Pulmonary Hypertension Flashcards
Definition of pulmonary arterial hypertension
- Mean Pulmonary Artery Pressure >25 mmHg
- Pulmonary capillary wedge pressure < 15mmHg
- R atrial pressure often elevated
Pulmonary wedge pressure - left atrium
Types of pulmonary hypertension
- Pulmonary Arterial Hypertension
- Left sided heart disease
- Lung disease or hypoxia
- Chronic thromboembolic pulmonary HTN
- Unclear of multifactorial causes
- Pulmonary Arterial Hypertension
- Idiopathic
- Heritable: BMPR2 loss of function mutation, associated with poor prognosis
- Drug and toxin induced
- Associated conditions
Connective tissue disease
HIV infection
Portal hypertension
Congenital heart disease
Schistiosomiasis - Left sided heart disease
Heart failure due to preserved/reduced LVEF
Valvular heart disease - Lung disease or hypoxia
COPD, asthma, interstitial fibrosis - Chronic thromboembolic pulmonary HTN
PE - Unclear of multifactorial causes
Hematologic disorders: myeloproliferative disorders,
splenectomy
5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans
cell histiocytosis: lymphangioleiomyomatosis,
neurofibromatosis, vasculitis
5.3 Metabolic disorders: glycogen storage disease,
Gaucher disease, thyroid disorders
5.4 Others: tumoral obstruction, fibrosing mediastinitis,
chronic kidney failure on dialysis
What is the most common cause of pulmonary arterial hypertension?
- Schistosomiasis is the most common cause worldwide
- Without endemic schistosomiasis:
>50% of PAH is idiopathic
10% heritable
What are the risk factors for Group 1 PAH?
- Connective Tissue Disease
- Systemic sclerosis, Raynauds, SLE, MCTD, RA can all be complicated by PAH
- Can also cause PH through development of ILD and/or heart failure
- Systemic Sclerosis:
most commonly associated, more common in limited cutaneous systemic sclerosis than diffuse. - HIV infection
- 0.5% of HIV positive patients - Portal Hypertension
- Congenital heart disease eg: septal defects, eisenmenger syndrome
- Schistosomiasis
Medications associated with PAH
Definite
- Dosatinib
- Methamphetamines
- Fenfluramine
- Phenteramine
- Dexfenfluramine
Possible: cocaine, bosutinib, amphetamines
Clinical features of pulmonary hypertension
- Dyspnoea - exertional normally
- Fatigue
- Syncope on exertion
- Chest pain
- Peripheral oedema
Physical Exam
- Loud and palpable 2nd heart sound (often split)
- Jugular vein distention
- Prominent jugular venous a wave
- Signs of RHF: peripheral oedema, hepatojugular reflex
- Parasternal heave
- Palpable P2
What gene mutation is associated with type 1 PAH?
BMPR - bone morphogenetic protein
- Loss of function mutation of BMPR
- BMPR normally inhibits smooth muscle proliferation and induces apoptosis
- Abnormalities of BMPR2 result in proliferation of pulmonary vascular cells –> vascular remodelling
- Tend to present at younger age, more severe disease, increased risk of death compared to those without BMPR2 mutations.
- Transmitted as autosomal dominant trait with incomplete penetrance and variable expressivity.
Other genes associated
- Activin 1 like kinase receptor (ALK1)
- SMAD9
- ENG
What are the vascular mediators that can perpetuate and worsen PAH?
In addition to genetic causes or risk factors, VASCULAR MEDIATORS can perpetuate and worsen PAH
- INCREASED ENDOTHELIN levels (vasoconstrictor and mitogen)
- DECREASED NITRIC OXIDE level (Normal function: vasodilator and is anti-prolferative)
- DECREASE PROSTACYCLIN levels (normal function: vasodilator, antiproliferative, inhibits platelet function)
All three of these factors cause endothelilal dysfunction and vascular injury
So: increased endothelin + decreased vasodilators (NO + prostacyclin) = vasoconstriction =increased pulmonary vascular resistance
What predicts mortality in IPAH?
- HYPOCAPNOEA but not hypoxia predicts mortality in patients with PAH
- RVEF is a predictor of survival in PAH
- Younger patients with PAH are more commonly female:
gender distribution is similar in older age groups. Variables
associated with worse outcomes include increasing age, advanced functional limitation and elevated levels of cardiac biomarkers such as N-terminal pro B-type natriuretic peptide. - Echocardiographic findings of pericardial effusion, right atrium
enlargement and poor R contractile reserve during stress
testing also portend a worse prognosis.
Diagnosis + Investigations of PAH
- TTE is the initial test
- Confirmatory test with right heart cath looking for mPAP > 20 at rest and pulmonary capillary wedge pressure > 15 due to left heart disease
- ECG: right axis deviation
- CXR: right heart hypertrophy - prominent right heart border
- Laboratory studies to
explore group I disease may include HIV serology. liver chemistry studies and autoantibody titers. - Prior to treatment exercise testing such as the 6 minute walk test should be performed lo determine functional impairment and to serve as baseline with which to compare therapeutic response.
Pharmacological management of PAH
- Calcium channel blockers: only for patients with acute vasodilator response (vasoreactive testing) at catheterisation, acute response does not assure chronic response
- Phosphodiesterase-5 inhibitors (sildenafil, tadalafil): prolongs effect of intrinsic vasodilator cyclic GMP by inhibiting hydrolysis by phosphdiesterase-5.
- Prostonoids (iloprost, epoprsteonol): supplements endogenous levels of prostacyclin, a vasodilator with anti-smooth muscle proliferative properties.
- Endothelin-1 receptor antagonist (bosentan, ambrisentan): blocks action of endogenous vasoconstrictor and smooth muscle mitogen endothelin, class wide risk of liver injury and teratogenic
What is the treatment for PAH?
- Long term O2
- Diuretic therapy for fluid overload, + RV failure
- Oral anticoagulant therapy may be considered
- Supervised exercise training
If there is a positive response to acute vasodilator testing (a minority of patients)
• oral calcium channel blockers
If there is a negative response to acute vasodilator testing (the vast majority of patients)
• prostacyclin analogues: treprostinil, iloprost
• endothelin receptor antagonists: bosentan, ambrisentan
• phosphodiesterase inhibitors: sildenafil
Patients with progressive symptoms should be considered for a heart-lung transplant.
- If acute vasoreactive testing responsive during catherization = CCB
Involves patient having inhaled NO or IV epoprostenol or IV adenosine - Low or intermediate risk: combination phosphodiesterase 5 inhibitor + endothelin receptor antagonist
Based on 1 year mortality
- Low risk < 5%
- Intermediate risk 5-10%
- High risk >10%
Endothelin Receptor Antagonist
Bonsentan
- Endothelin A and B receptor antagonist
- Hepatotoxicity in ~10%
- Improves 6MWT, WHO functional class, symptoms, echo, time to clinical worsening, favourable
survival compared to historical controls
Ambrisentan
- Selective endothelin A receptor antagonist
- Less hepatoxicity ~1-3%
- Possible worsening ILD in patients with IPF
Macitentan
- Endothelin A + B receptor antagonist
- Nasopharyngitis and anaemia
PAH drugs that target the NO pathway
Phosphodiesterase 5 inhibitors
- Sildenafil + Gadalafi
Increases intracellular concentration of cAMP and cGMP –> pulmonary vasodilation
- Improves haemodynamics, exercise capacity, WHO functional class, quality of life
SE: headaches, flushing, lightheadedness, visual defects (blue tinted vision)
- Contraindications: alpha blockers and nitrates can cause life threatening hypotension
Riociguat
- Vasodilator: stimulates soluble guanylate cyclase
- Dual mode of action
1. increases the sensitivity of sGC to endogenous NO
2. Direct stimulation of the NO receptor - Improvements in 6MWT, WHO functonial glass, symptoms
- Should NOT be used as combination with PDE5i because of HYPOTENSION and DEATH in post trial extension
What combination therapy is effective for PAH
Tadalafil + Ambrisentan best evidence of efficacy for patients with class II and III PAH.
