In the cardiologist's routine, the echocardiographic finding of pulmonary hypertension (PH) is extremely common. PH on echocardiogram can be identified in up to 2.8% of the general population
The diagnosis of PH has major prognostic implications, both when it is attributable to cardiovascular diseases,
Traditionally, PH is defined through invasive hemodynamic monitoring, with a recent review of the value assumed as pathological. Since 1973, the diagnosis of PH was arbitrarily made when mean arterial pulmonary pressure (mPAP) was equal to or greater than 25 mmHg.
When, in the presence of this level of pulmonary pressure, the pulmonary artery occlusion pressure (PAOP) is equal to or less than 15 mmHg, circulatory impairment begins to occur in the pulmonary circulation, either due to pulmonary arterial hypertension (PAH), or to pulmonary thromboembolism or pulmonary parenchymal disease. If the PAOP is higher than 15 mmHg, the PH is considered postcapillary. In this case, increased pressure in the pulmonary arterial territory is due to retrograde transmission of increased left atrial hydrostatic pressure into the pulmonary veins and pulmonary capillaries and, ultimately, into the pulmonary arterial circulation. There are situations in which the PAOP is above 15 mmHg, but this fact does not seem suficient to justifify the severity of mPAP increase. These patients display a pulmonary vascular resistance greater than 3 Woods units and, usually, the diastolic pulmonary gradient is higher than 7 mmHg (GDP - the difference between the pulmonary artery diastolic pressure and the pulmonary capillary pressure).
This condition is called combined pre- and post-capillary PH. This hemodynamic profile can occur in patients with left heart disease and pulmonary vascular remodelling secondary to chronic congestion, but can also be seen in severely hypervolemic patients with PAH, and reverse Bernheim effect (when PH is so severe that results in the interventricular septum bulging toward the left ventricle, thus increasing the left ventricular pressure and, therefore, the PAOP).
Right heart catheterization is indispensable for the diagnosis of PH, with a morbidity of 1.1% and mortality of 0.055%, in experienced centers.
The current classification of PH takes into account data of clinical presentation, pathophysiology, anatomopathological findings and hemodynamic parameters,
| Group 1 | Pulmonary Arterial Hypertension |
| Group 2 | Pulmonary hypertension due to left heart disease |
| Group 3 | Pulmonary hypertension due to Pulmonary Disease and/or Hypoxia |
| Group 4 | Chronic thromboembolic pulmonary hypertension and other diseases of pulmonary artery obstruction |
| Group 5 | Pulmonary hypertension with unclear multifactorial mechanisms |
Patients with PAH. These are the patients with idiopathic PAH, heritable PAH, associated with HIV infection, connective tissue disease, portal hypertension, drugs or congenital heart diseases. Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) are also categorized as Group 1.
Patients with HP due to left heart disease: valvular disease, left ventricular diastolic or systolic dysfunction. These patients have hemodynamic patterns of post-capillary hypertension. In the cases where combined post-capillary PH with a pre-capillary component is observed, the prognosis is worse than that for patients with isolated post-capillary PH.
Patients with HP due to pulmonary disease and/or hypoxia. For instance: chronic obstructive pulmonary disease, interstitial lung disease, obstructive sleep apnea, high altitude exposure. The hemodynamic pattern is that of pre-capillary HP.
Patients with chronic thromboembolic pulmonary hypertension (CTEPH) or diseases of pulmonary artery obstruction such as arteritis, neoplasms, or congenital pulmonary artery stenosis, with hemodynamic pattern of pre-capillary PH.
Patients with HP and unclear multifactorial mechanisms, as in the cases of renal failure, sarcoidosis, myeloproliferative disorders and hemolytic anemia.
The diagnostic suspicion is based on unspecified symptoms (dyspnea to effort and/or syncope), not always accompanied by signs suggestive of PH or right ventricular dysfunction (hyperphonesis of the second heart sound, tricuspid systolic murmur, jugular stasis, hepatomegaly and lower limb edema). Considering these findings, the non-invasive test of choice to begin the investigation is the transthoracic echocardiography.
The interval between the symptom onset and the diagnosis of PH is about two years, which hinders early treatment.
The investigation should begin by searching for the most frequent causal factors: left heart disease, lung disease or pulmonary thromboembolism. Only after excluding these conditions, should the presence of PAH be considered, as proposed in the algorithm (
It can show prominence of the pulmonary artery trunk, as well as of the right (> 16 mm) and/or left (> 18 mm) branches, increased right chambers (bulging of the right mediastinal contour, boot shaped heart and filling of retrosternal space).
Traditionally, the electrocardiography shows signs of overload in the right chambers - axis shift to the right and P-wave pulmonale (p ≥ 2.5 mm in DII); as in the X-ray, the electrocardiographic changes are more evident in the stages when there is cardiac structure repercussion. In up to 13% of the cases, the EGC is normal.
Computed angiotomography of the chest plays an important role in the differential diagnosis of PH and its classification, helping to investigate diseases that affect the pulmonary parenchyma and chronic thromboembolism. It can also increase the suspicion of the diagnosis of pulmonary veno-occlusive disease. Computed tomography findings of increased pulmonary artery diameter, of secondary importance compared to echocardiography, are also suggestive of PH and, thus, can be used in indirect screening. This measurement of the pulmonary artery diameter exhibits quite high specificity for the presence of HP when the diameter is greater than 33.2 mm.
Ventilation/perfusion scintigraphy is essential for CTEPH screening due to its high sensitivity (96-97%), combined with a specificity of 90-95%, while chest CT angiography can have a sensitivity of up to 50%.
It is the best non-invasive screening method for PH, but it does not establish the definitive diagnosis, nor does it make a clear distinction between the different PH groups (
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).
| Prognostic marker/RisK | Low risk (Estimated |
Intermediate risk (Estimated mortality 5-10% year) | High risk (Estimated |
|---|---|---|---|
| Signs of heart failure | Absent | Absent | Present |
| Progression of symptoms | No | Slow | Rapid |
| Syncope | No | Occasional | Frequent |
| Functional class | I, II | III | IV |
| 6MWD | > 440 m | 165-440 m | < 165 m |
| Cardiopulmonary exercise testing | Peak VO2 > 15 ml/min/kg (> 65% pred.) |
Peak VO2 11-15 ml/min/kg (35-65% pred.) |
Peak VO2 < 11ml/min/kg (< 35% pred.) |
| BNP levels | BNP < 50 ng/L |
BNP 50-300 ng/L |
BNP > 300 ng/L |
| Imaging | RA area < 18 cm2 |
RA area 18-26 cm2 |
RA area > 26 cm2 |
| Hemodynamics | RAP < 8 mmHg |
RAP 8-14 mmHg |
RAP > 14 mmHg |
VO2: consumo de oxigênio; VCO2: liberação de dióxido de carbono; Slope VE/VCO2: equivalente respiratório para o dióxido de carbono; BNP: peptídeo natriurético cerebral; NT pro BNP: fragmento N-terminal do pró BNP; AD: átrio direito; In.C: índice cardíaco; SVO2: saturação venosa mista de oxigênio
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.
General measures for PH include: physical rehabilitation, avoiding excessive physical activity, psychosocial support, avoiding pregnancy, immunization against influenza and pneumococcal infection. Treatment with diuretics, O2therapy and digoxin are considered supportive therapy. Oral anticoagulant therapy may be considered in patients with IPAH, HPAH and anorexigen-induced PAH.
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.
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 (
| Pathophysiological pathways | Class | Drug |
|---|---|---|
| Endothelin | Endothelin Receptor Antagonists 1 | Ambrisentan |
| Bosentan | ||
| Macitentan | ||
| Nitric Oxide | Phosphodiesterase type5 inhibitors | Sildenafil |
| Tadalafil | ||
| Vardenafil | ||
| Soluble Guanylate Cyclase Stimulants | Riociguat | |
| Prostaglandins | Prostacyclin | Epoprostenol |
| Prostacycline Analogues | Iloprost | |
| Treprostinil | ||
| Beraprost | ||
| Selective IP receptor agonists | Selexipag |
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.
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.
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.
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.
Twenty years ago, Califf et al.
Blockade of ETA receptors in patients with group 2 PH can be useful not only for the well-known effects on pulmonary circulation, but also because of its potential direct benefits to the systemic circulation and myocardium. In 1998, Sütsch etal.
Another study, with bosentan, assessed the impact of the medication in high dosage (500 mg 2x/day) and for an extended period of time (26 weeks) in 370 patients with advanced HF, in FC III or IV and with LVEF < 35%. The primary outcome was clinical worsening. The study was interrupted precociously due to the high incidence of hepatotoxicity, so that less than half of the case reports had completed the 26 weeks of follow-up. This data is important since, in general, there was no difference between the bosentan and placebo groups, but for those patients who completed the 6 months of follow-up, the use of bosentan was associated with clinical improvement. We do not have the hemodynamic data of the mentioned study.
So far we have discussed studies that analysed patients with LV systolic dysfunction, and mostly, though not entirely, PH registries (not always by right heart catheterization). If on one hand there seems to be hemodynamic improvement in the early stage of endothelin receptor inhibitor therapy, on the other hand, there may be clinical decompensation, probably due to hydrosaline retention. In the medium-term, sustained usage can bring clinical benefits, as suggested in the latest study discussed above.
In 2007, Lewis et al.
Other small studies have also demonstrated hemodynamic benefits in patients with LV systolic dysfunction who received silnadefil, even after the first dose.
The impact of sildenafil when compared with placebo throughout 12 weeks was tested in patients with heart failure with preserved ejection fraction. In this multicenter study, 216 patients were randomized and there was no difference in the primary outcome (peak consumption of O2) or in the clinical Picture.
Finally, the subgroup of patients with valvular heart disease deserves special attention. Most patients with significant aortic valvular disease and almost all patients with symptomatic mitral insufficiency have PH. Even after correction of the valvular disease, some patients remain with PH and others who did not have PH before surgical treatment can develop the disease evolutionarily. Recently, the impact of sildenafil in patients with residual PH, after heart valve surgery, was assessed in a multicenter randomized study.
Thus, althought early data from small case reports performed in single-centers encourage the use of sildenafil in grupo 2 PH, there is no evidence supporting its routine recommendation.
Riociguat acts on the same pathway as phosphodiesterase type 5 inhibitors, directlty stimulating guanylate cyclase, in addition to having an established role in the management of patients with PH due to chronic pulmonary thromboembolism (group 4) and in pulmonary arterial hypertension. Its role in group 2 PH has been recently tested in the LEPHT study.
Thus, so far, there is no indication for the routine use of any of the specific medications for group 1 PH in individuals with group 2 PH. In selected cases, when, after optimization of cardiomyopathy, with special attention to volemia, PH remains with pre-capillary component apparent on cardiac catheterization, the decision upon the use of specific medication should be individualized, in a reference center, preferably, in the context of clinical study to deliver more evidence.
It is considered the second most common cause of PH and the pulmonary diseases most commonly associated with PH are: chronic obstructive pulmonary disease (COPD), interstitial pulmonary disease and combined pulmonary fibrosis and emphysema.
Although there is high prevalence of increased pulmonary artery pressure in patients with chronic pulmonary diseases, only a small minority of these patients present with severe PH, characterized by mPAP > 35 mmHg. In some patients with pulmonary disease and HP, especially in patients with mild pulmonary disease, but with severe PH, it may be difficult to determine whether PH is caused by pulmonary disease or related to concomitant pulmonary vascular disease.
CTEPH is the main disease of group 4, and is characterized by chronic obstruction of pulmonary artery and vascular remodelling due to pulmonary thromboembolism. It is the only potentially curable form of PH, once effective pulmonary thromboendarterectomy is perfomed. For this reason, it is always necessary to investigate chronic pulmonary thromboembolism in patients with PH, and refer the diagnosed cases to a reference center.
Group 5 includes several diseases which may behave similarly to other groups, but whose mechanisms associated with the development of PH are not clear yet. Thus, treatment is heterogeneous and essentially focused on the underlying disease.