Effects of Treprostinil on Right Ventricular Structure and Function in Patients With Pulmonary Arterial Hypertension

Effects of Treprostinil on Right Ventricular Structure and Function in Patients With Pulmonary Arterial Hypertension

In a group of patients with PAH treated with treprostinil, the current study aims to investigate the effect of treatment on RV structure and function; and correlate changes in RV structure and function with: World Health Organisation (WHO) class, Six-minute walk test, Quality of life (QoL), and Pre-specified biomarkers (N-terminal B-type natriuretic peptide (NT-ProBNP), Tissue growth factor-B B-type natriuretic peptide BNP, and Profibrotic markers)

A) Right ventricle (RV) in pulmonary hypertension

RV failure is the main cause of death in patients with pulmonary arterial hypertension (PAH), and the ability of the RV to adapt to the progressive increase in pulmonary vascular resistance associated with changes to the pulmonary vasculature in PAH is the main determinant of a patient's functional capacity and survival.

The response of the right ventricle (RV) to the increase in afterload produced by the pulmonary vascular changes characteristic of PAH is the key factor in the development of symptoms and in determining survival. Structurally, rising systolic and diastolic ventricular pressures increase diastolic and systolic stretch on the RV wall, which leads initially to an increase in muscle mass (adaptive hypertrophy) due to increased protein synthesis and an increase in cardiomyocyte size through the addition of sarcomeres. However, the RV cannot maintain adaptive hypertrophy in the face of sustained pressure overload, and eventually there is a transition to dilatation. At this stage there is no further increase, or even a decrease, in RV contractility, despite a further increase in load. One consequence of RV dilatation is an increase in wall tension, which increases myocardial oxygen demand and simultaneously decreases RV perfusion, leading to further compromised contractility and dilatation.

The exact mechanisms leading to the development of RV failure in patients with PAH are still unclear. Several mechanisms have been hypothesized: RV myocardial ischaemia, microvascular endothelial cell dysfunction, and myocyte apoptosis. In severe end-stage PAH, the RV changes its shape from the normal conformation to a more spherical one, and RV wall stress increases because RV wall thickness does not increase proportionally.

Given the importance of the RV in PAH, preservation and improvement of its function should be important aspects of therapy; however, there are currently few data specifically related to this aspect of treatment response.

B) Vasodilator therapy and RV in pulmonary hypertension Although RV failure is the main cause of death in patients with pulmonary arterial hypertension (PAH), there is insufficient data about the effects of PAH treatment on RV geometry and function mainly because the RV assessment has been hampered by its complex crescentic shape, large infundibulum, and its trabecular nature. . This is specifically true for vasodilator therapies. Such therapies may affect the RV via direct cardiac-specific effects or indirect effects by reducing RV load. In a meta-analysis of clinical studies of PAH-specific therapies, active treatment was associated with a reduction in pulmonary vascular resistance which was accompanied by a decrease in pulmonary artery pressure, and an increase in stroke volume, but without an increase in contractility, suggesting that current PAH therapies have predominantly pulmonary vasodilating effects and have limited cardiac-specific effects. In a study of epoprostenol therapy, beneficial effects on RV structure and function (RV dilatation, curvature of the interventricular septum and maximal tricuspid regurgitant jet velocity) compared with placebo were reported following 12 weeks of treatment, with change in 6-min walk distance between baseline and 12 weeks being inversely related to the change in diastolic eccentricity index and pericardial effusion size. Such improvements may contribute to the clinical improvement and prolonged survival observed with epoprostenol in other studies.

Other evidence of improvements in RV parameters has come from descriptive studies using a number of PAH-specific therapies; however, these generally include a small number of patients, and this, together with the fact that such studies evaluated different parameters (both in terms of functional parameters and measures of RV size/mass), makes the assessment of results difficult. longer term studies of epoprostenol have not shown a positive treatment effect on RV size/mass although without a comparator arm it is not possible to determine whether long-term therapy slowed down the rate of RV hypertrophy or dilatation.

Overall, therefore, the effects of PAH-specific therapies on RV function remain to be fully investigated.

C) Treprostinil Treprostinil is a tricyclic benzindene analogue of prostacyclin, and has as such similar anti-platelet and vasodilatory actions, including acute pulmonary vasodilation.

Treprostinil, a stable prostacyclin analog, has similar pharmacologic effects to epoprostenol, However, in contrast to epoprostenol, treprostinil is chemically stable at room temperature and neutral 'power of hydrogen' (pH) and has a longer half-life (elimination half-life of 4.5 h with distribution half-life of 40 min, compared with 2 to 3 min for epoprostenol) permitting continuous subcutaneous infusion (16). Treprostinil has been shown in a large multicenter randomized controlled trial to improve exercise capacity, clinical state, functional class, pulmonary hemodynamics, and quality of life in patients with pulmonary arterial hypertension.

D) Assessment of RV with cardiac magnetic resonance imaging Currently, the most widely used noninvasive techniques are echocardiography and cardiac magnetic resonance imaging), and a number of potential indicators assessed using these methods have been proposed. Cardiac magnetic resonance imaging provides a higher spatial resolution, and is not limited by factors affecting echocardiography (e.g. acoustic window). Cardiac magnetic resonance imaging allows for the visualisation and measurement of complex three-dimensional geometry and it is therefore particularly suited to the complex morphology of the RV. Precise, noninvasive assessment of cardiac volumes and function is possible, without the need for geometric approximations, while assessments such as flow measurements in the heart and great vessels using techniques such as cine phase-contrast provide more comprehensive data on cardiac function than echocardiography.

• Inclusion Criteria:

  • PAH defined as a mean pulmonary artery pressure >25 mmHg on right heart catheterization at rest in the setting of a normal pulmonary arterial wedge pressure ≤15 mm Hg
  • PAH that is idiopathic, familial, or associated with connective tissue disease.
  • WHO class III or class IV despite the use of Endothelin receptor antagonists (ERA) and/or phosphodiesterase-5 inhibitors
  • Age > 18 years
  • Sinus rhythm

• Exclusion Criteria:

  • Patients with PAH associated with HIV infection, portal hypertension, congenital heart disease, schistosomiasis, chronic haemolytic anaemia
  • Patients with pulmonary hypertension due to veno-occlusive disease and/or pulmonarycapillary haemangiomatosis, thromboembolism.
  • Patients with left side heart disease that may contribute to pulmonary hypertension. Those patients are identified by having pulmonary wedge pressure >15 mmHg or elevated Left Ventricle (LV) end-diastolic pressure
  • Patients who are severely disabled and will not be able to complete the study
  • Patients with significant lung disease as shown by forced vital capacity (FVC) < 70% predicted, or forced expiratory volume at one second (FEV1)/FVC < 50% - Life expectancy <1 year due to severe PAH or any other forms of terminal disease.
  • Pregnant women
  • Refusal to give informed consent.