Term
| What alterations to respiratory mechanics in intrinsic pulmonary vascular disease? |
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Definition
None!
Since IPVD does not affect parenchyma or airways, elastic recoil, compliance and airway resistance remains the same. |
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Term
| What alterations to gas exchange occur in intrinsic pulmonary vascular disease? |
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Definition
V/Q mismatch
1) Low V/Q units lower PaO2 and increase AA gradient
2) High V/Q units create Vd, which increases Ve to maintain PaCO2. |
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Term
| Why do you see a fall in PaO2 during exercise in intrinsic pulmonary vascular disease? |
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Definition
Same mechanism as emphysema and interstitial disease.
CO increases, so more BF to well ventilated areas in less time, so less time for gas exchange |
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Term
| What PFT results would you expect to see in intrinsic pulmonary vascular disease? |
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Definition
1) Normal volumes and flow rates
2) Lower DLCO due to vascular narrowing and occlusion decreasing SA of alveolar-capillary interface. |
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Term
| What are the effects of pulmonary vascular disease on CV function? |
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Definition
1) Pulmonary HTN increases RV after-load, with RVH and ultimately RVF (peripheral edema, hepatomegaly and JVD)
2) RVF decreases LV preload and output by a) reducing amount of blood being pumped to left heart and b) decreasing LV compliance (RV dilation impinging on LV)
**Decreased CO and hypotension can result** |
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Term
| How does Dyspnea and Exercise intolerance arise in intrinsic pulmonary vascular disease? |
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Definition
CV is most important, but diffusion impairment and V/Q mismatch also contribute.
1) CO increases, and since PVR is already high, PA pressure increases (pulmonary HTN)
** Diffusion impairment and V/Q inequality also contribute**
2) PA pressure increases RV after-load and leads to RVF
3) RVF causes inadequate LV preload (less pumped blood and impinging RV dilation)
4) CO cannot be ramped up enough and dyspnea and intolerance occur. |
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Term
| What are the primary risk factors for venous thromboembolism? |
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Definition
Remember, this means DVT and PE.
1) Hypercoagulability
- Factor V lein (20% of DVT)
- Prothrombin 20210A mutation (5-6%)
2) Stasis of blood flow
- Surgery
- Lower extremity paralysis
- Immobilization
3) Vessel injury
- Surgery
- Trauma |
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Term
| What are the 2 most common causes of primary hyper-coagulable states that predispose patients to VTE? |
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Definition
1) Factor V leiden
- Arginine to Glutamine mutation in factor V that makes it resistant to cleavage by activated Protein C (APC)
- risk of VTE increases by 80x in homozygotes!
2) Prothrombin 20210A mutation |
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Term
| What are the 4 important causes of acquired or secondary hyper-coagulable states that predispose patients to VTE? |
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Definition
1) Malignancy- pro-coagulant material released from malignant cells (adenocarcinoma is the worst risk)
2) Estrogens (high dose therapy for something like prostate cancer is major concern).
3) Pregnancy
- Greatest in post-partum period
4) Anti-phospholipid Ab
- Lupus anti-coaglulant
- Anti-cardiolipid Ab |
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Term
| What are the major causes of morbidity and mortality associated with pulmonary Embolism? |
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Definition
Remember, this is dislodged DVT that impacts pulmonary arterial circulation.
Size and underlying pulmonary diseases are critical factors
1) Altered gas exchange
- V/Q mismatch
- No intrapulmonary shunt
2) Hemodynamics
- Reduced CA area of vascular bed increases PVR and RV afterload
- RVF can produce LVF and drop CO and lead to hypotension. |
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Term
| What diagnostic studies should be run to confirm PE? |
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Definition
They will present with dyspnea and tachypnea, but this is non-specific.
1) D-dimer (lysis of cross-linked fibrin caused by fibrinolysis) has low PPV but good NPV (if its negative, they don't have it).
2) CT angiography
- Visualize PA and look for opacified spots with contrast
3) Venous US (NOT diagnostic)
- Diagnose DVT as possible cause of PE
- Measured loss-of-compressibility of vein
- Good because therapy of DVT and PE are usually the same |
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Term
| Why is Venous ultrasonography useful in the case of suspected PE despite its poor sensitivity/specificity? |
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Definition
Treatments of DVT and PE tend to be the same, so if you see DVT, you can still treat.
- Anticoagulation with Heparin and Warfarin
- Thrombolytics
- IVC filters |
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Term
| How do you anti-coagulate a patient with DVT/PE? |
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Definition
Remember, you anti-coagulate, use thrombolytics and IVC filters
Start with IV bolus of heparin and follow with IV infusion. Warfarin is given once a day, and started with heparin.
**don't stop heparin until Warfarin has done the trick**
1) Warfarin
- Inhibits synthesis of vitamin K-dependent clotting factors II, VII, IX and X.
2) Heparin
- enhances effect of anti-thrombin III, inhibiting factor II (thrombin), factor X and factor IX. |
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Term
| How is thrombolytic therapy used for DVT/PE? When is it appropriate? |
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Definition
1) Plasminogen activators to break up thrombi.
2) Use with massive PE accompanied by hemodynamic compromise |
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Term
| How/why are IVC filters used to treat DVT/PE? |
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Definition
1) Precautionary filters that prevent venous thrombi in the legs and pelvis from embolizing to the lungs
2) Use in case of
a) recurrent PE despite anticoagulation
b) inability to use anticoagulants (bleeding)
c) high risk for recurrent PE (coagulability, stasis, vessel injury) |
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Term
| How is pulmonary hypertension defined clinically? |
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Definition
- Mean Pulmonary Arterial Pressure (MPAP) > 25 at rest or >30 during exercise
- Normal pulmonary capillary or left atrial pressure |
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Term
| What is primary pulmonary hypertension? |
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Definition
| A kind of Idiopathic pulmonary arterial hypertension which is very rare with a very poor prognosis (mean age of survival is 2.3 years) |
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Term
| What is the genetic basis for familial pulmonary arterial hypertension? |
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Definition
6-10% of IPAH patients characterized by mutations in TGF-beta family of growth factors.
1) BMPR-2
- BMP is osteoinductive cytokine that regulates smooth muscle growth and apoptosis (signaling through SMAD pathways)
- BMPR-2 mutation leads to altered p28 MAPK/ERK pathway and causes smooth muscle proliferation.
2) Activin-like kinase type-1 (ALK-1) and Endoglin (ENG) mutations that cause hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu) also confer susceptibility.
3) 5-HTT mutations causing long allele homozygosity (LL) leads to increased risk and early onset PAH
- Anorexinogen-induced PAH in vascular smooth muscle |
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Term
Which of the following is not associated with familial PAH?
1) ALK-1 Mutation
2) BMPR-2 Mutation
3) PTH-R Mutation
4) 5-HTT Mutation
5) ENG Mutation |
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Definition
3) PTH is not associated with FPAH.
- ALK-1 and ENG are associated with hereditary hemorrhagic telangiectasia (Osler-Weber-Randu) and PAH
- BMPR-2 mutations prevent inhibition of smooth muscle proliferation
- 5-HTT mutations increase risk and cause earlier onset (drug-induced in vascular smooth muscle) |
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Term
What disease is not associated with the onset of PAH?
1) Osler-Weber-Randu
2) Collagen Vascular disease
3) HIV
4) Hepatopulmonary syndrome
5) Protopulmonary Hypertension |
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Definition
4) Hepatopulmonary syndrome involves progressive hypoxemia due to oxygenation defect form intrapulmonary vascular dilations. It does not cause PAH and resolves after transplant.
This is different from Portopulmonary Hypertension, which presents with PAH but not hypoxemia
It can involves a) hyperdynamic circulatory state, b) excess volume and c) vasoproliferative disease.
- Osler-Weber-Randu, Collagen Vascular Disease and HIV are all associated with PAH. |
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Term
| What the 3 subsets of Portopulmonary hypertension that can produce PAH? |
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Definition
You can tell by looking at CO and PVR.
1) Hyperdynamic circulatory state
- Moderate increase in pulmonary pressure and severe increase in CO
- REDUCED PVR
2) Excess volume
- moderately increased pulmonary pressure and CO
- NORMAL PVR
3) Vasoproliferative disease
- rare with increased pulmonary pressure and PVR
- DECREASED CO (need t/x) |
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Term
| Why is PAH seen in HIV patients? |
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Definition
HHV-8 producing Kaposi sarcoma is implicated.
Give them HART! |
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Term
Which of the following conditions is not associated with PAH?
1) Anorexinogen use
2) Sick-cell disease
3) Idiopathic pulmonary fibrosis
4) Obstructive sleep apnea
5) Chronic thromboembolic PAH |
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Definition
| NONE! They are all associated |
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Term
| Why might OSA be associated with PAH? |
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Definition
Autonomic dysfunction and decrease in NO activity
**Not clear** |
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Term
| What is the basic pathophysiological process underlying PAH? |
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Definition
1) Endothelial damage causes imbalance of vasoconstrictive (Endothelin-1 and Thromboxane A2 increase) and vasodilating (Prostacyclin and NO decrease) factors
2) Smooth muscle activation and dysfunction follows
3) Inflammation, fibrosis and angiogenesis
4) Progressive vascular remodeling and damage |
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Term
| What does the voltage-gated potassium-ion channel Kv 1.5 have to do with PAH? |
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Definition
| Impaired function in this channel decreases K+ efflux from smooth muscle and increases intracellular calcium (vasoconstriction) |
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Term
| How does the endothelin-1 system function under normal conditions? |
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Definition
Vasoconstriction, cell proliferation and differentiation determined by ET-A:ET-B balance.
1) ET-1 synthesized and released by endothelial cells (as well as many other cell types) under conditions of hypoxemia, pulsatile stretch, low shear stress and inflammation.
2) Endothelin released into cytoplasm as prepro-endothelin, where it is cleaved by furin-like enzyme to Big-endothelin (bET-1)
3) bET-1 is cleaved by ECE into ET-1, which binds ET-A (vascular smooth muscle) and ET-B (endothelial cells)
3a) ET-A on smooth muscle leads to smooth muscle contraction via PLC pathway
3b) ET-B on endothelial cells leads to NO-dependent vasodilation and ET-1 clearance. |
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Term
| How does ET-1 dysfunction produce PAH pathogenesis? |
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Definition
Endothelial damage causes imbalance of vasoconstrictive (Endothelin-1 and Thromboxane A2 increase) and vasodilating (Prostacyclin and NO decrease) factors
Normally, ET-1 reduces heart rate, decreases coronary BF and coronary sinus O2 saturation and increases cardiac contractility.
Under pathological conditions
1) Acute
- vasoconstriciton and inflammation
2) Chronic
- Fibroblast proliferation and ECM components
- Increase ACE activity
- Cardiac myocyte hypertrophy |
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Term
| How can dysfunction in the Prostacyclin pathway contribute to PAH pathogenesis? |
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Definition
Remember, Prostacyclin and NO inhibit ET-1
1) Major lipid-mediator product on endothelium, which relaxes smooth muscle by increasing cAMP and inhibiting platelet aggregation and smooth muscle proliferation.
2) In IPAH, prostacyclin synthase is down-regulated (especially in collagen vascular disease) |
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Term
| How is NO signaling impaired in PAH? |
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Definition
NO increases cGMP (broken down by PDEs) via soluble GC leading to smooth muscle relaxtion.
1) Reduced eNOS expression in lungs of PAH with impaired activity of soluble GC prevents appropriate dilation.
2) PDE5 may be a good target to prevent cGMP breakdown. |
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Term
| Why might you give a PDE-5 inhibitor to treat PAH? |
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Definition
In PAH, eNOS activity is decreased, so there is less NO and less cGMP produced.
If you inhibit PDE-5, which breaks down cGMP, you will have more NO "effect" left over for smooth muscle dilation. |
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Term
| How does hypoxic pulmonary vasoconstriction occur in the pulmonary vasculature? |
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Definition
1) Hypoxia sensed by endothelium.
2) Inhibition of pulmonary vascular smooth muscle K+ channel (less K+ efflux and more intracellular Ca2+) |
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Term
| What are the 4 major molecular players in vasoconstriction/dilation balance in PAH? |
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Definition
In PAH, medial thickening and vasoconstriction causes media and intimal remodeling
1) NO and Prostacyclin are for dilation
2) ET-1 and TXA2 are for constriction |
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Term
| What are the major physiological issues that limit pharmacological options in PAH? |
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Definition
Low SA and CO
1) Loss of cross-esectional area of pulmonary vasculature limits RV CO and is difficult to change
2) Limited RVCO limits LVCO, leading to bi-ventricular CO reduction (patients cannot tolerate agents that cause systemic vasodilation).
** Need to find vascular-bed specific receptor populations** |
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Term
| How is NO signaling regulated? |
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Definition
1) Receptor-medaited increases in Ca2+ induce eNOS to make NO in endothelium.
**NO synthesized from L-arginine**
2) NO diffuses into the vascular smooth muscle, binds sGC and increases cGMP, which produces vasodilation |
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Term
| How is inhaled NO delivered selectively to the lungs? |
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Definition
1) NO combines with and is deactivated by oxygenated (forming Methemoglobin and NO3-) and deoxygenated (nitrosylhemoglobin) Hemoglobin a
2) Vasodilation occurs in well-ventilated alveolar units, |
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Term
| Why is inhaled NO generally only used in the ICU for neonates with PAH? |
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Definition
It has a short half life (2-6s) and can cause rebound hypertension.
metabolized to nitrate by kidneys and excreted in the urine at rate of GFR. |
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Term
| Why might you prescribe Epoprostenol, Treprotinil or Iloprost? |
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Definition
All 3 PGI2 analogues directly induce pulm/systemic vasodilation and inhibit platelet aggregation.
All may have jaw pain, flushing, syncope (less pronounced in Iloprost)
Difference is method of administration and half life (Epoprostenol is shorter half life and given IV)
1) Epoprostenol is given IV to central venous circulation (t1/2 6min)
2) Treprostinil is given by sub-q infusion with 100% bioavailability (t1/2 2-4h)
3) Iloprost is 4R:4S diasteromer mixture administered by aerosol and lasting 30-60min |
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Term
You start a hypovolemic patient on a drug to increase their blood pressure but notice an immediate drop in arterial blood pressure.
You are concerned, but the BP starts to increase.
What happened? |
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Definition
You gave an ET-1 analouge.
1) ET-1 causes rapid and transient decrease in BP because of ET-B-mediated PGI2 and NO release from vascular endothelium.
2) This is countered by ET-A activation in vascular smooth muscle, which produces constriction. |
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Term
| Why might you prescribe Ambrisentan, Bostentan, or Sitaxsentan for PAH? |
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Definition
ET-1 inhibitors.
ETA-selectivity is really the issue here and Abrisentan/Sitaxsentan are better than Bostentan
1) Abrisentan is a highly selective ETA antagonist
- dose-dependent hepatotoxicity (not major issue)
2) Bostentan is competitive antagonist of ETA and ETB (slightly more ETA)
3) Sitaxsentan is the BEST ETA-selectivity, with drug interactions (only available in research).
- Hepatotoxic
- Don't give with anti-glycemic agents, cyclosporine A or during pregnancy! |
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Term
| Why might you prescribe Sildenefil or Tadalafil in PAH? |
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Definition
Both are orally administered PDE 5 inhibitors that prevent cGMP breakdown and prolong NO action.
Both have minor headache, flushing and nasal congestion.
1) Sildenefil (viagra)
- drug-drug interactions are issue
- some PD3 (cardiac contractility) and PD6 (color vision) activity
2) Tadalafil (Cialis)
- drug-drug interactions
- longer half life than Sildenifil
- some PDE11 activity (unclear effect) |
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Term
An older patient presents to your office complaining that he is having difficulty "seeing the color of his wife's eyes). He also says he has been having abnormal heart rythms.
What could be going on? |
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Definition
| He might be on Viagra for PAH and/or ED and these are side effects due to PDE6 and PDE3 inhibition (supposed to hit only PDE5) |
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