*39 Pulmonary Hypertension Flashcards
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
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
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
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
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
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
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
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
- A hyperdynamic circulatory state
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
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
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
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
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
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
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