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.
Which of the following best describes the mechanism of action of riociguat? A. Calcium channel blockade B. Endothelin A receptor antagonist C. Endothelin A&B receptor antagonist D. Phosphodiesterase type 5 inhibition E. Soluble guanylate cyclase stimulation
E. Soluble guanylate cyclase stimulation
Prostacyclin
Prostonoids - Iloprost (nebulised) - Selexipag (oral) - Epopostenol (IV) (iloprost, epoprsteonol): supplements endogenous levels of prostacyclin, a vasodilator with anti-smooth muscle proliferative properties
SE: jaw pain, facial/generalised flushing
Can also be used for critical limb ischaemia.
Surgical treatment for PAH
Lung Transplantation
- Patients with IPAH refractory to medical therapy
- Provided that LV function is preserved
- Bilateral lung transplantation is preferred
- Severe RV dysfunction often improves
- High incidence of obliterative brohnchiolitis in IPAH patients
- 3 year survival for heart lung transplant - 50% in idiopathic PAH
Atrial Balloon Septoplasty
- Balance between hypoxia and RHF
- Only for patient with severe RHF
Regarding idiopathic pulmonary arterial hypertension, which is the most correct?
A. All patients with BMPR2 mutations develop pulmonary HTN
B. CCB are effective in 90% of patients with PAH
C. Endothelin A and B receptors are present on smooth muscle and produce vasoconstriction
D. Endothelin A receptors on vascular epithelium release NO which results in vasodilation
E. Patients with elevated BNP levels have a better prognosis than patients with low BNP levels.
C. Endothelin A and B receptors are present on smooth muscle and produce vasoconstriction
