Pulmonary Artery Hypertension (PAH) Flashcards
**What symptoms should bring PAH into your differential?
Insidious onset, gradually progressive shortness of breath without wheezing.
**What are two important things you are likely to notice when doing the chest exam of someone with PAH?
Right side Parasternal heave with loud P2 on exam
Pulmonary valve is slamming shut causing the enhanced P2 sound. Often the S2 sounds become widely split because the right heart must squeeze for longer to get all of the blood out
**What findings do you expect to see in someone with pulmonary artery hypertension (PAH)?
Essentially normal in idiopathic PAH (group 1)
**What findings do you expect to see in the pulmonary function test of someone with PAH?
PULMONARY VASCULAR DISEASE PATTERN:
**What is the screening test of choice for PAH?
• what can you detect with this test?
Echocardiography
1 - Look to see if there is Right Ventricular Hypertrophy/ Septal Deviation
2 - Estimate Right Ventricular Pressure:
RVSP = 4V^2 + RA pressure (estimated by ultrasound)
RVSP is a good estimation of pulmonary ARTERY hypertension because SYSTOLIC RV pressure should only be slightly greater than PULMONARY ARTERY pressure
**After screening for PAH with echocardiography, what should you do?
• why do you need this test?
• what values confirm suspicion of PAH?
Confirmatory test with Right Heart Catheterization
Right Heart Catheter measures the PULMONARY CAPILLARY WEDGE PRESSURE (PCWP) - this is an estimate of the pressure in the LEFT VENTRICLE
***IF left ventricular pressures are NORMAL (aka less than 15 mmHg) then you can assume the pressure is not due to backup of pulmonary venous circulation into pulmonary arteries.
**What are the criteria that need to be met to diagnose PAH?
PA Hypertension:
MPAP (mean pulmonary arterial pressure) over 25 mmHg
PCWP (pulmonary capillary wedge pressure) less than 15 mmHg
**What is the visibly activity agent of choice for PAH?
Nitric Oxide
**If patient with PAH continues to worsen after treatment what do you do?
Refer them for a lung transplantation
What are the 2 general types of pulmonary hypertension?
•how do they differ?
Pulmonary HTN:
• Primary - no demonstrable cause
• Secondary - etiologic agent/mechanism can be defined
What are some causes of secondary pulmonary HTN?
Secondary PAH: • Parenchymal lung disease (and damage e.g. bleomycin) •Chronic Thromboemboli • Left-sided valvular disease • Myocardial disease • Congenital heart disease • Systemic connective tissue disease
note: remember any type of connective tissue disease or damage to the pulmonary parenchyma may result in vascular damage that reduces the cross-sectional area of the pulmonary capillary bed leading to HTN.
note: remember any type of connective tissue disease or damage to the pulmonary parenchyma may result in vascular damage that reduces the cross-sectional area of the pulmonary capillary bed leading to HTN.
Pulmonary artery hypertension is caused by increased vasoconstrictors and decreased vasodilators. Name 6 vasoconstrictors that are commonly up regulated?
- Endothelin - 1 (most potent)
- TXA-2 (constricts and causes platelet aggregation)
- Serotonin (found in dense granules of platelets)
- VEGF
- CNS stimulants like COCAINE
- Anorexiants
What are the 2 vasodilators whose down regulation may contribute to the development of PAH?
- NO
2. Prostacyclin (PGI2)
What symptom may be a tip off that someone has a connective tissue disorder underlying their pulmonary artery HTN?
Raynaud’s - this is seen in patients with Scleroderma (most common CT disorder leading to PAH), SLD, Rheumatoid arthritis
What are 5 non-connective tissue diseases that can cause PAH?
- HIV
- HHV-8
- Sickle Cell (10% of pts.)
- Portal HTN
- Thrombocytosis
- HHT
Why do sickle cell patients and people with hemoglobinopathies get PAH?
FREE HEME AND IRON ACTS AS A SCAVENGER OF NO.
**What is primary cause of pulmonary HTN?
• is this heritable? If so, how?
BMPR2 (bone morphogenic protein receptor 2) is found on Chromosome 2.
• 6-10% of the population has this and it is AUTOSOMAL DOMINANT INHERITANCE with REDUCED penetrance
note: asymptomatic carriers may have abnormal response during excercise
What diet pills are associated with causing PAH?
Fenfluramine/phentermine
What is the significance of many PAH patients showing negligible NOS enzyme? Where is this enzyme found?
• what is the function of NO?
NO synthase in the Vascular Endothelium:
• makes NO
NO functions to:
• Promote Vasodilation
• Inhibit Smooth Muscle Growth**
What is the function of Endothelin-1?
Potent Vasoconstrictor and acts as a MITOGEN for smooth muscle cells
What key factor is expressed by endothelial cells in plexiform lesions?
VEGF
What cytokines induce the formation of VEGF?
TGF-ß and PDGF
Where is serotonin stored (mainly)?
• what is its role in PAH?
• What PAH patients typically show higher concentrations of serotonin in their plasma?
Serotonin is mainly stored in the dense granules of platelets. It causes VASOCONTRICTION and PROLIFERATION of smooth muscle cells.
In patients with PRIMARY pulmonary hypertension their blood levels or Serotonin are typically elevated.
**Why are calcium channel blockers a good potential therapy for Pulmonary HTN?
- Voltage-gated K+ channels control the cell membrane potential and release of Ca2+.
- Release of Ca2+ leads to smooth muscle constriction (remember ca2+ activates MLK kinase that phosphorylates smooth muscle and allows it to contract)
Why do appetite suppressants like fen/phen cause pulmonary artery hypertension?
Block voltage-gated potassium channels
what is the mean age of diagnosis for patients with PAH?
• why is dx often delayed?
• How do they present?
Mean age of Dx = 36, diagnosis is often delayed because of non-specific symptoms such as Fatigue, Exertional dyspnea, exertional chest pain, exertional syncope, edema
How long does it take a patient to move from compensated PAH to fully decompensated PAH?
• what features tell you that the person is starting to decompensate?
How Long:
• 3-5 years until the pt. completely decompensates
When patient becomes symptomatic they have started to decompensate. They are experience Right Sided Heart Failure, and Increasing Pulmonary vascular resistance.
Note: pulmonary arterial pressure maxes out and begins to decline shortly after the heart fails
note: on CXR you may see prominent pulmonary arteries and on DLCO you may see that it is slightly reduced
note: on CXR you may see prominent pulmonary arteries and on DLCO you may see that it is slightly reduced
What treatment options are available to vasoreactive patients that aren’t available to most patients with pulmonary HTN?
• how do you determine if they are candidates?
• why does this test work?
Vasoreactive patients respond to use of CCBs, a positive response is defined as a greater than 20% reduction in PAP and PVR.
REQUIREMENTS:
• Greater then 10 mmHg drop
• Should drop BELOW 40 mmHg
Why does it work:
• NO is used in the vasoreactivity test because it activates guanylyl cyclase that leads to cGMP formation that causes Ca2+ sequestration. This opposes the effect of Ca2+ that drives MLK kinase to phosphoryate myosin. Reversal with NO implies that overphosphorylation (too much Ca2+) may be your issue
T or F: NO is used in vasoreactivity test because people tolerate it better than intravenous dilators.
True
What do we mean when we say paradoxical movement of IVS?
Intraventricular septum should protrude into the RV because of greater pressure generation in LV. However in prolonged pulmonary hypertension this is flipped.
**What is the pulmonary vascular disease pattern?
• what happens with these patients when they try to walk?
FVC and FEV1 = normal
TLC normal
DLCO = LOW
Everything is normal except a low DCLO
When these patients walk they will get a diffusion defect AND THEY WILL DESATURATE.
What other condition cause desaturation on exertion?
• how can you tell these diseases apart?
Fibrosis patients often desaturate on exertion
• These diseases differ in that Spirometry and TLC shows NORMAL Values.
**What are some prostacyclin (PGI2) analogues used to treat Pulmonary Artery HTN?
• method of administration?
Epoprostenol - IV
Treprostinil - IV, SQ, PO
Iloprost - Inhalation
**What are some prostacyclin receptor agonists used to treat PAH?
Slexipag
**What are some ET1 antagonists used to treat PAH?
Bosentan/Ambrisentan and Masitentan
**What are some PDE5 inhibitors used to treat PAH?
Sildenafil
Tadalafil
**Note PDE5 is a phosphdiesterase for cGMP. cGMP stimulation causes Ca2+ sequestration and relaxation of smooth muscle
What drugs increase cGMP to treat PAH?
Riociguat
MOA of Epoprostenol?
• administration?
• Side effects
MOA:
Mimics the effects of Prostacyclin (PGI2) and inhibits platelet aggregation and smooth muscles proliferation
Administration:
• IV administration typically via a portable pump
Side Effects:
• Jaw pain, diarrhea, and arthralgias
• Infection, thrombosis
Bosentan
• MOA
• Adverse Effects
• Interactions
MOA:
• Endothelin-1 antagonists
Adverse Effects:
• Terratogenic
Heavily acted on by the liver therefore Interacts with cyclosporine and glyburide
Do patients with PAH need to be anticoagulated?
• what is the anticoagulation method of choice in these patients?
YES, they are at increased risk for intrapulmonary thormbosis due to sluggish blood flow, dilated heart chambers (right side), Venous stasis, Sedentary Lifesytles
WARFARIN (inhibitor of vit. K dependent coagulation enzymes II, VII, IX, and X, protein C and S)
What 2 drugs are acutally shown to increase the survival of patients with PAH?
• MOA(s)
Epoprostenol - Prostacyclin mimicry
Bosentan - endothelin-1 inhibition
