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lesions ( see figure 3 ); these are
characterised by proliferation of myofibroblasts , smooth muscle cells and undifferentiated mesenchymal cells . 11 Within these abnormal vessels , endothelial dysfunction , reduced nitric oxide production , increased ET-1 production , smooth muscle proliferation / hypertrophy , thrombotic lesions and perivascular inflammation have been described in some or all of the five groups of PH . 12-16 The role of inflammation in PH pathogenesis is becoming increasingly recognised and may represent another target for future therapeutics . 17
In Groups 1 , 3 and 4 PH , the pre-capillary pulmonary arterial vasculature is affected , known as pre-capillary PH . In Group 2 PH , the post-capillary / venous vasculature is initially affected , known as isolated post-capillary PH . As Group 2 PH progresses , the pre-capillary vasculature may become affected , known as combined pre- and post-capillary PH . This anatomical localisation of disease is achieved by performing a right heart catheterisation ( RHC ), discussed later .
The final common pathway is irreversible pulmonary vascular remodelling and luminal narrowing , which leads to a reduced pulmonary vascular compliance , increased pulmonary vascular resistance ( PVR ) and therefore increased RV afterload . Compensatory RV remodelling ensues , which may become maladaptive and lead to eccentric hypertrophy , dilatation and myocardial fibrosis . RV failure will eventually develop , and , if untreated , 17 , 18 can lead to death .
HISTORY AND EXAMINATION
THE symptoms of PH are non-specific
and typically occur with exertion / exercise early in the course of the disease . 3 , 17 Common early symptoms include exertional dyspnoea and / or fatigue . Dyspnoea is categorised into WHO-functional classes that range from I ( minimal dyspnoea ) to IV ( dyspnoea at rest ) and is essentially the same as the New York Heart Association ( NYHA ) classification ( see table 1 ).
With advanced disease , symptoms may occur on minimal exertion or at rest . 18 Palpitations , cough , haemoptysis , dysphonia from compression of the left recurrent laryngeal nerve , bendopnoea ( dyspnoea experienced during the first 30 seconds after bending forward ) and angina from compression of the left main coronary artery have also been reported . 3 Reg flag symptoms appear in box 4 . History taking can also be helpful to identify the cause of the PH . For example , a history of joint pain , Raynaud ’ s phenomenon , dysphagia and skin thickening should raise suspicion of systemic sclerosis ( SSc , see figure 4 ) and therefore connective tissue disease-related PAH . Other connective tissue disorders associated with PAH are SLE , mixed connective tissue disease and , less commonly , dermatomyositis and Sjogren ’ s syndrome . 3 A history of obesity , snoring , witnessed apnoeas and daytime somnolence suggests sleep disordered breathing , which is associated with Group 3 PH .
About 6-10 % of patients with PAH have an inheritable form of the disease (‘ heritable PAH ’, HPAH or ‘ familial PAH ’); asking about a family history of the condition may be warranted . 3 Given the associations with medications and illicit drugs , obtain a full drug and social history , including recreational drug use .
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Figure 1 . Pulmonary hypertension .
Box 1 . Classification of pulmonary hypertension
• Group 1 pulmonary hypertension ( PH ) — pulmonary arterial hypertension .
• Group 2 PH — left heart disease .
• Group 3 PH — lung disease .
• Group 4 PH — chronic thromboembolic pulmonary hypertension .
• Group 5 PH — unclear or multifactorial mechanisms .
Box 2 . ESC / ERS guidelines — a three-step approach
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• Step 1 — Suspicion of pulmonary hypertension ( PH ) by GP .
• Step 2 — Detection of PH by echocardiogram .
• Step 3 — Confirmation by right heart catheter in specialist PH centre .
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Examination for signs of connective tissue disease , lung disease or heart disease is important when a patient has breathlessness that might be from raised pulmonary pressure . Cardiac findings such as a loud pulmonary component of the second heart sound ( P 2
) and a parasternal heave are associated with the presence of severe PH ( mean pulmonary artery pressure greater than 45mmHg ) and represent advanced disease . Abdominal signs of right heart failure include distension , ascites and hepatomegaly that may be pulsatile from severe tricuspid regurgitation . Unfortunately , no combination of signs
3 , 19 , 20 can be used to reliably exclude PH .
Box 5 lists the situations where one should suspect PH .
DIAGNOSIS AND INVESTIGATIONS
THE gold standard test to diagnose PH
is RHC . However , there are other more accessible investigations that GPs can arrange that significantly contribute to the workup of a suspected case of PH . These include a 12-lead ECG , blood
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Box 3 . Classification of pulmonary hypertension
• Group 1 — pulmonary arterial hypertension ( PAH ): — 10-25 cases per one million adults and female : male preponderance
17 , 18
of 3-4:1 . — Idiopathic PAH . — Connective tissue-related PAH — especially systemic sclerosis
( scleroderma , systemic sclerosis ). — Drug- or toxin-associated PAH — eg , methamphetamine . — Portopulmonary PAH . — HIV-associated PAH . — Adult congenital heart disease . — Schistosomiasis-related PAH .
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• Group 2 — left heart disease — The leading cause of pulmonary hypertension ( PH ) worldwide , accounting for 65-80 % of all PH cases . 3 — Heart failure with reduced ejection fraction ( systolic dysfunction ). — Heart failure with preserved ejection fraction ( diastolic dysfunction ). — Valvular heart disease . |
• Group 3 — lung disease : — Severe PH is uncommon , affecting only 1-5 % of those with COPD and less than 10 % of those with interstitial lung disease ( ILD ). 3 — COPD . — ILD . — Chronic alveolar hypoventilation . — Sleep disordered breathing |
• Group 4 — chronic thromboembolic pulmonary hypertension ( CTEPH ): — Three per cent of patients post-pulmonary embolism ( PE ). 33 — However , 25-50 % of patients diagnosed with CTEPH have no documented history of acute PE . 34 — 3.2-50 cases per million inhabitants . 34 — Approximately 10 % of those with CTEPH have antiphospholipid syndrome . 3 |
• Group 5 — unclear or multifactorial mechanisms : — Sarcoidosis . — Pulmonary Langerhans cell histiocytosis . — Neurofibromatosis type 1 . — Haemoglobinopathies . — Chronic haemolytic anaemias . — Chronic myeloproliferative neoplasms .
Adapted from European Society of Cardiology / European Respiratory Society 2022 guidelines 3
tests and transthoracic echocardiogram ( TTE ).
Transthoracic echocardiogram
As a GP , arranging a TTE for a
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patient who you suspect has PH is the single most useful investigation . TTE allows estimation of pulmonary artery pressure and simultaneous cardiac assessment of systolic , diastolic and valvular function , which is |
Box 4 . Red flag symptoms in pulmonary hypertension
• Exertional chest pain .
• Exertional pre-syncope .
• Syncope .
Source : Humbert M et al 2022 3 , Le Rachel J et al 2010 . 35
Box 5 . When to suspect pulmonary hypertension
• Given the non-specific symptoms and absence of clinical signs during the earlier stages of pulmonary hypertension ( PH ), timely diagnosis relies on GPs having a high index of suspicion , especially in at-risk groups , which include : — Young women with unexplained respiratory and / or cardiac symptoms — Group 1 PH ( specifically idiopathic pulmonary arterial hypertension ).
— Patients with connective tissue disease , particularly systemic sclerosis — Group 1 PH .
— Older patients ( over 65 years ) with metabolic syndrome , AF and / or heart failure with preserved ejection fraction — Group 2 PH .
— In patients where symptoms cannot be reasonably explained by the severity of their underlying lung disease and / or sleep disordered breathing — Group 3 PH .
— Patients with previous pulmonary embolism who have ongoing symptoms despite 3-6 months of treatment dose anticoagulation — Group 4 PH .
Source : Humbert M et al 2022 3
important in the diagnosis of Group 2 PH .
There are two key echocardiographic findings that should trigger further investigation if PH is suspected ( see box 6 ).
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