The keys to diagnosis are a detailed history and thorough clinical examination of the patient. The affected person should be transferred to a specialist centre for clarification. Only those patients in whom the risk of developing PH is substantially raised should undergo screening. This includes patients with a known BMPR II mutation, scleroderma and patients with portal hypertension who are being assessed for a liver transplant.
International specialist associations differentiate between 4 diagnostic steps: suspicion, detection, categorisation in the Dana Point classification system, evaluation of the severity. Functional classification is undertaken on the basis of NYHA Classes I-IV (Table 2). Patients in NYHA classes I or II at the time of diagnosis have a mean survival of 6 years in comparison with a mean survival of 2.5 years and 6 months respectively in NYHA classes III and IV where the disease is already at an advanced stage. Another option for assessing severity is provided by the 6-minute walk test (6-minute walk distance, 6MWD), in which the distance covered by a patient in 6 minutes is measured. The 6MWD has good prognostic value and is therefore used as a primary endpoint in many studies. It also constitutes a good parameter for progress during treatment. The maximum oxygen uptake (peak VO2) measured during a bicycle ergometer test is also an independent predictor of mortality .
Symptoms usually develop gradually and only manifest at a loss of more than 60% of pulmonary vasculature. Although dyspnoea (particularly breathlessness caused by activity) is a common early symptom, it is not a cardinal symptom. Fatigue, reduced performance, chest pain, recurring syncope on activity and after attacks of coughing, haemoptysis (which may occur with all forms of pulmonary hypertension) and dizziness are other symptoms.
Tachycardia and left parasternal or epigastric heaves of the right ventricle are observed. The second heart sound is emphasised and a pansystolic heart murmur can be heard, suggesting tricuspid insufficiency. Pulmonary insufficiency can occasionally be heard on auscultation. In the advanced stage, oedema of the legs, ascites, distention of the veins of the neck, hepatomegaly and cyanosis are also present as signs of right heart decompensation. Findings from auscultation of the lungs are usually normal.
Blood gas analysis is normal in the early stages, later pO2 is reduced, pCO2 increased, later reduced and HCO3 increased. The red blood count in advanced stages of PH secondary to congenital heart disease or hypoxaemia presents polycythaemia and haematocrit > 50%. In cases of iPAH, both atrial natriuretic peptide (ANP) and “brain natriuretic peptide” (BNP) correlate with survival, and BNP and NT-BNP are independent predictors of mortality . Increased uric acid (resulting from compromised oxidative metabolism) and increased troponin T levels (resulting from right ventricular ischaemia) correlate with a poor prognosis  . At present, proBNP levels are the most commonly used biomarkers. They correlate with enlargement, compressive stress and reduced function of the right ventricle.
ECG has specificity of 70% and sensitivity of 55% in the diagnosis of PH . The ECG signs of right ventricular dysfunction are right bundle branch block, rotation of the electrical cardiac axis to the right, right heart hypertrophy (R>S in V1), right ventricular repolarisation dysfunction (“right ventricular strain” RVS) and a “P pulmonale” indicating an enlarged right atrium (Figure 1) .
New algorithm with ECG and NT-proBNP
In the event of clinical and echocardiographic suspicion of PAH, the ECG is first checked for the presence of T wave inversions/ ST segment depressions in the chest leads (V2–V4) (“right ventricular strain pattern” – RVS). If RVS is found, the patient should always be referred for RHC. If RVS is not present, the serum concentration of NT-proBNP decides whether RHC should be performed. PAH can be ruled out with a probability verging on certainty in patients with no RVS and NT-proBNP levels ≤ 80 pg/ml. RHC is therefore not required. Thus, by using an electrocardiogram and serum values of n-terminal natriuretic peptide, 90% of all exclusion catheterisations can be avoided without overlooking a single case of genuine pulmonary arterial hypertension .
Typical findings involve abrupt changes in diameter in pulmonary blood vessels with dilated central pulmonary arteries and a loss of peripheral blood vessels. Enlargement of the right atrium and/or ventricle can also be seen. A normal chest x-ray does not rule out PH.
TRANSTHORACIC ECHOCARDIOGRAPHY (TTE)
The importance of echocardiography as a screening method in cases of clinical suspicion of PAH is undisputed. However, it is not possible to use it to distinguish between pre- and post-capillary pulmonary hypertension. A further limitation is the fact that the pressure in the small circulation system estimated using echocardiography is under- or overestimated by over 20% in more than 50% of cases. If the systolic pulmonary pressure estimated with echocardiography is between 37 and 50 mmHg, PAH is a possibility and the European guidelines currently in force provide for a Class IIa indication for carrying out right heart catheterisation (RHC). If the systolic pulmonary pressure in the echocardiogram is more than 50 mmHg, PAH is likely and RHC should always be performed (Class I indication).
Parameters for assessment of the pulmonary circulation are: systolic pulmonary arterial pressure, right heart dimensions, right ventricular function, right ventricular mass and tricuspid regurgitation. Prognostic parameters that can be ascertained using echocardiography are pericardial effusion, the size of the right atrium and the size ratio between right and left end-diastolic diameter. TAPSE (Tricuspid Annular Plane Systolic Excursion) can also be used to draw conclusions about mean survival. A TAPSE <1.8cm is linked to greater right ventricular systolic dysfunction. In addition, TTE allows the diagnosis of a potential underlying cause (e.g. shunt defect, valvular or myocardial disease).
VENTILATION/PERFUSION SCINTIGRAPHY OF THE LUNG (V/Q SCAN)
The V/Q scan is important for the diagnosis of CTEPH. A segmentally positive V/Q scan is diagnostic for CTEPH if at least one major defect is present .
A spiral CT investigation with intravenously administered contrast medium is an informative option for diagnosis. CT is particularly suitable for assessment of the lung parenchyma and the vessels around the heart.
For patients with CTEPH, surgical thrombendarterectomy is a possible cure. Pulmonary angiography is a valuable method for planning the operation. It provides accurate information about the location of intraluminal filling defects, stenosis and occlusions.
RIGHT HEART CATHETER AND HAEMODYNAMIC TESTING
A diagnosis of PH can only be made with a positive right heart catheterisation finding. Measurement of the pulmonary vascular resistance (PVR), cardiac index (CI) and mean right atrial pressure (mRAP) allows statements to be made regarding the severity and hence the prognosis for the patient. On the basis of current data, the CI, mRAP and mPAP parameters are independent predictors of survival, although it must be borne in mind that mPAP also falls with decreased right ventricular function.
A complete right heart catheter examination should include measurement of the pulmonary capillary wedge pressure (PCWP) using a balloon catheter in various sections of the pulmonary vascular system. This permits differentiation between pre- and post-capillary PH. If optimal measurement of the PCWP is not possible or is in doubt, left ventricular end-diastolic pressure (LVEDP) may also be determined. A primary measurement of LVEDP is also recommended in patients in whom there is a high probability of a left ventricular cause of the symptoms (e.g. orthopnoea).
A test of pulmonary vasoreactivity is recommended in principle for all patients with documented pulmonary hypertension. The acute response to vasodilators correlates well with the underlying vascular morphology and thus constitutes a good prognostic parameter. Those patients in whom the mean pulmonary arterial pressure (mPAP) drops by at least 10 mmHg below an absolute value of 40 mmHg are described as responders. Cardiac output should increase or at least remain unchanged at the same time. The vasoreactivity test should only be performed using substances with a short half-life. Test substances recommended by the European Society of Cardiology (ESC) are epoprostenol, adenosine and nitric oxide (NO). Approximately 10% of all adults with idiopathic PAH are haemodynamic responders. High-dose calcium channel blocker therapy is indicated for these patients. Genuine responders have an excellent prognosis with a 5-year survival rate of almost 95% .
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