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Bay Four

          Patterns, pearls and practical medicine

Pulmonary hypertension

  • Defined by mean PAP (pulmonary artery pressure) > 20mmHg on right heart catheter
      • Subdivided into post and pre-capillary depending upon PA wedge pressure
      • PAP on an echo is the systolic PAP not the mean pressure – so not used to diagnose
      • Little evidence for treatment if mean PAP 20-25 mmHg
  • Types
      • Group 1 – Lung artery problem (50 cases/million)
          • Idiopathic pulmonary arterial hypertension
          • CTDs – Vasculitides, scleroderma (12% get PH), collagen disorders
          • Large VSD / congenital HD
          • Portal HTN
          • HIV
          • Inherited (especially BMPR2 gene variants)
          • Schistosomiasis
          • Drugs (amphetamines, Desatinib – used in AML)
          • Pulmonary veno-occlusive disease PVOD/pulmonary capillary haemangiomatosis
      • Group 2 – Back pressure problem (very common)
          • Left heart disease
          • MV disease
          • Cardiomyopathy
      • Group 3 – Hypoxic vasoconstriction (quite common)
          • COPD, asthma, OSA, ILD
      • Group 4 – Chronic thromboembolic pulmonary hypertension (CTEPH, rare)
      • Group 5 – Multifactorial / associated with rare disease (rare)
  • Type 1 PH (PAH) is often misdiagnosed. Average diagnostic delay 18 months
  • The rarer, directly treatable forms of PH are PAH (Group 1) and CTEPH (Group 4). Important to pick these up (but types 2 and 3 are probably 200 times more prevalent)
  • Refer to PH centre if high risk of treatable cause, or rapidly progressing symptoms (7 Pulmonary HTN specialist centres in UK. 3 in London: Royal Free, Hammersmith, Royal Brompton)
  • Treatment options include digoxin, diuretics, anticoagulation, pulmonary rehab and pulmonary vasodilators like sildenafil and other targeted therapies depending on the cause

Assessment

  • Symptoms
      • SOB, chest pain, fatigue, syncope, oedema (although might not be marked in younger patients), exertional dizziness, hoarse voice (dilated PA can compress recurrent laryngeal nerve), early satiety (fluid in gastric mucosa).
      • All come late and only when cardiac output starts to drop
      • Patients can be misdiagnosed as asthmatic due to the SOB (but SOB in PH not so episodic, no diurnal variation, and is progressive and persistent)
  • Signs
      • Elevated JVP, oedema, TR, loud P2
      • Often not hypoxic, and chest can be clear
      • Patients often look fine and only get symptoms on exertion
  • Assess for symptoms of rapid progression
      • Very reduced exercise tolerance, syncope/presyncope, right heart failure
      • If patient with PH acutely hypotensive – inotropes early and slow down AF
  • Assess for risk factors
      • Systemic sclerosis (and other CTDs – though 75% of CTD associated PH is associated with SS, and 20% of patients with systemic sclerosis get PH)
      • Portal HTN / schistosomiasis
      • HIV (5% of HIV get PH)
      • Family hx of PAH
      • Amphetamine use
      • CV risk factors (for left heart disease)
      • Respiratory disease
      • For CTEPH – previous PEs, intravascular devices, IBD, thrombocythemia, splenectomy, high dose thyroxine, cancer

Investigations

  • BNP can be normal, however useful prognostically, and if very high, consider left heart disease
  • Troponin may be elevated
  • CxR features – large pulmonary arteries, cardiomegaly, peripheral oligaemia
  • ECG features
      • Right Axis Deviation (RAD)
      • Delayed transition zone
      • Dominant R wave V1 and S wave in V5/6 (both >7mm)
      • Signs of RV strain (inverted T wave and/or ST depression inferior and V1-V3) or RA enlargement (however this is not a good screening tool)
  • If suspected lung disease
      • Consider chest CT, pulmonary function tests, ABG and exercise tests
      • FEV1<60% of predicted in COPD or FVC <70% in ILD is suggestive of type 3 PH. If numbers are better, consider type 1 PH as a cause (exercise testing can also be a useful way to tell these apart).
      • If significant reduction in gas exchange this also implies lung disease as a cause of PH.
      • CT indicated if suspected ILD (but type 1 PH can have some ground glass due to neovascularisation – puff of smoke / cotton wool balls) and also for CTEPH.
      • If PA is larger in diameter than adjacent aorta at point at which it bifurcates – this suggests PH, but can’t diagnose it. Get an echo
  • Echo
      • Gives probability of pulmonary hypertension being present and cannot be used alone to diagnose
      • Can offer clues to aetiology (especially due to left heart disease in cases of left ventricular systolic dysfunction, severe left-sided valvular heart disease, or isolated left atrial dilatation implying diastolic dysfunction).
      • PA pressure and RV are usually the same. If RV pressure high, then more of a difference compared to RA pressure, and velocity of TR jet is elevated
      • Features of PH on echo
          • RV dilatation (RV:LV basal diameter ratio >1)
          • Flattening of intraventricular septum (or bowed towards the left)
          • Enlarged PA (>25mm)
          • Dilated IVC (>21mm) with decreased inspiratory collapse
          • RA enlarged (>18cm2)
          • Reduced LV function
          • RV outflow doppler acceleration time < 105 msecs
          • Reduced coronary perfusion
          • High peak tricuspid regurgitation velocity (ie >3, >3.4 gives high likelihood of PH)
      • High probability of PAP > 35 by right heart catheter if on echo there is: RVSP > 64, RA area > 25, ratio of RV to LV diameter > 1 on short axis, and other factors.
      • Composite scores can predict severe PH with sensitivity of 87% (specificity 70%)
      • We no longer rely on the RVSP on the echo (which is very error prone) but on the TR velocity (if >2.9, with other echo PH signs, or >3.4 without, means high probability of PH. Low probability is TR velocity <2.8 and no other signs)
      • If LA dilated, and patient in SR, the cause must be high left atrial pressure ie left heart disease. If in AF, that can cause LA enlargement on its own, rather than left heart disease, so can’t be relied upon diagnostically
  • VQ scan
      • Useful if concerned about previous thromboembolic disease and no history of heart/lung problems.
      • Better than CTPA if the emboli are subsegmental or more distal
      • If negative and other tests point to PH, then could be type 1
  • Right heart catheter
      • Only way to confirm PH (mean PAP >20mmHg)
      • Helps define where the pathology is
          • If pulmonary capillary wedge pressure is >15mmHg (post capillary PH), then you have high LA pressure, and it’s likely that you have either left heart disease or pulmonary venous HTN, you do not have type 1 PH
          • If PCWP < 15mmHg (pre-capillary PH), patient either has type 1 PH, PH due to lung disease or CTEPH
      • Nitric oxide challenge can be given during procedure if suspected idiopathic PH
          • A positive result (10% of type 1 PH) is mean PAP drops by 10mmHg to an absolute value of <40mmHg without a drop in cardiac output.
          • These patients don’t respond well to usual therapies but respond very well to CCBs and can have a normal life expectancy
  • Consider
      • Cardiac MRI
      • USS liver
      • Sleep studies
  • In systemic sclerosis of > 3 years duration – screen annually. Use the Detect algorithm (requires FVC, transfer factor, anticentromere antibodies, BNP, uric acid, ECG, hx of telangiectasia)

Group 1 Pulmonary Hypertension (PAH)

  • Pre-capillary (PAWP < 15mm)
  • Increased pulmonary vascular resistance (> 3 wood units)
  • Absence of significant lung disease, PEs, rare diseases
  • Similar pathological change for all causes
  • Median age of diagnosis 60, more often women, more often overweight
  • Can be associated with Raynaud’s
  • Causes right heart failure
  • Cardiovascular and respiratory comorbidities are common and further complicate diagnosis and treatment options in PAH
  • Around 15% inherited (eg BMPR2 variants)
  • Subtypes of PAH
      • The classic phenotype of young, predominantly female patients without comorbidity accounts for a minority (around 12%) of patients. Best prognosis.
      • The majority of patients (around 52%) are in the cardiopulmonary cluster, mostly consisting of elderly men with CV risk factors and a significant smoking history. Often hypoxaemic with a low transfer factor. Worst prognosis.
      • The remaining 36% of patients are left heart phenotype – predominantly elderly women with risk factors for HFpEF, just under one-third have a history of AF
  • Pulmonary vaso-occlusive disease (PVOD) 
      • Rare subtype, poor prognosis and responds poorly to pulmonary vasodilators
      • Typical imaging findings – mediastinal lymph nodes, interlobular septal thickening
      • Can be familial or associated with mitomycin chemotherapy
  • For patients with PAH without significant comorbidity, initial combination therapy with PDE5i and endothelin receptor antagonist is the standard of care.
  • If the patient is high risk at presentation intravenous prostanoid (epoprostenol) also considered.
  • Treatments
      • Endothelin receptor antagonists (Bosentan, Ambrisentan, Macitentan, all oral)
          • Can cause hypotension, anaemia, headaches, sinusitis, GI disturbance, muscle cramps, fluid retention, abnormal LFTs
          • Interact with warfarin, statins, cyclosporin, antifungals
          • Contraindicated if significant liver disease, pregnancy/breastfeeding
      • Phosphodiesterase inhibitors PDE5i (sildenafil, Tadalafil)
          • Can cause hypotension, headaches, GI disturbance, muscle cramps, optic neuropathy, sinusitis
          • Interact with nitrates (avoid GTN), alpha blockers, antifungals, cyclosporin
      • Soluble GC activators (Riociguat)
      • Prostanoids (Epoprostenol, Iloprost, trepostinil) and IP receptor antagonists (selexipag)
          • Again cause hypotension, headaches, sinusitis, cramps. Also jaw pain, flushing.
          • Contraindicated in bleeding disorders, severe liver disease
          • Addition of the oral prostacyclin receptor agonist selexipag is recommended in patients with an intermediate-low risk profile after initial PH therapy. Patients in the intermediate-high or high risk categories should be considered for intravenous prostanoid and/or lung transplantation
      • Sotatercept, an activin receptor type IIA-Fc fusion protein, is a potential therapy of promise in PAH. Given by s/c every 3 weeks
      • Consider anticoagulation
      • Consider LTOT
      • Structured exercise programme
  • Outlook is poor
      • 3-year survival around 60% (better if congenital HD associated, worse if CTD associated).
      • Treating early is best
      • Survival prediction score 
  • Giving these treatments to people with left heart disease can precipitate pulmonary oedema (as happened in the trials), that’s why getting the diagnosis right is key
  • Counsel regarding pregnancy (very high risk)

Group 4 Pulmonary Hypertension (chronic thromboembolic – CTEPH)

  • Need to have been anticoagulated for 3 months before you can diagnose
  • If ongoing SOB after 3 months of anticoagulation an acute PE, plus mismatched perfusion defects, refer to a PH centre after considering the results of an echo
  • About 3% of patients post PE will develop it by 2 years
  • 45% have no known history of PE
  • However symptoms post PE are common (deconditioned, comorbidities, persistent thrombi), but only 20 cases per million in UK diagnosed with type 4 PHTN.
  • Due to failure to lyse the clot, obstructive PA remodelling, organisation of thrombus, development of occlusions of pulmonary vasculature
  • This is not due to failure of anticoagulation – no need to consider changing anticoagulation if no new thrombus present
  • Risk factors – some procoagulant states (eg APLS, elevated factor 8), history of cancer, splenectomy (especially), ventriculoatrial shunt, infected PPM, chronic inflammatory conditions, hypothyroidism, large PE on CTPA, IBD
  • CTPA
      • Review previous CTPA of index PE – any evidence of acute on chronic changes?
      • Look for thrombus remaining / extrinsic thrombus (lining vessel wall)
      • Webs – thrombus partially lysed but remnants of clot across vessel wall (turn down gain so that the thrombus is not too bright in order to see them)
      • Look for mosaic attenuation due to peripheral pulmonary emboli – differential is COPD, but this has plenty of pulmonary vessels in the hypoattenuated regions unlike PH)
      • Dilated PA
  • VQ scan – useful for all CTEPH patients (can pick up problems not on CTPA)
  • Do an echo, ECG and spirometry
      • The echo is a first line test for CTEPH
      • PAWP < 15
      • If PAP < 25, diagnosis is Chronic Thromboembolic Disease – which is slightly different
  • Patients with CTEPH should be tested for antiphospholipid syndrome and, if found, treated with warfarin
  • Treatment
      • Medical, percutaneous, and surgical treatment options are now available for CTEPH.
      • Lifelong anticoagulation – First line warfarin, target INR 2-3 (Can use DOAC if intolerant of warfarin)
      • Pulmonary endarterectomy (in Papworth)
          • In patients with anatomically suitable disease (in terms of distribution and burden), pulmonary endarterectomy (PEA) is the treatment of choice following evaluation by expert centres
          • Significantly improves survival
          • Suitable patients include those with severe symptoms, accessible clots (lobar or segmental, but not too distal), and when pulmonary vascular resistance is not too high (less effective)
          • Requires circulatory arrest, hypothermia and bloodless field
          • They pull out laminated thrombus
          • Repeat VQ should show a marked difference
          • Later do a repeat right heart catheter. Annual echo and exercise tests
      • The pulmonary vasodilator Riociguat is useful if PH persists post-surgery or not suitable for surgery
      • Percutaneous balloon pulmonary angioplasty (BPA) is a more recent treatment modality recommended in suitable patients with CTEPH who have inoperable disease or with residual CTEPH following PEA surgery.

Groups 2 and 3 Pulmonary Hypertension

  • Rarely any specific treatments given – treat the underlying cause
  • PAP pressure unlikely to be very high (outside of exacerbations)
  • Do not usually refer to specialist services
  • Usually right heart working ok
  • Will not respond to pulmonary vasodilators
  • Group 2 (PH due to left heart disease)
      • The most common type of PH and is defined by mPAP >20 mmHg in the presence of an elevated PAWP (>15 mmHg) and normal PVR (≤2 WU)
      • Targeted PH therapies are not recommended
      • Referral to a PH centre should still be considered in specific cases eg, features of predominant right heart failure or disproportionately severe PH in patients with left HD. These patients may have PAH (Group 1) or CTEPH (Group 4) with LHD comorbidities
      • Patients with diastolic heart failure can sometimes mimic patients with type 1 PHTN.
      • Clues that it’s not PAH: older patient, hx of IHD, AF, HTN, DM, CKD, echos show LVH, LA enlargement, raised LV filling pressures, bi-atrial dilation
  • Group 3 (PH due to lung disease)
      • The second commonest PH subtype. Like PH-LHD, it reflects the severity of the lung disease with treatment of the underlying cause being the focus of management
      • Do an echo when well-treated for lung disease – it often gets better

Group 5 Pulmonary Hypertension

  • Associated with
      • Haematological disorders (chronic haemolysis, splenectomy, myeloproliferative)
      • Systemic disorders (sarcoid, neurofibromatosis, pulmonary histiocytosis)
      • Metabolic disorders (glycogen storage diseases, thyroid disease)
      • Others (CKD, fibrosing mediastinitis, segmental PH)
  • Patients with sarcoid or CKD might benefit from pulmonary vasodilators

 

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