Pulmonary hypertension
Introduction and classification
Pulmonary hypertension (PH) is defined haemodynamically as an increase in mean pulmonary arterial pressure (mPAP) of at least 25 mmHg at rest, as assessed by right heart catheterization (RHC). At the 2008 World Symposium on Pulmonary Hypertension in Dana Point, mPAP of 20–25 mmHg was considered abnormal, and the term ‘pre-PH’ was proposed to signify this.1 Previously, the definition of PH included exercise-induced PH (mPAP ≥30 mmHg on exercise).2 However, the data for exercise-induced PH is limited, and the recent reclassification of PH does not include exercise-induced PH in its definition.
PH is a severe, progressive disorder, which may be idiopathic, or related to a spectrum of medical disorders. The clinical classification of PH was revised at the Dana Point symposium (Table 31.1).1 PH is classified into five groups with specific pathological, pathophysiological, and therapeutic characteristics. PH associated with left heart disease was identified as a distinct subgroup, with subcategories including PH related to systolic and diastolic dysfunction and valvular heart disease
Table 31.1 Dana Point classification of pulmonary arterial hypertension
1 | PAH |
1.1 | Idiopathic PAH |
1.2 | Heritable |
1.2.1 | BMPR2 |
1.2.2 | ALK1, endoglin (with or without hereditary haemorrhagic telangectasia) |
1.2.3 | Unknown |
1.3 | Drug and toxin induced |
1.4 | Associated with: |
1.4.1 | Collagen tissue diseases |
1.4.2 | HIV infection |
1.4.3 | Portal hypertension |
1.4.4 | Congenital heart diseases |
1.4.5 | Schistosomiasis |
1.4.6 | Chronic haemolytic aneamia |
1.5 | Associated with significant venous or capillary involvement |
1.5.1 | Pulmonary veno-occlusive disease |
1.5.2 | Pulmonary capillary haemangiomatosis |
1.6 | Persistent PH of the newborn |
2 | PH with left heart disease |
2.1 | Left-sided atrial or ventricular heart disease |
2.2 | Left-sided valvular heart disease |
3 | PH associated with lung diseases and/or hypoxaemia |
3.1 | COPD |
3.2 | Interstitial lung disease |
3.3 | Other pulmonary diseases with mixed restrictive and obstructive pattern |
3.4 | Sleep-disordered breathing |
3.5 | Alveolar hypoventilation disorders |
3.6 | Chronic exposure to high altitude |
3.7 | Developmental abnormalities |
4 | CTEPH |
5 | PH with unclear multifactorial mechanisms |
5.1 | Haematologic disorders: myeloproliferative disorders, splenectomy |
5.2 | Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis |
5.3 | Metabolic disorders: glycogen storage disease, Gaucher’s disease, thyroid disorders |
5.4 | Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis |
COPD, chronic obstructive pulmonary disease; CTEPH, chronic thromboembolic pulmonary hypertension; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension.
PH may be considered pre- or postcapillary (Table 31.2).3 Precapillary PH is defined as mPAP 25 mmHg or more, with pulmonary capillary wedge pressure (PCWP) 15 mmHg or less and a normal or reduced cardiac output (CO). PH associated with left heart disease is considered postcapillary, and defined on haemodynamic terms as having mPAP 25 mmHg or more, PCWP greater than 15 mmHg, and a normal or reduced CO. Furthermore, postcapillary PH can be considered in two subgroups: passive PH (in which the transpulmonary gradient, TPG ≤12 mmHg) and reactive or disproportionate PH (in which the TPG 〉12 mmHg).
Table 31.2 Haemodynamic definitions of pulmonary hypertension
Definition | Characteristicsa | Clinical groups |
|---|---|---|
PH | Mean PAP ≥25 mmHg | All |
Precapillary PH | Mean PAP ≥25 mmHg PCWP ≤15 mmHg CO normal or reduced | PAH PH due to lung diseases CTEPH Miscellaneous PH |
Postcapillary PH | Mean PAP ≥25 mmHg PCWP 〉15 mmHg CO normal or reduced | PH due to left heart disease |
Passive | TPG ≤12 mmHg | |
Reactive (out of proportion) | TPG 〉12 mmHg |
a All values measured at rest.
CO, cardiac output; CTEPH, chronic thromboembolic pulmonary hypertension; PAH, pulmonary arterial hypertension; PAP, pulmonary arterial pressure; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension; TPG, transpulmonary gradient.
Adapted from the European Cardiology Society (ECS)/European Respiratory Society (ERS) PH guidelines.
The transpulmonary gradient is the drop from mPAP to left atrial (or pulmonary capillary wedge) pressure, and is measured at right heart catheterization. A low TPG in the face of PH implies that the pulmonary circulation is likely to be structurally normal and that the PH is purely secondary to the back pressure effect of raised left heart filling pressure; whereas a high TPG implies that secondary changes have occurred to the pulmonary vasculature.
Prevalence and prognostic implications of pulmonary hypertension in left heart disease
The prevalence of PH in left heart disease increases with the severity of functional impairment. Forty to seventy per cent of patients with isolated diastolic dysfunction, and up to 60% of those with left ventricular systolic dysfunction (LVSD) have PH at presentation.3,4 In patients with valvular heart disease, the prevalence of PH increases with the severity of the valvular defect, and is reported in up to 100% of cases with severe left heart valvular disease.5
In general when PH develops in association with left heart disease, patients have a worse prognosis. In a chronic heart failure (HF) study, the mortality rate was higher in patients with PH (28%) than in those without PH (17%) at 28 months.6 PH (pulmonary vascular resistance 〉6–8 Wood’s units; TPG 〉16 mmHg) is also associated with an increased postoperative risk of right HF after cardiac transplantation.7
Histopathology of pulmonary hypertension associated with left heart disease
The histopathology of PH associated with left heart disease is characterized by pulmonary venous distension and thickening and pulmonary capillary and lymphatic dilatation, as well as interstitial oedema and alveolar haemorrhage. Over time, pulmonary vascular remodelling may lead to the classic changes of the distal pulmonary vasculature seen in pulmonary arterial hypertension (PAH) including medial hypertrophy, intimal proliferation and fibrosis, and adventitial changes (Fig. 31.1).8,9
Image courtesy of Peter Dorfmuller.
Pathophysiology of pulmonary hypertension associated with left heart disease
The pathophysiology of PH related to left heart disease is complex, and may be best considered as a combination of passive and active mechanisms. Passive pulmonary venous stretch resulting from backward transmission of elevated left heart filling pressures is important (Table 31.2). Purely passive PH is usually reversible with acute vasodilator testing, and may be more responsive to chronic HF treatment.10
However, in some cases there is an additional active component, leading to PH ‘out of proportion’ to the underlying left heart disease. In such patients, mPAP is disproportionately elevated above left heart filling pressures, leading to an elevation in TPG and a consequent increase in pulmonary vascular resistance (PVR). This elevation in PVR is attributed to an increase in the vasomotor tone of the distal pulmonary vasculature from pulmonary vasoconstriction and pulmonary vascular remodelling.11
Pulmonary vascular remodelling results from increase in cell number in all components of the vessel wall. This leads to a narrowed lumen and increase in vascular resistance proportional to radius4. Although the formation of plexiform lesions, characteristic of severe PAH, are not generally seen in PH associated with left heart disease, true remodelling of resistance vessels has been reported. These fixed, obstructive lesions lead to PH that is generally unresponsive to acute vasodilator testing.
It is not clear why pulmonary vascular remodelling and disproportionate PH develop in only some chronic HF patients. It is possible that pulmonary vascular remodelling develops in response to chronic activation of stretch receptors located in the left atrium and pulmonary veins. Patients with congestive cardiac failure also have endothelial dysfunction, and raised serum endothelin-1 (ET-1) levels, a pathological mediator known to be important in vascular remodelling in PAH.12 13
Other potential pathophysiological mechanisms include hypoxic pulmonary vasoconstriction and in situ thrombosis.
Diagnosis of pulmonary hypertension in left heart disease
Recognition of PH may be delayed, as it is often masked by the clinical picture of the underlying left heart disease. Symptoms including dyspnoea and fatigue are common to both PH and left heart disease. Physical signs reflective of PH (such as a loud pulmonary component of the second heart sound) are often difficult to hear. Signs of right HF (including peripheral oedema) are generally late findings.
It may be difficult to distinguish between PH associated with diastolic dysfunction and true PAH. Left ventricular diastolic dysfunction should be suspected (rather than PAH) in the presence of one or more of a number of clinical or echocardiographic risk factors (Box 31.1).3,14 However, a definite diagnosis of PH associated with left heart disease is only possible following RHC.
Right heart catheter
RHC remains the gold standard for the diagnosis of PH. It allows the measurement of mPAP, PCWP, and CO, and subsequent calculation of TPG and PVR. These data are important for the diagnosis of PH associated with left heart disease, and its subdivision into passive and active categories (Table 31.2).
The role of acute vasodilator testing is not clear in PH due to left heart disease. In general, patients with passive PH will have acute vasodilator reversibility, whereas patients with disproportionate PH will have fixed disease, unresponsive to vasodilator testing.10 At present, vasoreactivity testing is recommended for patients referred for cardiac transplantation.15 In these patients, lack of responseto vasodilator testing is associated with increased risk of post-transplantation right ventricular failure and early mortality.16A variety of agents are used for vasoreactivity testing, including nitrous oxide, phosphodiesterase-5 (PDE-5) inhbitors, prostanoids, and other vasodilators.
In the diagnosis of left ventricular diastolic dysfunction, the role of exercise testing, or volume challenge, remains unclear (Fig. 31.2). However, in some patients with apparently ‘normal’ left ventricular filling pressures (often following diuretic therapy and fluid restriction prior to RHC), an increase in pressure following exercise or fluid challenge may unveil occult left ventricular dysfunction.14
RHC is a moderately invasive procedure, and so a number of noninvasive investigations are often used in the assessment for PH.
Echocardiography
Continuous Doppler flow echocardiography is the best noninvasive tool for the assessment of PH associated with left heart disease. Echocardiography allows estimation of the systolic PAP from the maximal velocity of the tricuspid regurgitation jet (in the presence of tricuspid regurgitation). However, echocardiography also complements RHC as it provides other, structural and functional cardiac information.
Left ventricular systolic function is assessed by the left ventricular ejection fraction (LVEF). In contrast, left ventricular diastolic dysfunction is more difficult to assess, although there are several echocardiographic findings that should arouse suspicion for diastolic dysfunction (Table 31.3).3,14 Left ventricular filling pressures may be estimated by the ratio of mitral valve flow velocity (E) divided by early diastolic lengthening velocities (E′). However, accurate evaluation of left ventricular filling pressures requires RHC.
Table 31.3 Summary of long-term treatment trials with endothelin receptor antagonists in heart failure
Study name | Endothelin receptor antagonist | Subjects | Outcome |
|---|---|---|---|
RITZ 1–5 | Intravenous tezosentan (25–100 mg/h) | Acute heart failure | No difference in all endpoints |
VERITAS 1 and 2 | Intravenous tezosentan | Acute heart failure | No difference in dyspnoea at 24 h or survival at 7days Mild haemodynamic benefit No survival difference at 6 months |
REACH 1 | High dose bosentan (250 mg twice a day) | Chronic heart failure (WHO class IIIb–IV) | Early hepatotoxicity (10% versus 2% receiving placebo) Trial terminated early Trend towards clinical improvement in those receiving 6 months bosentan |
ENABLE 1 and 2 | Bosentan (125 mg twice a day) | Chronic heart failure (WHO class IIIb– IV) | No improvement in endpoints Early toxicity with clinical worsening of heart failure with bosentan |
ENCOR | Enrasentan | Chronic heart failure (WHO class II–III) | Increased adverse events, heart failure hospitalizations and trend towards increased mortality with enrasentan |
EARTH | Darusentan | Chronic heart failure (WHO class II–IV) | Increased adverse events, and worsening of cardiac failure in darusentan groups No benefit with darusentan |
RITZ, Randomized Intravenous TeZosentan Study; VERITAS, Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Studies.
Other noninvasive investigations
B-type natriuretic peptide (BNP) is released in response to atrial and ventricular wall stretch. Plasma BNP concentrations are elevated in PAH, and are associated with poorer outcomes.17 However, in BNP concentrations are also elevated in left heart disease. Therefore, it is not clear whether increased BNP levels are useful in identification or prognostic evaluation of PH in left heart disease.
Cardiopulmonary exercise tests (CPET) may be useful to identify early, or exercise-induced, PH as a cause of exercise-limitation in patients with underlying left heart disease. However, patients are often unable to perform a CPET, and six-minute walk testing is used instead. In patients with PAH, lower six-minute walk test distance portends a poorer prognosis.18,19
Cardiac MRI (CMR) provides the most accurate measurement of right ventricular mass and ejection fraction. Its role in the diagnosis of PH in this patient group is promising, but needs further study.
The main and segmental pulmonary artery size may be measured on CT scanning. There are few data to support the use of CT scanning in the diagnosis of PH in patients with left heart disease.
Management of pulmonary hypertension related to left heart disease
General principles
Management of PH related to left heart disease centres on the treatment of the underlying disorder with medications such as diuretics, angiotensin converting enzyme (ACE) inhibitors, β-adrenoreceptor blockers, or other interventions.10 In patients with valvular heart disease, corrective valve surgery is recommended, and is usually associated with clinical improvement, and resolution of the PH.5,20 The improvement may take several weeks to months, and may be incomplete, due to the fixed obstructive changes of pulmonary vascular remodelling.
Supplemental oxygen is recommended to reverse resting hypoxaemia in appropriate patients. Full assessment and treatment of comorbidities (including pulmonary emboli and obstructive sleep apnoea) is important. Early referral for cardiac transplantation is essential for selected cases. Patients with endstage cardiac failure and PH may be candidates for cardiac transplantation (in milder, largely reversible forms of PH), or heart–lung transplantation when PH is severe and/or fixed.
Specific therapy for pulmonary hypertension
Specific PH therapy is not routinely recommended for patients with PH secondary to heart disease, as there have been no successful placebo-controlled trials of disease-targeted PH therapies in this patient group.3,21 There is a potential risk of increasing intrapulmonary shunting and ventilation–perfusion mismatch, particularly with pulmonary vasodilators. However, the risk may be ameliorated by treatment to reduce left ventricular filling pressures. A number of pharmceutical trials have been performed, and the results are summarized below.
Nitric oxide and prostacyclin therapy
Nitric oxide (NO) and prostacyclin are potent pulmonary vasodilators. Both NO and prostacyclin have been shown to improve pulmonary haemodynamics acutely, with decreased PVR, and pulmonary arterial pressures.22–24 In patients with left heart disease, inhaled NO leads to a decrease in PVR, with an increase in left ventricular filling pressures. However, an international trial using intravenous epoprostenol in patients with severe left ventricular failure (FIRST trial) was terminated prematurely because of a trend towards increased mortality in patients receiving epoprostenol.25
Endothelin-1 receptor antagonists
The endothelin system is activated in chronic HF, and elevated plasma ET-1 (and its precursor big-ET1) levels are associated with increased morbidity and mortality in patients with left heart disease.26,27 Plasma ET-1 levels correlate with the symptomatic and haemodynamic severity of the HF.28,29 Intravenous infusions of ET-1 lead to increased systemic vascular resistance, and decreased cardiac index.30 ET-1 acts via two receptor subtypes (ETA and ETB receptors). Both receptor subtypes lead to pulmonary vasoconstriction, and vascular smooth muscle proliferation. Activation of ETB receptors also leads to vasodilation (via NO and prostacyclin), antiproliferative and antithrombotic effects, and clearance of ET-1. It is unclear whether selective ETA blockade is advantageous in chronic HF.
In preliminary small studies using the endothelin-1 receptor antagonists (ETRAs) bosentan, darusentan, and BQ-123, there was an acute improvement in mPAP, right atrial pressure, PCWP, and CO.31–33 Intravenous bosentan led to acute improvement in pulmonary haemodynamics in 24 patients with chronic HF.29 Acute treatment with the ETA receptor antagonist sitaxentan led to significant decreases in pulmonary arterial pressures and PVR.34 In a large placebo-controlled study of patients with acute decompensated HF, intravenous tezosentan led to an acute reduction in left ventricular filling pressures, and increased cardiac index.35
Longer-term studies have not confirmed a benefit for the use of ETRAs in patients with PH associated with left heart disease. The Research on Endothelin Antagonists in Chronic Heart Failure (REACH-1) study, a placebo-controlled study using bosentan, was terminated early because of elevated hepatic transaminase levels.36 However, there was a trend towards reduced HF mortality and morbidity with bosentan. The Endothelin Antagonist Bosentan or Lowering Cardiac Events in Heart Failure (ENABLE 1 and 2) studies did not show any benefit of bosentan over placebo with regard to morbidity or mortality.37 In a further study with enrasentan (Enrasentan Cooperative Randomized Evaluation, ENCOR study), no benefit was shown.38 The Endothelin A Receptor Antagonist Trial in Heart Failure (EARTH) study also showed no difference of left ventricular end-systolic volume on CMR imaging in patients treated with darusentan or placebo.39 The results of the ETRA trials in cardiac failure patients are summarized in Table 31.3.
It is somewhat difficult to reconcile the negative results in the trials described above with the positive findings in acute studies. One explanation for the disparity is that patients who have PH disproportionate to their underlying left heart disease are more likely to benefit from specific PH therapy, and many of the trials discussed included all patients with congestive HF, not only patients specifically with PH who might be expected to benefit. Alternatively, it is possible that the acute haemodynamic response to ETRAs does not lead to a sustained clinical benefit, or that any benefit is masked by the use of other HF therapies.40,41 Currently, the use of ETRAs is not recommended for the treatment of PH associated with left heart disease.
Phosphodiesterase-5 inhibitors
In PAH, NO mediates pulmonary vasodilation via cyclic guanosine monophosphate (cGMP), which is degraded by phosphodiesterases (particularly PDE-5). In PH, PDE-5 is up-regulated. PDE-5 inhibitors, such as sildenafil, cause pulmonary vasodilation, antiproliferative actions on pulmonary vascular smooth muscle cells, and protection from ischaemic reperfusion injury. In PAH, sildenfil is associated with increased six-minute walk test distance, and improved pulmonary haemodynamics at 12 weeks, with a sustained clinical benefit at 12 months.42
In chronic HF, sildenafil acutely lowers PVR and pulmonary arterial pressures, and improves endothelium-dependent flow-mediated pulmonary vasodilation.43–45 Longer-term studies have shown that sildenafil is associated with improvement in exercise capacity, and CO and skeletal muscle blood flow during exercise.46,47 A study of 34 patients with symptomatic HF and PH, showed an improvement in six-minute walk test distance, quality of life, exercise capacity, and fewer hospitalizations for HF, with sildenafil compared to placebo at 12 weeks. Despite these promising results, the routine use of sildenafil in patients with PH associated with left heart disease cannot be recommended. There is an urgent need for further longer-term trials, particularly in patients with PH disproportionate to the underlying heart disease.
To date, there have been no trials specifically addressing patients with left ventricular diastolic HF, in which PH is common. The PhosphodiesteRasE-5 Inhibition to Improve Quality of Life And EXercise Capacity in Diastolic Heart Failure (RELAX) study, a double-blind, placebo-controlled clinical trial using sildenafil, is currently under way. The primary endpoint of the study is the change in exercise capacity as assessed by peak VO2 after 24 weeks of treatment with sildenafil or placebo.
Summary
PH is common in patients with left heart disease, and is associated with increased morbidity and mortality. The underlying pathophysiological mechanisms are complex, including both passive and active components. PH disproportionate to the underlying left heart disease may be attributable to reactive pulmonary vascular remodelling. Left ventricular diastolic dysfunction may be difficult to diagnose, but is best assessed with echocardiography and RHC. Management of PH is focused on treatment of the underlying left heart disease, and reversal of hypoxaemia. There is no supporting evidence for the routine use of specific PH therapies at present. However, there is some suggestion that PDE-5 inhibitors may be useful, and their safety and efficacy needs to be formally evaluated in controlled trials before further recommendations are made.
Further reading
Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. New Engl J Med 2005;353(20):2148–57.
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Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: The 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 the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30(20):2493–537.
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Gibbs S. Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland. Thorax 2008;63(S2):ii1–41.
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Guazzi M, Samaja M, Arena R, Vicenzi M, Guazzi MD. Long-term use of sildenafil in the therapeutic management of heart failure. Journal of the American College of Cardiology 2007;50(22):2136–44.
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Hoeper MM, Barbera JA, Channick RN, et al. Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension. J Am Coll Cardiol 2009;54(1 Suppl):S85–96.
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Kelland NF, Webb DJ. Clinical trials of endothelin antagonists in heart failure: publication is good for the public health. Heart 2007;93(1):2–4.
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Kelland NF, Webb DJ. Clinical trials of endothelin antagonists in heart failure: a question of dose? Exp Biol Med (Maywood) 2006;231(6):696–9.
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Kirkby NS, Hadoke PW, Bagnall AJ, Webb DJ. The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house? Br J Pharmacol 2008;153(6):1105–19.
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Lewis GD, Shah R, Shahzad K, et al. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation 2007;116(14):1555–62.
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Melenovsky V, Borlaug BA, Rosen B, et al. Cardiovascular features of heart failure with preserved ejection fraction versus nonfailing hypertensive left ventricular hypertrophy in the urban Baltimore community: the role of atrial remodeling/dysfunction. J Am Coll Cardiol 2007;49(2):198–207.
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Simonneau G, Robbins IM, Beghetti M, Channick RN, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54(1 Suppl S):S43–54.
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Simonneau G. Proceedings of the 3rd World Symposium on Pulmonary Arterial Hypertension. Venice, Italy, June 23–25, 2003. J. Am. Coll. Cardiol 2004;43(12 Suppl S): S1–90.
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References
1. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54 (1 Suppl):S43–54.
Find This Resource
2. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43:5–12S.
Find This Resource
3. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: The 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 the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493–537.
Find This Resource
4. Ghio S, Gavazzi A, Campana C, et al. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol 2001;37:183–8.
Find This Resource
5. Vahanian A, Baumgartner H, Bax J, et al. Guidelines on the management of valvular heart disease: The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. Eur Heart J 2007;28:230–68.
Find This Resource
6. Abramson SV, Burke JF, Kelly JJ Jr, et al. Pulmonary hypertension predicts mortality and morbidity in patients with dilated cardiomyopathy. Ann Intern Med 1992;116:888–95.
Find This Resource
7. Addonizio LJ, Gersony WM, Robbins RC, et al. Elevated pulmonary vascular resistance and cardiac transplantation. Circulation 1987;76:V52–5.
Find This Resource
8. Pietra GG, Capron F, Stewart S, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol 2004;43:25–32S.
Find This Resource
9. Tuder RM, Abman SH, Braun T, et al. Development and pathology of pulmonary hypertension. J Am Coll Cardiol 2009;54:S3–9.
Find This Resource
10. Oudiz RJ. Pulmonary hypertension associated with left-sided heart disease. Clin Chest Med 2007;28:233–41, x.
Find This Resource
11. Delgado JF, Conde E, Sanchez V, et al. Pulmonary vascular remodeling in pulmonary hypertension due to chronic heart failure. Eur J Heart Fail 2005;7:1011–16.
Find This Resource
12. Love MP, McMurray JJ. Endothelin in chronic heart failure: current position and future prospects. Cardiovasc Res 1996;31:665–74.
Find This Resource
13. Cowburn PJ, Cleland JG, McArthur JD, et al. Endothelin-1 has haemodynamic effects at pathophysiological concentrations in patients with left ventricular dysfunction. Cardiovasc Res 1998;39:563–70.
Find This Resource
14. Hoeper MM, Barbera JA, Channick RN, et al. Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension. J Am Coll Cardiol 2009;54:S85–96.
Find This Resource
15. Costanzo MR, Augustine S, Bourge R, et al. Selection and treatment of candidates for heart transplantation. A statement for health professionals from the Committee on Heart Failure and Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association. Circulation 1995;92:3593–612.
Find This Resource
16. Costard-Jackle A, Fowler MB. Influence of preoperative pulmonary artery pressure on mortality after heart transplantation: testing of potential reversibility of pulmonary hypertension with nitroprusside is useful in defining a high risk group. J Am Coll Cardiol 1992;19:48–54.
Find This Resource
17. Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation 2000;102:865–70.
Find This Resource
18. Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am J Resp Crit Care Med 2000;161:487–92.
Find This Resource
19. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40:780–8.
Find This Resource
20. Roques F, Nashef SA, Michel P, et al. Risk factors and outcome in European cardiac surgery: analysis of the EuroSCORE multinational database of 19030 patients. Eur J Cardiothorac Surg 1999;15:816–22; discussion 22–3.
Find This Resource
21. Gibbs S. Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland. Thorax 2008;63:ii1–41.
Find This Resource
22. Fojon S, Fernandez-Gonzalez C, Sanchez-Andrade J, et al. Inhaled nitric oxide through a noninvasive ventilation device to assess reversibility of pulmonary hypertension in selecting recipients for heart transplant. Transplant Proc 2005;37:4028–30.
Find This Resource
23. Loh E, Stamler JS, Hare JM, Loscalzo J, Colucci WS. Cardiovascular effects of inhaled nitric oxide in patients with left ventricular dysfunction. Circulation 1994;90:2780–5.
Find This Resource
24. Haraldsson A, Kieler-Jensen N, Nathorst-Westfelt U, Bergh CH, Ricksten SE. Comparison of inhaled nitric oxide and inhaled aerosolized prostacyclin in the evaluation of heart transplant candidates with elevated pulmonary vascular resistance. Chest 1998;114:780–6.
Find This Resource
25. Califf RM, Adams KF, McKenna WJ, et al. A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: The Flolan International Randomized Survival Trial (FIRST). Am Heart J 1997;134:44–54.
Find This Resource
26. McMurray JJ, Ray SG, Abdullah I, Dargie HJ, Morton JJ. Plasma endothelin in chronic heart failure. Circulation 1992;85:1374–9.
Find This Resource
27. Kirkby NS, Hadoke PW, Bagnall AJ, Webb DJ. The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house? Br J Pharmacol 2008;153:1105–19.
Find This Resource
28. Cody RJ, Haas GJ, Binkley PF, Capers Q, Kelley R. Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failure. Circulation 1992;85:504–9.
Find This Resource
29. Kiowski W, Sutsch G, Hunziker P, et al. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet 1995;346:732–6.
Find This Resource
30. Cowburn PJ, Cleland JG, McArthur JD, MacLean MR, McMurray JJ, Dargie HJ. Pulmonary and systemic responses to exogenous endothelin-1 in patients with left ventricular dysfunction. J Cardiovasc Pharmacol 1998;31(Suppl 1):S290–3.
Find This Resource
31. Sutsch G, Kiowski W, Yan XW, et al. Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure. Circulation 1998;98:2262–8.
Find This Resource
32. Spieker LE, Mitrovic V, Noll G, et al. Acute hemodynamic and neurohumoral effects of selective ET(A) receptor blockade in patients with congestive heart failure. ET 003 Investigators. J Am Coll Cardiol 2000;35:1745–52.
Find This Resource
33. Cowburn PJ, Cleland JG, McArthur JD, MacLean MR, McMurray JJ, Dargie HJ. Short-term haemodynamic effects of BQ-123, a selective endothelin ET(A)-receptor antagonist, in chronic heart failure. Lancet 1998;352:201–2.
Find This Resource
34. Givertz MM, Colucci WS, LeJemtel TH, et al. Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure. Circulation 2000;101:2922–7.
Find This Resource
35. Torre-Amione G, Young JB, Colucci WS, et al. Hemodynamic and clinical effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2003;42:140–7.
Find This Resource
36. Mylona P, Cleland JG. Update of REACH-1 and MERIT-HF clinical trials in heart failure. Cardio.net Editorial Team. Eur J Heart Fail 1999;1:197–200.
Find This Resource
37. Teerlink JR. Recent heart failure trials of neurohormonal modulation (OVERTURE and ENABLE): approaching the asymptote of efficacy? J Card Fail 2002;8:124–7.
Find This Resource
38. Abrahams W. Progress in clinical trials: ENCOR. Clin Cardiol 2001;24:481–3.
Find This Resource
39. Anand I, McMurray J, Cohn JN, et al. Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial. Lancet 2004;364:347–54.
Find This Resource
40. Kelland NF, Webb DJ. Clinical trials of endothelin antagonists in heart failure: publication is good for the public health. Heart 2007;93:2–4.
Find This Resource
41. Kelland NF, Webb DJ. Clinical trials of endothelin antagonists in heart failure: a question of dose? Exp Biol Med (Maywood) 2006;231:696–9.
Find This Resource
42. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148–57.
Find This Resource
43. Lepore JJ, Maroo A, Bigatello LM, et al. Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension: combined administration with inhaled nitric oxide. Chest 2005;127:1647–53.
Find This Resource
44. Guazzi M, Tumminello G, Di Marco F, Fiorentini C, Guazzi MD. The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. J Am Coll Cardiol 2004;44:2339–48.
Find This Resource
45. Katz SD, Balidemaj K, Homma S, Wu H, Wang J, Maybaum S. Acute type 5 phosphodiesterase inhibition with sildenafil enhances flow-mediated vasodilation in patients with chronic heart failure. J Am Coll Cardiol 2000;36:845–51.
Find This Resource
46. Guazzi M, Samaja M, Arena R, Vicenzi M, Guazzi MD. Long-term use of sildenafil in the therapeutic management of heart failure. J Am Coll Cardiol 2007;50:2136–44.
Find This Resource
47. Lewis GD, Shah R, Shahzad K, et al. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation 2007;116:1555–62.
Find This Resource