ABC | Volume 113, Nº3, September 2019

Review Article Calderado et al. Pulmonary hypertension Arq Bras Cardiol. 2019; 113(3):419-428 Echocardiography allows for the assessment of pulmonary artery systolic pressure – according to the direct measure of the tricuspid regurgitation speed and the estimate of right atrial pressure – in addition to assessing the right and left ventricular functions. Besides the cavity dimension, specifically in relation to right ventricular assessment, several parameters are used, such as TAPSE – tricuspid annular plane systolic excursion, the area difference between RV diastolic and systolic areas, called right ventricular fractional area change (FAC), myocardial performance index (MPI), left ventricular ejection fraction (LVEF) as measured by two-dimensional (2D) and three-dimensional (3D) echocardiography, DTI‑derived tricuspid lateral annular systolic velocity (S'-wave) and longitudinal strain. 29 Prognosis Assessment In spite of all the advances of the last two decades, PAH remains a high-mortality disease (an approximate 25% mortality rate at 3 years, according to recent registries). 30 There are several markers associated with the prognosis of PAH which can be used in clinical practice for therapeutic follow-up of patients under specific therapy. 31 Based on the results of these prognostic markers, it is possible to decide on stabilisation of the medication or therapeutic escalation. Table 2 shows the values defined as better, intermediate or worse prognosis of each marker. 11 Recent researches have indicated the possibility of using noninvasive prognostic markers in follow-up assessments (BNP, 6-minute walk test and functional class), with a good survival prediction. 32 Treatment Pulmonary Arterial Hypertension (Group 1) After definition of the diagnosis, initiation of treatment can be considered. It should be highlighted that, in patients with PH associated with HIV infection, or in patients with systemic lupus erythematosus or mixed connective tissue disease, it is necessary to treat the underlying disease, which may be sufficient to treat PAH. 24 General measures for PH include: physical rehabilitation, avoiding excessive physical activity, psychosocial support, avoiding pregnancy, immunization against influenza and pneumococcal infection. Treatment with diuretics, O 2  therapy and digoxin are considered supportive therapy. Oral anticoagulant therapy may be considered in patients with IPAH, HPAH and anorexigen-induced PAH. 19 Calcium-channel blockers are recommended only in cases of PAH with a positive acute vasoreactivity test. This test is performed with nitric oxide (NO) inhalation (10-80 ppm) for 10 minutes, and is indicated in the cases of idiopathic, heritable or drug-induced PAH. 7 Epoprostenol, iloproste or adenosina can also be used. The test is deemed positive when, after the vasodilator infusion, the mPAP decreases to less than 40 mmHg, with a variation of at least 10 mmHg, in association with a maintained or increased cardiac output. This assessment allows for identification of the subpopulation with PAH (about 10%) whose main pathophysiological mechanism is pulmonary vasoconstriction, with a better medium- and long-term prognosis. 33 High doses of calcium‑channel blockers should only be used in this situation, because they worsen the prognosis of patients who do not respond to the test. Group 1 PAH-specific therapy arose from the decade of 1990 on. These medications target three pathophysiological pathways of the disease: the prostacyclin pathway, the nitric oxide pathway, and the endothelin pathway (Table 3). Endothelin Receptor Antagonists 1 (ambrisentan, bosentan and macitentan) and phosphodiesterase type 5 inhibitors (nitric oxide pathway – sildenafil and tadalafil) are more recurrent in Brazil, and are often used as monotherapy or in combination as first line in the treatment of pulmonary arterial hypertension. 15,34 Prostanoids were the first class of medication used in pulmonary arterial hypertension and, in addition to improving morbidity and exercise capacity, epoprostenol was the ony drug to show survival improvement in a clinical randomized trial. 35 This drug class should always be considered for patients with FC-IV symptoms. 35,36 In cases of progressive disease, or even in cases where prognostic stratification in the initial approach is already suggestive of high risk, the use of combined therapy should be considered. 36 Drugs that act in different pathways should be combined (Figure 2). 37 Once there are no more possibilities of clinical management of PAH, atrial septostomy or even lung transplantation should be considered. 11 Pulmonary hypertension due to left heart disease (Group 2) Pulmonary hipertension in patients with left-sided cardiomyopathy is the most frequent form of PH. It is difficult to establish its exact prevalence because most reports are based on echocardiographic findings, with no confirmation of diagnosis through catheterization. Pulmonary congestion, due to retrograde transmission of elevated filling pressures in the left heart, determines directly an increase in pulmonary artery blood pressure; what happens is that, in adittion to this passive mechanism, congestion is also associated with the activation of neuro-hormonal mechanisms and eventually with vascular remodelling. Thus, a pre-capillary component can arise, combined with the post-capillary component, characteristic of left heart disease. In this context, there might be rationale for the use of specific PAH medication; however, until now, there is no significant evidence of the benefits of such approach, as we shall see. Epoprostenol Twenty years ago, Califf et al. 38 carried out a study to assess the impact of epoprostenol in 471 patients with advanced heart failure (HF) (LVEF < 25%, NYHA functional class III or IV and optimized therapy for those times: ACE inhibitors/ diuretics/digitalis; many in need of inotropic support). 38 In spite of clear improvement of hemodynamic parameters with the use of epoprostenol (increased cardiac index, decreased pulmonary capillary pressure and reduced systemic and pulmonary vascular resistance), the study was precociously interrupted due to increased mortality within 6 months: 48% 422