventricular arrhythmias and PAH

Cardiac arrythmias are frequent in PAH patients, notably supraventricular tachycardias, caused by either by increased automation or re-entry. Retrospective studies have reported an annual incidence of sustained supraventricular tachycardia between 2.8%¹²¹ and 3.5%.¹²² However, these numbers underestimate the real incidence, due to the lack of prospective studies with a strategic search and strategy of continuous monitoring or of accessible demand. These arrythmias are caused by right ventricular pressure overload, cardiac remodeling, and increased adrenergic tone, associated with PH. Also, hypokalemia and hypomagnesemia caused by chronic treatment with diuretic may also be a cause of arrythmias.

The most common sustained arrythmias are atrial fibrillation and atrial flutter, followed by atrioventricular-nodal reentrant tachycardia and sustained atrial tachycardia. Most patients have worsening of functional class, and persistence of arrythmia leads to higher mortality.¹²¹ The treatment of arrhythmias is focused on restoring cardiac rhythm by using drugs of modest inotropic effect (e.g., amiodarone), programmed electrical cardioversion, and in some cases, electrophysiological study and ablation (which should be early considered in atrial flutter). In preparation for cardioversion, or in cases of recurrence or cardioversion failure, monitoring of ventricular response is essential to guarantee cardiac output, and tailor the therapy according to the right ventricular functional reserve. Patients with important right ventricular dysfunction caused by pulmonary hypertension have poor tolerance to betablockers, and even the use of calcium channel blockers may result in clinical decompensation. In these situations, digoxin and amiodarone may be convenient. It is worth pointing out that all patients with PH and atrial fibrillation should receive anticoagulant therapy, due to the high risk of systemic and cerebral thromboembolism.

Conclusion

In the last decades, important advances have been made in the treatment of PAH, a severe, progressive, incurable, and potentially fatal disease. For an adequate therapy, correct hemodynamic diagnosis and etiology classification are fundamental. Many etiologies – rheumatic disease, portal hypertension, CHDs, Sch – require specific measures, in addition to drug therapy for PAH. The specific therapy for PAH is based on medications that act on three pathophysiological pathways – prostacyclin, endothelin, and NO pathways. Today, it is recommended that initial treatment begins with a combination of two oral therapies and increases if patient does not achieve the desired therapeutic target, which was established based on the stratification of cardiovascular death risk.

Cardiovascular complications of PAH (LCMA compression, supraventricular arrhythmias) are common and should be promptly identified and treated, as they affect the quality of life and probably the prognosis of patients with PAH.

Referências

• ¹
  Humbert M. Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: Pathophysiology. Eur Respir Rev. 2010;19(115):59-63. doi: 10.1183/09059180.00007309.
• ²
  Alves JL Jr, Oleas FG, Souza R. Pulmonary Hypertension: Definition, Classification, and Diagnosis. Semin Respir Crit Care Med. 2017;38(5):561570. doi: 10.1055/s-0037-1606577.
• ³
  Hoeper MM, Humbert M, Souza R, Idrees M, Kawut SM, Sliwa-Hahnle K, et al. A global View of Pulmonary Hypertension. Lancet Respir Med. 2016;4(4):306-22. doi: 10.1016/S2213-2600(15)00543-3.
• ⁴
  D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Survival in Patients with Primary Pulmonary Hypertension. Results from a National Prospective Registry. Ann Intern Med. 1991;115(5):343-9. doi: 10.7326/0003-4819-115-5-343.
• ⁵
  Jardim C, Fernandes CJ, Souza R. Goal-Oriented Treatment of Pulmonary Arterial Hypertension. Curr Opin Pulm Med. 2014;20(5):409-13. doi: 10.1097/MCP.0000000000000086.
• ⁶
  Fernandes CJ, Martins BC, Jardim CV, Ciconelli RM, Morinaga LK, Breda AP, et al. Quality of Life as a Prognostic Marker in Pulmonary Arterial Hypertension. Health Qual Life Outcomes. 2014;12(1):130. doi: 10.1186/s12955-014-0130-3.
• ⁷
  O’Callaghan DS, Humbert M. A Critical Analysis of Survival in Pulmonary Arterial Hypertension. Eur Respir Rev. 2012;21(125):218-22. doi: 10.1183/09059180.00003512.
• ⁸
  Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, et al. Haemodynamic Definitions and Updated Clinical Classification of Pulmonary Hypertension. Eur Respir J. 2019;53(1):1801913. doi: 10.1183/13993003.01913-2018.
• ⁹
  Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J. 2015;46(4):903-75. doi: 10.1183/13993003.01032-2015.
• ¹⁰
  Maron BA, Hess E, Maddox TM, Opotowsky AR, Tedford RJ, Lahm T, et al. Association of Borderline Pulmonary Hypertension with Mortality and Hospitalization in a Large Patient Cohort: Insights from the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program. Circulation. 2016;133(13):1240-8. doi: 10.1161/CIRCULATIONAHA.115.020207.
• ¹¹
  Gavilanes F, Alves JL Jr, Fernandes C, Prada LFL, Jardim CV, Morinaga LT, et al. Left Ventricular Dysfunction in Patients with Suspected Pulmonary Arterial Hypertension. J Bras Pneumol. 2014;40(6):609-16. doi: 10.1590/S1806-37132014000600004.
• ¹²
  Maron BA, Brittain EL, Hess E, Waldo SW, Barón AE, Huang S, et al. Pulmonary Vascular Resistance and Clinical Outcomes in Patients with Pulmonary Hypertension: A Retrospective Cohort Study. Lancet Respir Med. 2020;8(9):873-84. doi: 10.1016/S2213-2600(20)30317-9.
• ¹³
  Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, et al. Haemodynamic Definitions and Updated Clinical Classification of Pulmonary Hypertension. Eur Respir J. 2019;53(1):1801913. doi: 10.1183/13993003.01913-2018.
• ¹⁴
  Calderaro D, Alves JL Jr, Fernandes CJCDS, Souza R. Pulmonary Hypertension in General Cardiology Practice. Arq Bras Cardiol. 2019;113(3):419-28. doi: 10.5935/abc.20190188.
• ¹⁵
  Nathan SD, Barbera JA, Gaine SP, Harari S, Martinez FJ, Olschewski H, et al. Pulmonary Hypertension in Chronic Lung Disease and Hypoxia. Eur Respir J. 2019;53(1):1801914. doi: 10.1183/13993003.01914-2018.
• ¹⁶
  Fernandes CJCS, Ota-Arakaki JS, Campos FTAF, Corrêa RA, Gazzana MB, Jardim CVP, et al. Brazilian Thoracic Society Recommendations for the Diagnosis and Treatment of Chronic Thromboembolic Pulmonary Hypertension. J Bras Pneumol. 2020;46(4): e20200204. doi: 10.36416/1806-3756/e20200204.
• ¹⁷
  Frost A, Badesch D, Gibbs JSR, Gopalan D, Khanna D, Manes A, et al. Diagnosis of Pulmonary Hypertension. Eur Respir J. 2019;53(1):1801904. doi: 10.1183/13993003.01904-2018.
• ¹⁸
  Jaïs X, Olsson KM, Barbera JA, Blanco I, Torbicki A, Peacock A, et al. Pregnancy Outcomes in Pulmonary Arterial Hypertension in the Modern Management Era. Eur Respir J. 2012;40(4):881-5. doi: 10.1183/09031936.00141211.
• ¹⁹
  Guillevin L, Armstrong I, Aldrighetti R, Howard LS, Ryftenius H, Fischer A, et al. Understanding the Impact of Pulmonary Arterial Hypertension on Patients’ and Carers’ Lives. Eur Respir Rev. 2013;22(130):535-42. doi: 10.1183/09059180.00005713.
• ²⁰
  Mereles D, Ehlken N, Kreuscher S, Ghofrani S, Hoeper MM, Halank M, et al. Exercise and Respiratory Training Improve Exercise Capacity and Quality of Life in Patients with Severe Chronic Pulmonary Hypertension. Circulation. 2006;114(14):1482-9. doi: 10.1161/CIRCULATIONAHA.106.618397.
• ²¹
  Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary Pulmonary Hypertension: Natural History and the Importance of Thrombosis. Circulation. 1984;70(4):580-7. doi: 10.1161/01.cir.70.4.580.
• ²²
  Olsson KM, Delcroix M, Ghofrani HA, Tiede H, Huscher D, Speich R, et al. Anticoagulation and Survival in Pulmonary Arterial Hypertension: Results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA). Circulation. 2014;129(1):57-65. doi: 10.1161/CIRCULATIONAHA.113.004526.
• ²³
  Galiè N, Channick RN, Frantz RP, Grünig E, Jing ZC, Moiseeva O, et al. Risk stratification and Medical Therapy of Pulmonary Arterial Hypertension. Eur Respir J. 2019;53(1):1801889. doi: 10.1183/13993003.01889-2018.
• ²⁴
  Langleben D, Orfanos SE, Giovinazzo M, Schlesinger RD, Hirsch AM, Blenkhorn F, et al. Acute Vasodilator Responsiveness and Microvascular Recruitment in Idiopathic Pulmonary Arterial Hypertension. Ann Intern Med. 2015;162(2):154-6. doi: 10.7326/M14-1402.
• ²⁵
  Rich S, Kaufmann E, Levy PS. The Effect of High Doses of Calcium-Channel Blockers on Survival in Primary Pulmonary Hypertension. N Engl J Med. 1992;327(2):76-81. doi: 10.1056/NEJM199207093270203.
• ²⁶
  Sitbon O, Humbert M, Jaïs X, Ioos V, Hamid AM, Provencher S, et al. Long-term Response to Calcium Channel Blockers in Idiopathic Pulmonary Arterial Hypertension. Circulation. 2005;111(23):3105-11. doi: 10.1161/CIRCULATIONAHA.104.488486.
• ²⁷
  Stacher E, Graham BB, Hunt JM, Gandjeva A, Groshong SD, McLaughlin VV, et al. Modern Age Pathology of Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2012;186(3):261-72. doi: 10.1164/rccm.201201-0164OC.
• ²⁸
  Humbert M, Sitbon O, Simonneau G. Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2004;351(14): 1425-36. doi: 10.1056/NEJMra040291.
• ²⁹
  Mitchell JA, Ahmetaj-Shala B, Kirkby NS, Wright WR, Mackenzie LS, Reed DM, et al. Role of Prostacyclin in Pulmonary Hypertension. Glob Cardiol Sci Pract. 2014;2014(4):382-93. doi: 10.5339/gcsp.2014.53.
• ³⁰
  Tuder RM, Cool CD, Geraci MW, Wang J, Abman SH, Wright L, et al. Prostacyclin Synthase Expression is Decreased in Lungs from Patients with Severe Pulmonary Hypertension. Am J Respir Crit Care Med. 1999;159(6):1925-32. doi: 10.1164/ajrccm.159.6.9804054.
• ³¹
  Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, et al. An Imbalance Between the Excretion of Thromboxane and Prostacyclin Metabolites in Pulmonary Hypertension. N Engl J Med. 1992;327(2):70-5. doi: 10.1056/NEJM199207093270202.
• ³²
  Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, et al. A Comparison of Continuous Intravenous Epoprostenol (prostacyclin) with Conventional Therapy for Primary Pulmonary Hypertension. N Engl J Med. 1996;334(5):296-301. doi: 10.1056/NEJM199602013340504.
• ³³
  Galiè N, Manes A, Branzi A. Prostanoids for Pulmonary Arterial Hypertension. Am J Respir Med. 2003;2(2):123-37. doi: 10.1007/BF03256644.
• ³⁴
  Olschewski H, Simonneau G, Galiè N, Higenbottam T, Naeije R, Rubin LJ, et al. Inhaled Iloprost for Severe Pulmonary Hypertension. N Engl J Med. 2002;347(5):322-9. doi: 10.1056/NEJMoa020204.
• ³⁵
  Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galiè N, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2015;373(26):2522-33. doi: 10.1056/NEJMoa1503184.
• ³⁶
  Kawanabe Y, Nauli SM. Endothelin. Cell Mol Life Sci. 2011;68(2):195-203. doi: 10.1007/s00018-010-0518-0.
• ³⁷
  Chester AH, Yacoub MH. The Role of Endothelin-1 in Pulmonary Arterial Hypertension. Glob Cardiol Sci Pract. 2014;2014(2):62-78. doi: 10.5339/gcsp.2014.29.
• ³⁸
  Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et al. Bosentan Therapy for Pulmonary Arterial Hypertension. N Engl J Med. 2002;346(12):896-903. doi: 10.1056/NEJMoa012212.
• ³⁹
  Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani HA, et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med. 2013;369(9):809-18. doi: 10.1056/NEJMoa1213917.
• ⁴⁰
  Galiè N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, et al. Ambrisentan for the Treatment of Pulmonary Arterial Hypertension: Results of the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-blind, Placebo-controlled, Multicenter, Efficacy (ARIES) Study 1 and 2. Circulation. 2008;117(23):3010-9. doi: 10.1161/CIRCULATIONAHA.107.742510.
• ⁴¹
  Chester AH, Yacoub MH, Moncada S. Nitric Oxide and Pulmonary Arterial Hypertension. Glob Cardiol Sci Pract. 2017;2017(2):14. doi: 10.21542/gcsp.2017.14.
• ⁴²
  Sim JY. Nitric Oxide and Pulmonary Hypertension. Korean J Anesthesiol. 2010;58(1):4-14. doi: 10.4097/kjae.2010.58.1.4.
• ⁴³
  Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension. N Engl J Med. 2005;353(20):2148-57. doi: 10.1056/NEJMoa050010.
• ⁴⁴
  Boutou AK, Pitsiou G. Treatment of Pulmonary Hypertension with Riociguat: A Review of Current Evidence and Future Perspectives. Expert Opin Pharmacother. 2020;21(10):1145-55. doi: 10.1080/14656566.2020.1727446.
• ⁴⁵
  Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, et al. Riociguat for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2013;369(4):330-40. doi: 10.1056/NEJMoa1209655.
• ⁴⁶
  Ghofrani HA, D’Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, et al. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension. N Engl J Med. 2013;369(4):319-29. doi: 10.1056/NEJMoa1209657.
• ⁴⁷
  Galiè N, Barberà JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015;373(9):834-44. doi: 10.1056/NEJMoa1413687.
• ⁴⁸
  Lajoie AC, Lauzière G, Lega JC, Lacasse Y, Martin S, Simard S, et al. Combination Therapy versus Monotherapy for Pulmonary Arterial Hypertension: A Meta-analysis. Lancet Respir Med. 2016;4(4):291-305. doi: 10.1016/S2213-2600(16)00027-8.
• ⁴⁹
  Sitbon O, Jaïs X, Savale L, Cottin V, Bergot E, Macari EA, et al. Upfront Triple Combination Therapy in Pulmonary Arterial Hypertension: A Pilot Study. Eur Respir J. 2014;43(6):1691-7. doi: 10.1183/09031936.00116313.
• ⁵⁰
  Chin KM, Sitbon O, Doelberg M, Gibbs JSSR, Hoeper MM, Martin N, et al. Efficacy and Safety of Initial Triple Oral Versus Initial Double Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension (PAH): Results of The Randomized Controlled Triton Study. Am J Respir Crit Care Med. 2020; 201:A2928. doi: 10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A2928.
• ⁵¹
  Coghlan JG, Channick R, Chin K, Di Scala L, Galiè N, Ghofrani HA, et al. Targeting the Prostacyclin Pathway with Selexipag in Patients with Pulmonary Arterial Hypertension Receiving Double Combination Therapy: Insights from the Randomized Controlled GRIPHON Study. Am J Cardiovasc Drugs. 2018;18(1):37-47. doi: 10.1007/s40256-017-0262-z.
• ⁵²
  Fernandes CJCS, Humbert M, Souza R. Challenging the Concept of Adding More Drugs in Pulmonary Arterial Hypertension. Eur Respir J. 2017;50(3):1701527. doi: 10.1183/13993003.01527-2017.
• ⁵³
  Boucly A, Weatherald J, Savale L, Jaïs X, Cottin V, Prevot G, et al. Risk Assessment, Prognosis and Guideline Implementation in Pulmonary Arterial Hypertension. Eur Respir J. 2017;50(2):1700889. doi: 10.1183/13993003.00889-2017.
• ⁵⁴
  Hoeper MM, Kramer T, Pan Z, Eichstaedt CA, Spiesshoefer J, Benjamin N, et al. Mortality in Pulmonary Arterial Hypertension: Prediction by the 2015 European Pulmonary Hypertension Guidelines Risk Stratification Model. Eur Respir J. 2017;50(2):1700740. doi: 10.1183/13993003.00740-2017.
• ⁵⁵
  Kylhammar D, Kjellström B, Hjalmarsson C, Jansson K, Nisell M, Söderberg S, et al. A Comprehensive Risk Stratification at Early Follow-up Determines Prognosis in Pulmonary Arterial Hypertension. Eur Heart J. 2018;39(47):4175-81. doi: 10.1093/eurheartj/ehx257.
• ⁵⁶
  Benza RL, Gomberg-Maitland M, Elliott CG, Farber HW, Foreman AJ, Frost AE, et al. Predicting Survival in Patients With Pulmonary Arterial Hypertension: The REVEAL Risk Score Calculator 2.0 and Comparison with ESC/ERS-Based Risk Assessment Strategies. Chest. 2019;156(2):323-37. doi: 10.1016/j.chest.2019.02.004.
• ⁵⁷
  Alves JL Jr, Souza R. Prognostic Relevance of Appropriate Renal Function Evaluation in Pulmonary Arterial Hypertension. J Heart Lung Transplant. 2018;37(6):692-3. doi: 10.1016/j.healun.2018.02.005.
• ⁵⁸
  Aithala R, Alex AG, Danda D. Pulmonary Hypertension in Connective Tissue Diseases: An Update. Int J Rheum Dis. 2017;20(1):5-24. doi: 10.1111/1756-185X.13001.
• ⁵⁹
  Alves JL Jr, Gavilanes F, Jardim C, Fernandes CJCDS, Morinaga LTK, Dias B, et al. Pulmonary arterial hypertension in the southern hemisphere: results from a registry of incident Brazilian cases. Chest. 2015;147(2):495-501. doi: 10.1378/chest.14-1036.
• ⁶⁰
  Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, et al. Pulmonary Arterial Hypertension: Baseline Characteristics from the REVEAL Registry. Chest. 2010;137(2):376-87. doi: 10.1378/chest.09-1140.
• ⁶¹
  Assad APL, Oleas FG, Alves JL Jr, Fernandes CJCS, Sampaio-Barros PD, Souza R. Survival of Connective Tissue Disease Associated Pulmonary Arterial Hypertension. Clin Exp Rheumatol. 2018;36(4):186.
• ⁶²
  Hao YJ, Jiang X, Zhou W, Wang Y, Gao L, Wang Y, et al. Connective Tissue Disease-Associated Pulmonary Arterial Hypertension in Chinese Patients. Eur Respir J. 2014;44(4):963-72. doi: 10.1183/09031936.00182813.
• ⁶³
  Avouac J, Airò P, Meune C, Beretta L, Dieude P, Caramaschi P, et al. Prevalence of Pulmonary Hypertension in Systemic Sclerosis in European Caucasians and Metaanalysis of 5 Studies. J Rheumatol. 2010;37(11):2290-8. doi: 10.3899/jrheum.100245.
• ⁶⁴
  Ruiz-Irastorza G, Garmendia M, Villar I, Egurbide MV, Aguirre C. Pulmonary Hypertension in Systemic Lupus Erythematosus: Prevalence, Predictors and Diagnostic Strategy. Autoimmun Rev. 2013;12(3):410-5. doi: 10.1016/j.autrev.2012.07.010.
• ⁶⁵
  Kim JS, Kim D, Joo YB, Won S, Lee J, Shin J, et al. Factors Associated With Development and Mortality of Pulmonary Hypertension in Systemic Lupus Erythematosus Patients. Lupus. 2018;27(11):1769-77. doi: 10.1177/0961203318788163.
• ⁶⁶
  Coghlan JG, Denton CP, Grünig E, Bonderman D, Distler O, Khanna D, et al. Evidence-Based Detection of Pulmonary Arterial Hypertension in Systemic Sclerosis: The DETECT study. Ann Rheum Dis. 2014;73(7):1340-9. doi: 10.1136/annrheumdis-2013-203301.
• ⁶⁷
  Denton CP, Wells AU, Coghlan JG. Major Lung Complications of Systemic Sclerosis. Nat Rev Rheumatol. 2018;14(9):511-27. doi: 10.1038/s41584-018-0062-0.
• ⁶⁸
  Launay D, Sobanski V, Hachulla E, Humbert M. Pulmonary Hypertension in Systemic Sclerosis: Different Phenotypes. Eur Respir Rev. 2017;26(145):170056. doi: 10.1183/16000617.0056-2017.
• ⁶⁹
  Desai CS, Lee DC, Shah SJ. Systemic Sclerosis and the Heart: Current Diagnosis and Management. Curr Opin Rheumatol. 2011;23(6):545-54. doi: 10.1097/BOR.0b013e32834b8975.
• ⁷⁰
  Kiely DG, Lawrie A, Humbert M. Screening Strategies for Pulmonary Arterial Hypertension. Eur Heart J Suppl. 2019;21(Suppl K):9-20. doi: 10.1093/eurheartj/suz204.
• ⁷¹
  Hao Y, Thakkar V, Stevens W, Morrisroe K, Prior D, Rabusa C, et al. A Comparison of the Predictive Accuracy of Three Screening Models for Pulmonary Arterial Hypertension in Systemic Sclerosis. Arthritis Res Ther. 2015;17(1):7. doi: 10.1186/s13075-015-0517-5.
• ⁷²
  Jais X, Launay D, Yaici A, Le Pavec J, Tchérakian C, Sitbon O, et al. Immunosuppressive Therapy in Lupus- and Mixed Connective Tissue Disease-Associated Pulmonary Arterial Hypertension: A Retrospective Analysis of Twenty-three Cases. Arthritis Rheum. 2008;58(2):521-31. doi: 10.1002/art.23303.
• ⁷³
  Sanchez O, Sitbon O, Jaïs X, Simonneau G, Humbert M. Immunosuppressive Therapy in Connective Tissue diseases-Associated Pulmonary Arterial Hypertension. Chest. 2006;130(1):182-9. doi: 10.1378/chest.130.1.182.
• ⁷⁴
  Hachinski V, Oveisgharan S, Romney AK, Shankle WR. Optimizing the Hachinski Ischemic Scale. Arch Neurol. 2012;69(2):169-75. doi: 10.1001/archneurol.2011.1698.
• ⁷⁵
  Speich R, Jenni R, Opravil M, Pfab M, Russi EW. Primary Pulmonary Hypertension in HIV Infection. Chest. 1991;100(5):1268-71. doi: 10.1378/chest.100.5.1268.
• ⁷⁶
  Petitpretz P, Brenot F, Azarian R, Parent F, Rain B, Herve P, et al. Pulmonary Hypertension in Patients With Human Immunodeficiency Virus Infection. Comparison with Primary Pulmonary Hypertension. Circulation. 1994;89(6):2722-7. doi: 10.1161/01.cir.89.6.2722.
• ⁷⁷
  Degano B, Guillaume M, Savale L, Montani D, Jaïs X, Yaici A, et al. HIV-Associated Pulmonary Arterial Hypertension: Survival and Prognostic Factors in the Modern Therapeutic Era. AIDS. 2010;24(1):67-75. doi: 10.1097/QAD.0b013e328331c65e.
• ⁷⁸
  Jarrett H, Barnett C. HIV-associated Pulmonary Hypertension. Curr Opin HIV AIDS. 2017;12(6):566-71. doi: 10.1097/COH.0000000000000418.
• ⁷⁹
  Pergola V, Caruso C, Gnarini R, Fazio S, Ferraro S. Efficacy of Sildenafil in HIV-Related Pulmonary Arterial Hypertension. J Cardiovasc Med. 2015;16(Suppl 2):136-7. doi: 10.2459/JCM.0b013e3283388fb3.
• ⁸⁰
  Muirhead GJ, Wulff MB, Fielding A, Kleinermans D, Buss N. Pharmacokinetic Interactions Between Sildenafil and Saquinavir/Ritonavir. Br J Clin Pharmacol. 2000;50(2):99-107. doi: 10.1046/j.1365-2125.2000.00245.x.
• ⁸¹
  DeJesus E, Saleh S, Cheng S, van der Mey D, Becker C, Frey R, et al. Pharmacokinetic Interaction of Riociguat and Antiretroviral Combination Regimens in HIV-1-Infected Adults. Pulm Circ. 2019;9(2):2045894019848644. doi: 10.1177/2045894019848644.
• ⁸²
  Degano B, Yaïci A, Le Pavec J, Savale L, Jaïs X, Camara B, et al. Long-term Effects of Bosentan in Patients with HIV-Associated Pulmonary Arterial Hypertension. Eur Respir J. 2009;33(1):92-8. doi: 10.1183/09031936.00094808.
• ⁸³
  Aguilar RV, Farber HW. Epoprostenol (Prostacyclin) Therapy in HIV-Associated Pulmonary Hypertension. Am J Respir Crit Care Med. 2000;162(5):1846-50. doi: 10.1164/ajrccm.162.5.2004042.
• ⁸⁴
  Chinello P, Petrosillo N. Pharmacological Treatment of HIV-Associated Pulmonary Hypertension. Expert Rev Clin Pharmacol. 2016;9(5):715-25. doi: 10.1586/17512433.2016.1151785.
• ⁸⁵
  Kaufmann P, Niglis S, Bruderer S, Segrestaa J, Äänismaa P, Halabi A, et al. Effect of Lopinavir/Ritonavir on the Pharmacokinetics of Selexipag an Oral Prostacyclin Receptor Agonist and its Active Metabolite in Healthy Subjects. Br J Clin Pharmacol. 2015;80(4):670-7. doi: 10.1111/bcp.12650.
• ⁸⁶
  Porres-Aguilar M, Zuckerman MJ, Figueroa-Casas JB, Krowka MJ. Portopulmonary Hypertension: State of the Art. Ann Hepatol. 2008;7(4):321-30. doi: 10.1016/S1665-2681(19)31832-0
• ⁸⁷
  Alves JL Jr, Gavilanes F, Jardim C, Fernandes CJCDS, Morinaga LTK, Dias B, et al. Pulmonary arterial hypertension in the southern hemisphere: results from a registry of incident Brazilian cases. Chest. 2015;147(2):495-501. doi: 10.1378/chest.14-1036. (Citação repetida (vide nº 59). Verificar com os autores a possibilidade de incluir outra citação no lugar da 87 ou se será preciso renumerar todas as citações a partir deste ponto.)
• ⁸⁸
  Ramsay MA, Simpson BR, Nguyen AT, Ramsay KJ, East C, Klintmalm GB. Severe Pulmonary Hypertension in Liver Transplant Candidates. Liver Transpl Surg. 1997;3(5):494-500. doi: 10.1002/lt.500030503.
• ⁸⁹
  Le Pavec J, Souza R, Herve P, Lebrec D, Savale L, Tcherakian C, et al. Portopulmonary Hypertension: Survival and Prognostic Factors. Am J Respir Crit Care Med. 2008;178(6):637-43. doi: 10.1164/rccm.200804-613OC.
• ⁹⁰
  Elliott CG, Barst RJ, Seeger W, Porres-Aguilar M, Brown LM, Zamanian RT, et al. Worldwide Physician Education and Training in Pulmonary Hypertension: Pulmonary Vascular Disease: The Global Perspective. Chest. 2010;137(Suppl 6):85-94. doi: 10.1378/chest.09-2816.
• ⁹¹
  Cosarderelioglu C, Cosar AM, Gurakar M, Pustavoitau A, Russell SD, Dagher NN, et al. Portopulmonary Hypertension and Liver Transplant: Recent Review of the Literature. Exp Clin Transplant. 2016;14(2):113-20. doi: 10.6002/ect.2015.0351.
• ⁹²
  Hoeper MM, Seyfarth HJ, Hoeffken G, Wirtz H, Spiekerkoetter E, Pletz MW, et al. Experience with Inhaled Iloprost and Bosentan in Portopulmonary Hypertension. Eur Respir J. 2007;30(6):1096-102. doi: 10.1183/09031936.00032407.
• ⁹³
  Raevens S, Fallon MB. PORTICO: First Randomized Controlled Trial of Vasomodulator Therapy in Portopulmonary Hypertension. Hepatology. 2020;71(5):1870-2. doi: 10.1002/hep.31166.
• ⁹⁴
  Provencher S, Herve P, Jais X, Lebrec D, Humbert M, Simonneau G, et al. Deleterious Effects of Beta-blockers on Exercise Capacity and Hemodynamics in Patients with Portopulmonary Hypertension. Gastroenterology. 2006;130(1):120-6. doi: 10.1053/j.gastro.2005.10.013.
• ⁹⁵
  Krowka MJ, Swanson KL, Frantz RP, McGoon MD, Wiesner RH. Portopulmonary Hypertension: Results From a 10-year Screening Algorithm. Hepatology. 2006;44(6):1502-10. doi: 10.1002/hep.21431.
• ⁹⁶
  Gavilanes F, Fernandes CJ, Souza R. Pulmonary Arterial Hypertension in Schistosomiasis. Curr Opin Pulm Med. 2016;22(5):408-14. doi: 10.1097/MCP.0000000000000300.
• ⁹⁷
  Fernandes CJC, Piloto B, Castro M, Oleas FG, Alves JL Jr, Prada LFL, et al. Survival of Patients with Schistosomiasis-Associated Pulmonary Arterial Hypertension in the Modern Management Era. Eur Respir J. 2018;51(6):1800307. doi: 10.1183/13993003.00307-2018.
• ⁹⁸
  Fernandes CJ, Jardim CV, Hovnanian A, Hoette S, Morinaga LK, Souza R. Schistosomiasis and Pulmonary Hypertension. Expert Rev Respir Med. 2011;5(5):675-81. doi: 10.1586/ers.11.58.
• ⁹⁹
  Fernandes CJCS, Dias BA, Jardim CVP, Hovnanian A, Hoette S, Morinaga LK, et al. The Role of Target Therapies in Schistosomiasis-Associated Pulmonary Arterial Hypertension. Chest. 2012;141(4):923-8. doi: 10.1378/chest.11-0483.
• ¹⁰⁰
  Hoette S, Figueiredo C, Dias B, Alves JL Jr, Gavilanes F, Prada LFL, et al. Pulmonary Artery Enlargement in Schistosomiasis Associated Pulmonary Arterial Hypertension. BMC Pulm Med. 2015;15:118. doi: 10.1186/s12890-015-0115-y.
• ¹⁰¹
  Fernandes CJC, Jardim C, Souza R. The Global View. Curr Opin Pulm Med. 2019;25(5):391-7. doi: 10.1097/MCP.0000000000000603.
• ¹⁰²
  Engelfriet PM, Duffels MG, Möller T, Boersma E, Tijssen JG, Thaulow E, et al. Pulmonary Arterial Hypertension in Adults Born with a Heart Septal Defect: The Euro Heart Survey on Adult Congenital Heart Disease. Heart. 2007;93(6):682-7. doi: 10.1136/hrt.2006.098848.
• ¹⁰³
  Beghetti M, Galiè N. Eisenmenger Syndrome a Clinical Perspective in a New Therapeutic Era of Pulmonary Arterial Hypertension. J Am Coll Cardiol. 2009;53(9):733-40. doi: 10.1016/j.jacc.2008.11.025.
• ¹⁰⁴
  Broberg CS, Ujita M, Prasad S, Li W, Rubens M, Bax BE, et al. Pulmonary Arterial Thrombosis in Eisenmenger Syndrome is Associated with Biventricular Dysfunction and Decreased Pulmonary flow Velocity. J Am Coll Cardiol. 2007;50(7):634-42. doi: 10.1016/j.jacc.2007.04.056.
• ¹⁰⁵
  Sandoval J, Aguirre JS, Pulido T, Martinez-Guerra ML, Santos E, Alvarado P, et al. Nocturnal Oxygen Therapy in Patients with the Eisenmenger Syndrome. Am J Respir Crit Care Med. 2001;164(9):1682-7. doi: 10.1164/ajrccm.164.9.2106076.
• ¹⁰⁶
  Galiè N, Beghetti M, Gatzoulis MA, Granton J, Berger RM, Lauer A, et al. Bosentan Therapy in Patients with Eisenmenger Syndrome: A Multicenter, Double-blind, Randomized, Placebo-controlled Study. Circulation. 2006;114(1):48-54. doi: 10.1161/CIRCULATIONAHA.106.630715.
• ¹⁰⁷
  Rosenzweig EB, Abman SH, Adatia I, Beghetti M, Bonnet D, Haworth S, et al. Paediatric Pulmonary Arterial hypertension: Updates on Definition, Classification, Diagnostics and Management. Eur Respir J. 2019;53(1):1801916. doi: 10.1183/13993003.01916-2018.
• ¹⁰⁸
  Olsson KM, Jais X. Birth Control and Pregnancy Management in Pulmonary Hypertension. Semin Respir Crit Care Med. 2013;34(5):681-8. doi: 10.1055/s-0033-1355438.
• ¹⁰⁹
  Hemnes AR, Kiely DG, Cockrill BA, Safdar Z, Wilson VJ, Al Hazmi M, et al. Statement on Pregnancy in Pulmonary Hypertension from the Pulmonary Vascular Research Institute. Pulm Circ. 2015;5(3):435-65. doi: 10.1086/682230.
• ¹¹⁰
  Thorne S, Nelson-Piercy C, MacGregor A, Gibbs S, Crowhurst J, Panay N, et al. Pregnancy and Contraception in Heart Disease and Pulmonary Arterial Hypertension. J Fam Plann Reprod Health Care. 2006;32(2):75-81. doi: 10.1783/147118906776276486.
• ¹¹¹
  Olsson KM, Channick R. Pregnancy in pulmonary arterial hypertension. Eur Respir Rev. 2016;25(142): 431-7. doi: 10.1183/16000617.0079-2016
• ¹¹²
  Sliwa K, van Hagen IM, Budts W, Swan L, Sinagra G, Caruana M, et al. Pulmonary Hypertension and Pregnancy Outcomes: Data From the Registry of Pregnancy and Cardiac Disease (ROPAC) of the European Society of Cardiology. Eur J Heart Fail. 2016;18(9):1119-28. doi: 10.1002/ejhf.594.
• ¹¹³
  Duarte AG, Thomas S, Safdar Z, Torres F, Pacheco LD, Feldman J, et al. Management of Pulmonary Arterial Hypertension During Pregnancy: A Retrospective, Multicenter Experience. Chest. 2013;143(5):1330-1336. doi: 10.1378/chest.12-0528.
• ¹¹⁴
  Thomas E, Yang J, Xu J, Lima FV, Stergiopoulos K. Pulmonary Hypertension and Pregnancy Outcomes: Insights From the National Inpatient Sample. J Am Heart Assoc. 2017;6(10):e006144. doi: 10.1161/JAHA.117.006144.
• ¹¹⁵
  Terek D, Kayikcioglu M, Kultursay H, Ergenoglu M, Yalaz M, Musayev O, et al. Pulmonary Arterial Hypertension and Pregnancy. J Res Med Sci. 2013;18(1):73-6.
• ¹¹⁶
  Madden BP. Pulmonary hypertension and pregnancy. Int J Obstet Anesth. 2009;18(2):156-64. doi: 10.1016/j.ijoa.2008.10.006.
• ¹¹⁷
  Galiè N, Saia F, Palazzini M, Manes A, Russo V, Reggiani MLB, et al. Left Main Coronary Artery Compression in Patients With Pulmonary Arterial Hypertension and Angina. J Am Coll Cardiol. 2017;69(23):2808-2817. doi: 10.1016/j.jacc.2017.03.597.
• ¹¹⁸
  Kajita LJ, Martinez EE, Ambrose JA, Lemos PA, Esteves A, Gama MN, et al. Extrinsic Compression of the Left Main Coronary Artery by a Dilated Pulmonary Artery: Clinical, Angiographic, and Hemodynamic Determinants. Catheter Cardiovasc Interv. 2001;52(1):49-54. doi: 10.1002/1522-726x(200101)52:1<49::aid-ccd1012>3.0.co;2-0.
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• ¹¹⁹
  Fernandes CJ, Steigner ML, Piazza G, Goldhaber SZ. Collaborative Cardiology and Pulmonary Management of Pulmonary Hypertension. Chest. 2019;156(2):200-202. doi: 10.1016/j.chest.2019.04.099.
• ¹²⁰
  Saia F, Dall’Ara G, Marzocchi A, Dardi F, Palazzini M, Manes A, et al. Left Main Coronary Artery Extrinsic Compression in Patients With Pulmonary Arterial Hypertension: Technical Insights and Long-Term Clinical Outcomes After Stenting. JACC Cardiovasc Interv. 2019;12(3):319-21. doi: 10.1016/j.jcin.2018.08.002.
• ¹²¹
  Tongers J, Schwerdtfeger B, Klein G, Kempf T, Schaefer A, Knapp JM, et al. Incidence and Clinical Relevance of Supraventricular Tachyarrhythmias in Pulmonary Hypertension. Am Heart J. 2007;153(1):127-32. doi: 10.1016/j.ahj.2006.09.008.
• ¹²²
  Drakopoulou M, Nashat H, Kempny A, Alonso-Gonzalez R, Swan L, Wort SJ, et al. Arrhythmias in Adult Patients With Congenital Heart Disease and Pulmonary Arterial Hypertension. Heart. 2018;104(23):1963-69. doi: 10.1136/heartjnl-2017-312881.

• Study Association
  This study is not associated with any thesis or dissertation work.

• Sources of Funding: There were no external funding sources for this study.

Publication Dates

• Publication in this collection
  25 Oct 2021
• Date of issue
  Oct 2021

History

• Received
  24 June 2020
• Reviewed
  13 Sept 2020
• Accepted
  04 Nov 2020