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Flashcards in *39 Pulmonary Hypertension Deck (24)
1

Pulmonary hypertension

  • Pulmonary vascular disease (PVD) and pulmonary hypertension (PH) 
  • Pulmonary hypertension 
  • Pulmonary arterial hypertension (PAH) 
  • The natural progression of PAH 

  • Pulmonary vascular disease (PVD) and pulmonary hypertension (PH)
    • Associated with a number of disease states
    • Characterized by progressive pulmonary vascular remodeling that leads to right ventricular (RV) hypertrophy and failure
  • Pulmonary hypertension
    • Defined hemodynamically as a mean pulmonary arterial pressure (mPAP) that is greater than 25 mmHg at rest
  • Pulmonary arterial hypertension (PAH)
    • Mean pulmonary arterial pressure (mPAP) >25mmHg
    • Pulmonary arterial wedge pressure (PAWP) <15mmHg
    • Pulmonary vascular resistance of >3 WU
  • The natural progression of PAH
    • Follows a series of pathologic changes within the pulmonary artery (PA) resulting in the formation the plexiform lesion
    • Along with these pathologic changes signs and symptoms of disease progress, resulting in worsening echocardiographic and hemodynamic trends and eventual right heart failure and death

2

Pulmonary arterial hypertension:
Idiopathic pulmonary arterial hypertension (iPAH)

  • Incidence and prevalence of idiopathic pulmonary arterial hypertension (IPAH) 
  • Mean age at diagnosis 
  • Female-to-male ratio 
  • Median survival 
  • Despite advances in awareness about PAH, the mean duration between symptom onset and diagnostic right heart catheterization has remained...
  • The plexiform lesion 

  • Incidence and prevalence of idiopathic pulmonary arterial hypertension (IPAH) 
    • ~2.0 and 10.6 cases per million adult inhabitants
    • Prevalence may have increased because of heightened awareness and early recognition in minimally symptomatic patients
  • Mean age at diagnosis
    • 1981: 36 years 
    • Now: 50-65
  • Female-to-male ratio
    • 2:1
  • Median survival
    • 1981: 2.8 years from diagnosis
    • Now: 7 years from diagnosis
  • Despite advances in awareness about PAH, the mean duration between symptom onset and diagnostic right heart catheterization has remained...
    • High at 2.8 years
  • The plexiform lesion
    • Pathognomonic of severe iPAH (though it can be seen in other forms of PH)
    • Represents the pathologic progression of pulmonary arterial endothelial and smooth muscle cell proliferation and hypertrophy
    • Usually discovered post mortem, as transbronchial biopsies are contraindicated patients with severe PAH

3

Pulmonary arterial hypertension:
Heritable pulmonary arterial hypertension

  • Accounts for...
  • BMPR-2 mutation
  • Bone morphogenetic protein (BMP) 
  • In the presence of BMPR-2 mutations, there is disruption of...
  • Because the presence of the BMPR-2 mutation confers only a 15% to 20% lifetime risk of developing PAH,...

  • Accounts for
    • 6% to 10% of IPAH patients
    • ~75% of familial cases and ~25% of sporadic cases
  • BMPR-2 mutation
    • A gene that codes for a type II receptor member for the transforming growth factor [TGF]- β family
  • Bone morphogenetic protein (BMP)
    • An osteoinductive cytokine that regulates smooth muscle cell growth and apoptosis
    • Binds to a heteromeric complex of two receptors, BMPR-1 and BMPR-2
    • Phosphorylates a family of signaling molecules (Smad proteins) that translocate to the nucleus and interact with specific proteins messaging suppression of smooth muscle cell growth
  • In the presence of BMPR-2 mutations, there is disruption of...
    • This normal Smad pathway, leading to signaling via an alternate p38 mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway that results in smooth muscle proliferation and inhibition of apoptosis
  • Because the presence of the BMPR-2 mutation confers only a 15% to 20% lifetime risk of developing PAH,...
    • A second hit may be required to complete the interaction between this mutation and the development of PAH

4

Pulmonary arterial hypertension:
Heritable pulmonary arterial hypertension

  • Germline mutations of other genes in the TGF-beta receptor family
  • Autoantibodies to BMPR-2 or ALK-1 
  • Genetic polymorphisms of the serotonin transporter (5-HT) 

  • Germline mutations of other genes in the TGF-beta receptor family
    • Such as the activin-like kinase type-1 (ALK-1) gene and endoglin (ENG) in patients with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease)
    • Also confer susceptibility to PAH
  • Autoantibodies to BMPR-2 or ALK-1
    • May also play a role in the development of PAH associated with connective tissue disease
  • Genetic polymorphisms of the serotonin transporter (5-HT)
    • Have been implicated in the pathogenesis of PH
    • The long (L) allele is associated with increased 5-HT transcription
    • Homozygosity for the L-allele (LL) leads to...
      • An increased risk of developing PAH
      • Early onset of the disease in affected individuals

5

Pulmonary arterial hypertension:
Drug and toxin induced

  • First well-established risk factor for the development of PAH
  • The use of these drugs for more than 3 months 
  • Fenfluramine derivatives
  • SSRIs 
  • Tyrosine kinase inhibitor, dasatinib 

  • First well-established risk factor for the development of PAH
    • The association with use of appetite suppressants 
  • The use of these drugs for more than 3 months
    • Confers a 30fold higher risk of PAH than in the general population
    • The absolute number of PAH cases, is quite low
  • Fenfluramine derivatives
    • Potent serotonin (5-HT) uptake inhibitors
    • Interact directly with 5-HT transporter
    • In PAH, elevated levels of 5-HT may act as a growth factor for pulmonary artery smooth muscle cells, thus contributing to the development of PAH
  • SSRIs
    • Associated with the development of persistent pulmonary hypertension in the newborn through the maternal intake of SSRI
  • Tyrosine kinase inhibitor, dasatinib
    • Use in CML
    • Has been upgraded to a definite cause of PAH which occurs during therapy
    • Patients improved after dasatinib therapy was discontinued

6

Pulmonary arterial hypertension:
PAH associated with collagen vascular diseases

  • These disorders are associated with both...
  • The prevalence of PAH 
  • With some patients there is a significant overlap between...
  • The prognosis of PAH associated with scleroderma 
  • One-year mortality for SSc-PAH compared to iPAH 
  • Prevalence of PAH
  • Scleroderma patients at risk for developing PAH

  • These disorders are associated with both...
    • Pulmonary involvement
    • The development of PAH
  • The prevalence of PAH
    • Well established only in scleroderma with a rate of occurrence between 7 – 12%
  • With some patients there is a significant overlap between...
    • Interstitial lung disease and pulmonary vascular disease
    • Can complicate the diagnosis
  • The prognosis of PAH associated with scleroderma
    • Poor
  • One-year mortality for SSc-PAH compared to iPAH
    • 30% vs 15%, respectively
  • Prevalence of PAH
    • Similar in limited and diffuse cutaneous SSc
  • Scleroderma patients at risk for developing PAH
    • Longstanding disease
    • Older age at scleroderma onset
    • Postmenopausal time period
    • Presence of cutaneous telangiectasias
    • Severe Raynaud’s phenomenon
    • Severe digital ischemia
    • Anticentromere antibody positive antibodies
    • Absence of anti-SCL-70 antibodies
    • Low DLco on PFTs (<50%) and FVC%/DLco%>1.6
    • Elevated uric acid and NTproBNP levels

7

Pulmonary arterial hypertension:
PAH associated with HIV-associated pulmonary arterial hypertension

  • Prevalence
  • HIV-associated PAH 
  • Prognosis for HIV-PAH before the era of HAART and PAH specific meds 
  • The current survival rate 
  • About 20% of these cases have...
  • Infection with human herpesvirus-8 (HHV-8)

  • Prevalence
    • > 1 million people with HIV infection in the US
  • HIV-associated PAH
    • Seen in 0.5% of patients
  • Prognosis for HIV-PAH before the era of HAART and PAH specific meds
    • Poor with mortality rate of 50% at 1 year
  • The current survival rate
    • 70% at 5 years
  • About 20% of these cases have...
    • Normalization of cardiopulmonary hemodynamics after several years of therapy (HIV)
  • Infection with human herpesvirus-8 (HHV-8)
    • Causes Kaposi sarcoma
    • Has been implicated in the pathogenesis of PH-HIV

8

Pulmonary arterial hypertension:
PAH associated with pulmonary arterial hypertension associated with liver disease

  • Hepatopulmonary syndrome 
    • Present in...
    • Characterized by...
    • Other
  • Portopulmonary hypertension 
    • Present in...
    • Characterized by...
    • Three hemodynamic subsets

  • Hepatopulmonary syndrome
    • Present in 20% of liver disease patients
    • Characterized by progressive hypoxemia due to an oxygenation defect from intrapulmonary vascular dilations
    • Does not cause pulmonary hypertension and resolves after liver transplantation
  • Portopulmonary hypertension
    • Present in ~20% of advanced liver disease patients
    • Characterized by pulmonary hypertension but not hypoxemia
    • Three hemodynamic subsets
      • A hyperdynamic circulatory state
        • Common
        • Associated with a moderate increase in mean pulmonary artery pressures (mPAP), severe increase in cardiac output (CO), normal pulmonary artery wedge pressure (PAWP), and a reduced pulmonary vascular resistance (PVR)
      • An excess volume subset
        • Common
        • Associated with moderate increases in mPAP and CO, severe increases in PAWP, and a normal PVR
      • A vasoproliferative state
        • Rare
        • Associated with severe increases in mPAP and PVR, a mild decrease in PAWP, and a moderate increase followed by a decrease in CO
        • Liver transplantation generally results in resolution of PH, although it can be risky

9

Pulmonary hypertension due to left heard disease (PH-LHD):
Left ventricular systolic dysfunction (PH-HFrEF)

  • Pulmonary hypertension related to left heart disease 
  • Chronic left ventricular failure
  • Echocardiogram indicates...
  • Prevalence of PH-LHD 

  • Pulmonary hypertension related to left heart disease
    • The most common cause of PH (PH-LHD)
  • Chronic left ventricular failure
    • Secondary to diminished left ventricular contractility, or systolic dysfunction leading to a reduced ejection fraction (EF%)- results in HF with reduced EF
  • Echocardiogram indicates...
    • If the ejection fraction is preserved (>45-50%) or reduced (<45%)
  • Prevalence of PH-LHD
    • ~25-100% of patients studied

10

Pulmonary hypertension due to left heard disease (PH-LHD):
Left ventricular diastolic dysfunciton (PH-HF preserved EF)

  • The prevalence of HFpEF 
  • Right heart catheterization
  • The pathogenesis of PH-LHD 
  • Many patients seen with PH-HFpEF or HFpEF alone often have metabolic syndrome
  • Treatment options 

  • The prevalence of HFpEF
    • Based upon echocardiographic studies
    • Between 11-27%
  • Right heart catheterization
    • The gold standard in the setting of a preserved ejection fraction to determine the difference between PH-HFpEF (reactive) and HFpEF (passive) (see table)
  • The pathogenesis of PH-LHD
    • High left atrial pressures due to ventricular or valvular dysfunction are transmitted to the pulmonary vascular tree results in increased PCWP and right heart dysfunction (passive)
    • Subsequent right heart and PA remodeling results in reactive or mixed PH
  • Many patients seen with PH-HFpEF or HFpEF alone often have metabolic syndrome
    • OSA
    • Diabetes mellitus 2
    • Systemic hypertension
    • Obesity
  • Treatment options
    • Limited
    • Often focused on reversing underlying disease state

11

Pulmonary hypertension due to left heard disease (PH-LHD):
Valvular disease

  • PH related to valvular disease is often due to either...
  • Treatment of choice in appropriate patients
  • PH commonly occurs in patients with mitral valve disease due to...
  • Pulmonary vascular remodeling may be...

  • PH related to valvular disease is often due to either...
    • Severe aortic stenosis
    • Mitral regurgitation
  • Treatment of choice in appropriate patients
    • Surgical aortic valve replacement
    • Can be curative, though some patients have persistent PH
  • PH commonly occurs in patients with mitral valve disease due to...
    • Persistently elevated left atrial pressures
    • Presumed remodeling of the pulmonary arteries
  • Pulmonary vascular remodeling may be...
    • Pulmonary venous rather than pulmonary arterial in patients with persistent PH after surgical treatment

12

Pulmonary hypertension associated with lung disease and/or hypoxia:
Pulmonary hypertension associated with COPD

  • Up to 90% of patients with advanced COPD (Gold stage IV) have a mPAP...
  • Most range from...
  • 3-5% of patients with COPD have...
  • The morphologic appearances of pulmonary vascular lesions correlate with...
  • When patients with PH-COPD exercise there is...
  • On average PH in COPD...
  • The presence of PH is a predictor of...
  • This is a better predictor than...
  • Additionally PA diameter on Chest CT scan predicts...

  • Up to 90% of patients with advanced COPD (Gold stage IV) have a mPAP...
    • >20mmHg
  • Most range from...
    • 20-35mmHg
  • 3-5% of patients with COPD have...
    • Severe PH with a mPAP>35- 40mmHg
  • The morphologic appearances of pulmonary vascular lesions correlate with...
    • The severity of PH
  • When patients with PH-COPD exercise there is...
    • A rapid increase in mPAP due to a loss of lung vascular distensibility +/- vessel recruitment capability
  • On average PH in COPD...
    • Increases slowly by 1mmHg/year
  • The presence of PH is a predictor of...
    • Mortality with a 5-year survival of 36% in patients with a PAP >25mmHg
  • This is a better predictor than...
    • FEV1 or gas exchange variables
  • Additionally PA diameter on Chest CT scan predicts...
    • Hospitalizations caused by acute exacerbations of COPD
    • i.e. the bigger the PA diameter, the more hospitalizations for COPD exacerbations

13

Pulmonary hypertension associated with lung disease and/or hypoxia:
Pulmonary hypertension associated with interstitial lung disease

  • Interstitial lung disease may be either...
  • The prevalence of IPF-associated PH 
  • When it is present, patients with idiopathic pulmonary fibrosis...
  • The presence of PH results in...
  • There is a linear inverse correlation between pulmonary pressures and...
  • Patients with PH have a threefold higher...
  • There are poor correlations between lung function testing (PFTs) or CT severity and...
  • The development of PH in IPF has been linked to...
  • The correlation of echocardiographic estimation of PAP and RHC are...
  • The gold standard remains...

  • Interstitial lung disease may be either...
    • Idiopathic
    • Associated with a large number of diseases or risk factors
  • The prevalence of IPF-associated PH
    • Vetween 8.1-14.9%
  • When it is present, patients with idiopathic pulmonary fibrosis...
    • Have lower diffusing capacity for carbon monoxide
    • Are more likely to require supplemental oxygen
  • The presence of PH results in...
    • Greater functional limitation, with lower 6-minute walk distance and higher mortality
  • There is a linear inverse correlation between pulmonary pressures and...
    • Clinical outcome
  • Patients with PH have a threefold higher...
    • Mortality
  • There are poor correlations between lung function testing (PFTs) or CT severity and...
    • Cardiopulmonary hemodynamics
  • The development of PH in IPF has been linked to...
    • Worse gas exchange at rest, low DLco, rapid desaturation with exercise, high BNP, enlarged RV on CXR
  • The correlation of echocardiographic estimation of PAP and RHC are...
    • Poor in subjects with all forms of lung disease
  • The gold standard remains...
    • RHC

14

Pulmonary hypertension associated with lung disease and/or hypoxia:
Combined pulmonary fibrosis and emphysema (CPFE)

  • Patients with CPFE are at increased risk for developing...
  • The hallmark 
  • High resolution CT scan is helpful in establishing the diagnosis of both...
  • One disease state can be more...
  • Outcomes are uniformly...

  • Patients with CPFE are at increased risk for developing...
    • PH with estimates of 30-50% affected
  • The hallmark
    • Severely decreased DLco
    • Severe PH
    • Normal to mildly abnormal lung volumes
    • Absence of airflow obstruction
  • High resolution CT scan is helpful in establishing the diagnosis of both...
    • Emphysema
    • Interstitial lung disease
  • One disease state can be more...
    • Predominant
  • Outcomes are uniformly...
    • Poor

15

Pulmonary hypertension associated with lung disease and/or hypoxia:
Pulmonary hypertension and sleep-disordered breathing

  • Obstructive sleep apnea (OSA) 
  • Physiologic consequences of OSA
  • The precise link between OSA and the aforementioned conditions 
  • Patients with OSA and PH 
  • Apnea-hypopnea index 
  • The apneic spells associated with OSA are associated with...

  • Obstructive sleep apnea (OSA)
    • The most common type of sleep-disordered breathing
    • Affects 5% to 15% of the adult population
  • Physiologic consequences of OSA
    • Systemic hypertension
    • Stroke
    • Coronary disease
    • Heart failure
    • Atrial arrhythmias
    • Pulmonary hypertension, especially with preexisting pulmonary disease
  • The precise link between OSA and the aforementioned conditions
    • Autonomic dysfunction
    • Increased daytime and nocturnal sympathetic activity
    • Endothelial dysfunction
    • Enhanced leukocyte adhesion
    • Increased platelet aggregation
    • Activation of proinflammatory and prothrombotic factors such as interleukin-6, fibrinogen, and plasminogen activator inhibitor
  • Patients with OSA and PH
    • Older
    • Heavier
    • Have worse lung function
    • Have decreased nitric oxide activity
  • Apnea-hypopnea index
    • A poor predictor of PH
  • The apneic spells associated with OSA are associated with...
    • Hypoxemia and elevations in pulmonary artery pressures, which resolve with restoration of ventilation

16

Chronic thromboembolic pulmonary hypertension

  • This form of PH develops in only...
  • Present in 60% of patients
  • Present in 30% of patients
  • Present in 30% of patients with chronic thromboembolic PH
  • Appropriate diagnosis of this form of PH is critical because some patients can be cured with...

  • This form of PH develops in only...
    • 0.1% to 4% of patients who survive an acute pulmonary embolism
    • Its prevalence may be underappreciated
  • Present in 60% of patients
    • A history of thromboembolic events
  • Present in 30% of patients
    • Coagulation disorders, most notably a positive lupus anticoagulant titer
  • Present in 30% of patients with chronic thromboembolic PH
    • A serotonin transporter gene polymorphism
    • The presence of this genetic polymorphism may unfavorably modulate the clinical course of the disease
  • Appropriate diagnosis of this form of PH is critical because some patients can be cured with...
    • Surgical thromboendarterectomy

17

Pulmonary hypertension associated with unclear multifactorial etiologies:
Hematologic disorders: chronic hemolytic anemia: sickle cell disease, thalassemia, spherocytosis and stomatocytosis

  • These disease states are associated with...
  • The cause of the PH is unclear and multifactorial including...
  • PH confirmed by RHC occurs in...
  • PH-LHD is seen in...
  • The prevalence of pre-capillary PH associated with SCD
  • Reported in patients with SCD-PH
  • Mortality in sickle cell anemia with pulmonary hypertension 

  • These disease states are associated with...
    • An increased risk for PH
  • The cause of the PH is unclear and multifactorial including...
    • CTEPH, splenectomy, high CO, left heart disease, hyperviscosity, liver disease and lung disease
    • Presence of cell-free hemoglobin, which inactivates nitric oxide
  • PH confirmed by RHC occurs in...
    • 6.2-10% of patients
  • PH-LHD is seen in...
    • 3.3-6.3%
  • The prevalence of pre-capillary PH associated with SCD
    • 2.9-3.7%
  • Reported in patients with SCD-PH
    • Plexiform lesions
  • Mortality in sickle cell anemia with pulmonary hypertension
    • Worse than in sickle cell anemia with normal pulmonary pressures

18

Pathophysiology of pulmonary arterial hypertension

  • Endothelial cell dysfunction, whether inherited or from other risk factors, results in...
  • This imbalance favors...

  • Endothelial cell dysfunction, whether inherited or from other risk factors, results in...
    • Increased intracellular transcription of constricting factors such as endothelin-1 and thromboxane A2
    • Decreased activity of relaxing factors like nitric oxide and prostacyclin
  • This imbalance favors...
    • Vasoconstriction
    • Smooth muscle cell activation and dysfunction
    • Hyperplasia and hypertrophy
    • Inhibition of apoptosis
    • Fibroblast proliferation
    • Collagen deposition
    • Activation of proinflammatory cytokines
    • Angiogenesis

19

Pathophysiology of pulmonary arterial hypertension

  • Growth factors that promote cell proliferation and angiogenesis
  • Impaired function or insufficiency of the voltage-gated potassium-ion channels (KV 1.5) on the pulmonary vascular smooth muscle cell results in..
  • Platelet activation releases...
  • What creates a procoagulant milieu within the pulmonary circulation predisposing to in-situ thrombosis
  • What combines to produce progressive and deleterious pulmonary vascular remodeling

  • Growth factors that promote cell proliferation and angiogenesis
    • Ex. Vascular endothelial growth factor and angiopoietin
    • Are up-regulated, which also promotes cell proliferation and angiogenesis
  • Impaired function or insufficiency of the voltage-gated potassium-ion channels (KV 1.5) on the pulmonary vascular smooth muscle cell results in..
    • Efflux of potassium and increased intracellular calcium
    • Induces further pulmonary vasoconstriction
  • Platelet activation releases...
    • Platelet-derived growth factor and serotonin into the circulation
  • What creates a procoagulant milieu within the pulmonary circulation predisposing to in-situ thrombosis
    • Increased availability of thromboxane A2, fibrinopeptide A, and plasminogen activator inhibitor-1
  • What combines to produce progressive and deleterious pulmonary vascular remodeling
    • Vasoconstriction, cell proliferation, fibrosis, angiogenesis, and thrombosis

20

The endothelin system

  • ET-1 is synthesized and released both by...
  • Factors that promote endothelin synthesis and release
  • What inhibits endothelin synthesis
  • The message for endothelin synthesis from the nucleus results in...
  • This precursor is then cleaved by...

  • ET-1 is synthesized and released both by...
    • The endothelial cell
    • Other cell types such as leukocytes, macrophages, cardiomyocytes, vascular and airway smooth muscle cells, and mesangial cells. Physicochemical
  • Factors that promote endothelin synthesis and release
    • Hypoxemia, pulsatile stretch, low shear stress
    • Other factors including proinflammatory cytokines, transforming growth factor-beta, endotoxin, and a number of circulating neurohormones
  • What inhibits endothelin synthesis
    • Nitric oxide and prostacyclin
  • The message for endothelin synthesis from the nucleus results in...
    • The release of an inactive precursor prepro-endothelin into the cytoplasm
  • This precursor is then cleaved by...
    • A furin-like enzyme into an inactive intermediate called big-endothelin
    • The big-endothelin (big ET-1) is further cleaved by the endothelin-converting enzyme (ECE) to active ET-1

21

The endothelin system

  • After release, ET-1 mediates its effects through...
  • ET-1 binding to these receptors activates...
  • The endothelin type A (ET-A) receptors 
  • The endothelin type B (ET-B) receptors 
  • Activation of ET-B receptors on endothelial cells mediates...
  • Activation of ET-B receptors on the smooth muscle cells mediate...
  • The net biologic effect of ET-1 depends on...
  • ET-B receptors are also important for...

  • After release, ET-1 mediates its effects through...
    • Interaction with two classes of cell surface receptors, which have different molecular and physiologic functions
  • ET-1 binding to these receptors activates...
    • The phosphatidyl inositol phospholipase C pathway, which in turn signals several key cell-specific events
  • The endothelin type A (ET-A) receptors
    • Located mainly on the vascular smooth muscle cells
    • They are also present on the cardiac myocyte, cardiac fibroblast, lung, kidney, and brain
    • Mediate vasoconstriction and cell proliferation
  • The endothelin type B (ET-B) receptors
    • Present predominantly on endothelial cells
    • Also located on the vascular smooth muscle cells and other organs such as the heart, kidney, brain, intestine, and melanocytes
  • Activation of ET-B receptors on endothelial cells mediates...
    • Nitric oxide dependent vasodilation and prostacyclin release as well as ET-1 clearance
  • Activation of ET-B receptors on the smooth muscle cells mediate...
    • Vasoconstriction
  • The net biologic effect of ET-1 depends on...
    • The density of ET-A receptors on the vascular smooth muscle cell
    • The ET-B receptors on the endothelial cell
  • ET-B receptors are also important for...
    • Sodium and water absorption in the distal renal tubules

22

The endothelin system

  • Under physiologic conditions, ET-1 causes...
  • ET-1 is important for...
  • In pathologic states, the ET receptors are regulated differently, which results in...
    • Acute effects
    • Chronic effects
  • ET-1 also...

  • Under physiologic conditions, ET-1 causes...
    • Vasoconstriction, cell proliferation, and differentiation determined by a complex interplay between its effects on ET-A and ET-B receptors
  • ET-1 is important for...
    • Maintenance of basal tone in many vascular beds
    • Reduction in heart rate, a decrease in coronary blood flow and coronary sinus oxygen saturation, and an increase in cardiac contractility
  • In pathologic states, the ET receptors are regulated differently, which results in...
    • Acute effects
      • Vasoconstriction and inflammation
    • Chronic effects
      • Fibroblast proliferation, synthesis of extracellular matrix components, hypertrophy of cardiac myocytes, neurohormonal secretion, and cell proliferation
  • ET-1 also...
    • Increases plasma renin activity, enhances conversion of angiotensin I to angiotensin II, and augments the synthesis and release of aldosterone from the adrenal glands

23

Prostacyclin pathway

  • Prostacyclin 
  • Its production depends on...
  • The excretion of urinary metabolites of thromboxane A2 
  • The excretion of prostacyclin 

  • Prostacyclin
    • A major lipid-mediator product of endothelium
    • Relaxes smooth muscle by increasing intracellular cyclic adenosine monophosphate
    • Inhibits platelet aggregation and smooth muscle cell proliferation
  • Its production depends on...
    • Prostacyclin synthase
    • The expression of prostacyclin synthase is downregulated in the small, medium, and large pulmonary vessels in patients with IPAH
  • The excretion of urinary metabolites of thromboxane A2
    • Increased
  • The excretion of prostacyclin
    • Decreased in patients with iPAH and PAH associated with collagen vascular disease when compared to normal control individuals

24

Nitric oxide pathway

  • The expression of endothelial NO synthase (eNOS) 
  • Reduced bioavailability of NO 
  • NO mediates its biologic effects through...
  • Because PDE5 is abundant in the pulmonary vasculature, its inhibition...
  • Impaired activity of soluble guanylate cyclase (sGC) may cause...

  • The expression of endothelial NO synthase (eNOS)
    • Reduced in lungs of patients with pulmonary hypertension
  • Reduced bioavailability of NO
    • Important in the pathogenesis of PH
  • NO mediates its biologic effects through...
    • An intracellular second messenger called cyclic guanosine monophosphate (cGMP), which is broken down and inactivated by phosphodiesterases (PDEs), especially the isozymes PDE1 and PDE5
  • Because PDE5 is abundant in the pulmonary vasculature, its inhibition...
    • Is an attractive therapeutic target in PAH
  • Impaired activity of soluble guanylate cyclase (sGC) may cause...
    • Hyporesponsiveness to NO in PAH

Decks in Pulm Class (47):