3. Pulmonary circulation
The pulmonary circulation is trapped between the two ventricles,
at the mercy of the right ventricle at one end and dependent on left
ventricular performance at the other end.
Low resistance, high compliance vascular bed
Only organ to receive entire cardiac output (CO)
Changes in CO as well as pleural/alveolar pressure affect
pulmonary blood flow
4. Pulmonary circulation
It begins at junction of right
ventricle with pulmonary
trunk and end at opening of
pulmonary veins with the left
atrium.
5. Vascular Pressure in Systemic
and Pulmonary Circulations
Pulmonary
Circulation
Systemic
Circulation Arteries Arteries
Veins Veins
120/80, mean 93 25/8, mean 14
Left
Atrium
Mean 5
Right
Atrium
Mean >6
Right
Ventricle
25/2-5
Left
Ventricle
120/5-10
LungBody
SVR= 17.6
PVR= 1.8
6. Pulmonary artery pressure
Systolic pulmonary artery pressure is about 20-30mmhg.
Diastolic pulmonary artery pressure is about 5-10mmhg.
Mean pulmonary artery pressure is about 10-12mmhg
Mean pulmonary artery pressure = diastolic pulmonary artery pressure
+ 1/3 pulse pressure.
Ageing is associated with slight increase in pulmonary artery pressure.
7. Pulmonary arteriovenous pressure
difference.
The drop in the mean pressure between pulmonary
artery and left atrium is small (10mmhg).
Micro puncture of sub pleural vessels suggest that
most of this drops occur in the pulmonary capillaries.
8.
9. Pulmonary vascular resistance (PVR).
⢠Definition.
ďś It is resistance offered by a vascular bed to the flow of blood through it.
⢠The vascular resistance of pulmonary circulation is low due to its low initial tone due to the balance
between V.D and V.C prostaglandins
⢠Site of PVR.
ďś Resistance vessels = pre-capillary vessels
⢠Small muscular arteries and arterioles are the only vessels that seems capable of appreciable V.C so
it is the principle site of pulmonary vasomotor activity.
⢠Determination of PVR.
R = (Pul. Artery pressure - Pul. Venous pressure)/ Blood flow
R = (PPA â PPV)/Q
R value for pulmonary circulation is 0.1
10. Important pathophysiological and clinicaldefinitions
Pulmonary hypertension
(PH) is a haemodynamic and pathophysiological condition defined as an increase
in the mean pulmonary arterial pressure 25 mmHg at rest as assessed by right heart
catheterization
PH can be found in multiple clinical conditions
Pulmonary arterial hypertension (PAH, group 1)
is a clinical condition characterized by the presence of pre-capillary PH and
pulmonary vascular resistance >3 Wood units, in the absence of other causes of pre-
capillary PH such as PH due to lung diseases, chronic thromboembolic PH, or other
rare diseases
PAH includes different forms that share a similar clinical picture and virtually
identical pathological changes of the lung microcirculation
11. Haemodynamic definitions of pulmonary
hypertensiona
Characteristics
PH PAPm ďł25 mmHg
Pre-capillary PH PAPm ďł25
mmHg PAWP
ďŁ15 mmHg
Post-capillary PH
Isolated post-capillary PH
Combined post-capillary
pre-capillary PH
PAPm ďł25
mmHg PAWP
>15 mmHg
DPG <7 mmHg
(diastolic PAP â mean PAWP)
and/or PVR ďŁ3
WUc
DPG ďł7 mmHg
and/or PVR >3
WUc
Clinical group(s)
All
Pulmonary arterial hypertension
PH due to lung diseases
Chronic thromboembolic PH
PH with unclear and/or multifactorial mechanisms
2. PH due to left heart disease
5. PH with unclear and/or
multifactorial mechanisms
18. Pathophysiology & pathology â group 1
Exact mechanism â unknown.
Multifactorial.
1)Excessive vasoconstriction -abnormal function or expression of
potassium channels in the smooth muscle cells .
2) Endothelial dysfunction leads to chronically impaired
production of vasodilator and Vasoconstrictors
(NO, prostacyclin, thromboxane A2 and endothelin-1)
19. 3) Reduced plasma levels of other vasodilator and
antiproliferative substances such as vasoactive intestinal
peptide
4) In the adventitia there is increased production of extracellular
matrix including collagen, elastin, fibronectin. Inflammatory
cells and platelets (through the serotonin pathway)
5) Prothrombotic abnormalities have been demonstrated in
PAH patients, and thrombi are present in both the small distal
pulmonary arteries and the proximal elastic pulmonary arteries
Pathophysiology & pathology â group 1
20. 1. Tunica media hypertrophy
2. Tunica intima proliferation
3. Fibrotic changes of tunica intima
4.Tunica adventitial thickening with moderate perivascular
infiltrates
5. Complex lesions (Plexiform)
6. Thrombotic lesions.
eccentricconcentric
Pathophysiology & pathology â group 1
21. Pathophysiology & pathology â group 2
Usually due to left-sided heart disease (valvular, coronary or
myocardial), ď obstruction to blood flow downstream from
the pulmonary veins.
Reversibility is variable, dependent on lesion.
22. Pathophysiology & pathology â group 3
PH due to lung diseases and/or hypoxia:
Multiple
1) hypoxic vasoconstriction,
2) mechanical stress of hyperinflated lungs,
3) loss of capillaries â emphysema, fibrosis
4) inflammation, and toxic effects of cigarette smoke.
5)endothelium-derived vasoconstrictorâvasodilator imbalance.
Hypoxia induced pulmonary vasoconstriction and anatomical destruction of
the vascular bed due to high pulmonary resistance and ultimately RV
failure.
23.
24. Pathophysiology & pathology â group 4
CTEPH: is a disease of obstructive PA remodelling as
a consequence of major vessel thromboembolism.
Non-resolution of acute embolic masses which later
undergo fibrosis leading to mechanical obstruction of
pulmonary arteries is the most important process.
The pathophysiological events in the progression of
pulmonary hypertension during this period have not
been well defined.
25. Pathophysiology & pathology â group 5
A common feature of these diseases is that the
mechanisms of PH are poorly understood and
may include pulmonary vasoconstriction,
proliferative vasculopathy, extrinsic
compression, intrinsic occlu- sion, high-output
cardiac failure, vascular obliteration and left
heart failure as causes
26. When to suspect PAH
ď§Unexplained dyspnea despite multiple diagnostic
tests
ď§Typical symptoms (look for Raynaudâs)
ď§Comorbid conditons:
ď§CREST, liver disease, HIV, sickle cell, OSA
ď§Family history of PAH
ď§History of stimulant/anorexigen use
29. CXR in PH
Large central
Pulmonary
arteries
Right Ventricular
Hypertrophy
Rapid attenuation of
pulmonary vessels
Clear Lung Fields
30.
31. Increased PA diameter (âĽ29
mm) and
pulmonary: ascending aorta
diameter ratio (âĽ1.0).
A segmental artery:
bronchus ratio 1 : 1 in three
or four
lobes has been reported to
have high specificity for
PH.
Cardiomegaly, enlarged RV
pericardial effusion
CT in PH
33. ECG in PH
⢠Right axis deviation
⢠An R wave/S wave ratio greater
than one in lead V1
⢠Incomplete or complete right
bundle branch block
⢠Increased P wave amplitude in
lead II (P pulmonale) due to
right atrial enlargement
34. Echocardiogram findings
⢠TR
⢠Right atrial and ventricular hypertrophy
⢠Flattening of interventricular septum
⢠Small LV dimension
⢠Dilated PA
⢠Pericardial effusion
⢠Poor prognostic sign
⢠RA pressure so high it impedes normal drainage from
pericardium
⢠Do not drain, usually does not induce tamponade
since RV under high-pressure and non-collapsible
35.
36. Right Heart Catheterization
â RA <6
â RV <30/6
â PA <30/12
â PCWP <12
⢠Pulmonary Vascular Resistance
⢠Pulmonary blood flow (cardiac
output)
⢠Vasoreactivity
37. Vasoreactivity Testing During RHC
⢠Inhaled Nitric Oxide (NO) is a preferential
pulmonary arterial vasodilator
⢠Positive if:
â Mean PAP decreases at least 10 mmHg and to a value
less than 40 mmHg
â Associated increased or unchanged cardiac output
â Minimally reduced or unchanged systemic blood pressure
⢠Only patients with Positive Vasoreactivity are given
treatment trials with Calcium Channel Blockers
38. Other Investigations
ďąLung function testing
ďąVentilation-perfusion scanning
ďąHRCT scanning
ďąLung biopsy
ďąPulmonary angiography
ďąExercise testing
41. Why treat PAH?
ď§ Age >45 years
ď§ (WHO) functional class III or IV
ď§ Failure to improve to a lower WHO functional class during treatment
ď§ Echocardiographic findings of a pericardial effusion, large right atrial size,
elevated right atrial pressure, or septal shift during diastole
ď§ Decreased pulmonary arterial capacitance (ie, the stroke volume divided by
the pulmonary arterial pulse pressure)
ď§ Increased N-terminal pro-brain natriuretic peptide level (NT-pro-BNP)
ď§ Prolonged QRS duration
ď§ Hypocapnia
ď§ Comorbid conditions (eg, COPD, diabetes)
44. How do we Treat Them?
General measures:
⢠It is recommended that PAH patients avoid pregnancy
⢠Immunization of PAH patients against influenza and pneumococcal infection
⢠Psychosocial support is recommended in PAH patients
⢠Supervised exercise training should be considered in physically deconditioned PAH patients
under medical therapy
⢠In-flight O2 administration should be considered for patients in WHO-FC III and IV and those
with arterial blood O2 pressure consistently ,8 kPa (60 mmHg)
⢠In elective surgery, epidural rather than general anaesthesia should be preferred whenever
possible
⢠Excessive physical activity that leads to distressing symptoms is not recommended in PAH
patients
46. Diuretics
⢠Principally to treat edema from right heart
failure
⢠May need to combine classes
⢠-Thiazide and loop diuretics
⢠Careful to avoid too much pre-load reduction
⢠Patients often require large doses of diuretics
47. Anticoagulants
⢠Studies only show benefit in IPAH patients,
based on improved survival.
⢠Other PAH groups not as clear, use in them
considered expert opinion.
⢠Generally, keep INR 2.0-2.5 thought to lessen
in-situ thrombosis
48. Oxygen
⢠Formal assessment of nocturnal and exertional oxygenation needs.
⢠Minimize added insult of hypoxic vasoconstriction
⢠Keep oxygen saturation âĽ90%
⢠May be impossible with large right to left shunt
⢠Exclude nocturnal desaturation
⢠Overnight oximetry
⢠Rule out concomitant obstructive sleep apnea and hypoventilation
syndromes
49. Principles of drug treatment
ďą Patients should undergo cardiac catheterization before initiating therapy.
ďą Obtain baseline assessments of the disease to know whether treatments are effective.
ďą Test Vasoreactivity.
ďą Reactive patients should be treated with calcium channel blockers.
ďą Nonreactive patients should be offered other therapies.
ďą Reassess at 8 weeks; patients who donât respond are unlikely to respond with longer exposure.
ďą Ineffective treatments should be substituted rather than new added.
ďą Patients who fail all treatments should be considered for lung transplantation.
ďą Only the addition of sildenafil to epoprostenol has been shown to be efficacious
51. Targets for current PAH-specific therapy
Arachidonic Acid
Prostacyclin
Synthase
Vasodilatation
and
Antiproliferation
Prostacyclin
cAMP
Prostacyclin
Derivatives
Prostacyclin
Derivatives
Prostacyclin Pathway
Big Endothelin
Endothelin-
converting
Enzyme
Endothelin
Receptor A
Endothelin
Receptor B
Vasoconstriction
and
Proliferation
Endothelin
Receptor
Antagonists
Endothelin-1
Endothelin Pathway
Arginine
Nitric Oxide
Synthase
Vasodilatation
and
Antiproliferation
Nitric Oxide
cGMP Exogenous
Nitric Oxide
Phosphodiesterase Type-5
Phosphodiesterase
Type-5 Inhibitors
Nitric Oxide Pathway
52.
53. Calcium Channel Blockers
⢠Use only when demonstrated vasoreactivity in RHC (about 10%
or less of patients)
⢠Diltiazem or nifedipine preferred.
⢠Titrate up to maximum tolerated dose.
⢠Systemic hypotension may prohibit use
⢠Only 50% of patients maintain response to CCB.
⢠Not in FC IV patients or severe right heart failure
54. Endothelin Receptor Antagonists (ETRA)
⢠Targets relative excess of endothelin-1 by blocking receptors
on endothelium and vascular smooth muscle
⢠Bosentan, Ambrisentan, Sitaxentan, Macitentan
⢠Ambrisentan is ET-A selective.
⢠Both show improvement in 6MWD and time to clinical
worsening.
⢠Monthly transaminase monitoring required for both
⢠Annual cost is high
55. Potential for serious liver injury (including very rare cases of
unexplained hepatic cirrhosis after prolonged treatment)
⢠Oral dosing
⢠Initiate at 62.5 mg BID for first 4 weeks
⢠Increase to maintenance dose of 125 mg BID thereafter
⢠Initiation and maintenance dose of 62.5 mg BID
recommended for patients >12 years of age with body weight
>40kg
⢠No dose adjustment required in patients with renal impairment
⢠No predetermined dose adjustments required for concomitant
warfarin administration.
56. Phosphodiesterase type 5 inhibitors
Sildenafil
⢠is an orally active, potent and selective inhibitor of phosphodiesterase
type 5
â Side effects: headaches, epistaxis, and hypotension (transient)
â Sudden hearing loss
â Drug interaction with nitrates
â FDA approved dose is 20 mg TID
â Tadalafil 40mg OD
â Vardenafil 5mg OD
58. Epoprostenol
⢠First PAH specific therapy available in the mid
1990âs
⢠Lack of acute vasodilator response does not
correlate well with epoprostenol unresponsiveness.
⢠Very short half life = 2 minutes
⢠Delivered via continuous infusion
⢠Cost about $100,000/year
59. ⢠Treprostinil (Remodulin)
⢠Continuous subcutaneous infusion or IV infusion
⢠Longer t1/2 = 4 hours
⢠Less risk of rapid fatal deterioriation if infusion stops
⢠Treprostinil
⢠Intravenous treprostinil
â Hemodynamic improvements and 6MWD improvements
â No site pain
â Risk of catheter related bloodstream infection and embolic phenomenon
â Recent concerns about increased gram-negative bloodstream infections.
60. Iloprost
⢠Inhaled prostacyclin
⢠Administered 6-9 times daily via special nebulizer
⢠Reported risk of morning syncope
⢠Improvements in 6MW, functional class and hemodynamics observed
⢠Safety and side effects
â Potential for increased hypotensive effect with antihypertensives
â Increased risk of bleeding, especially with co-administration of anticoagulants
â Flushing, increased cough, headache, insomnia
â Nausea, vomiting, flu-like syndrome
â Increased liver enzymes
61. Guanylate cyclase stimulant
⢠Stimulators of the nitric oxide receptor.
⢠Dual mode of action.
⢠They increase the sensitivity of sGC to endogenous nitric oxide (NO)
⢠Directly stimulate the receptor to mimic the action of NO.
⢠Riociguat
⢠is an oral sGC stimulant that has reported benefit in patients with inoperable
and persistent chronic thromboembolic pulmonary hypertension (CTEPH;
62.
63. Treatment naĂŻve
patient
PAH confirmed by
expert center
General measures
(Table 16)
Supportive therapy
(Table 17)
CCB Therapy
(Table 18)
Vasoreactive
Acute vasoreactivity test
(IPAH/HPAH/DPAH only)
N on-vasoreactive
Lowor intermediaterisk
(W HO FC IIâIII)a
High risk
(W HO FC IV)a
Initial
monotherapyb
(Table 19)
Initial oral
combinationb
(Table 20)
Initial combination
including i.v. PCAc
(Table 20)
Patient already
on treatment
Inadequate clinical response
(Table 15)
Consider referral for
lung transplantation
Double or triple sequential combination
(Table 21)
Inadequate clinical response
(Table 15)
Consider listing for lung transplantationd
(Table 22)
CCB= calcium channel blockers;DPAH = drug-induced PAH;HPAH = heritablePAH;IPAH = idiopathicPAH;i.v.= intravenous;PAH = pulmonaryarterial hypertension;
PCA = prostacyclinanalogues;W HO-FC =W orldHealthOrganizationfunctionalclass.
a
SomeW HO-FC III patientsmaybeconsidered high risk (seeTable13).
b
c
Intravenousepoprostenol should beprioritised asit hasreduced the3 monthsratefor mortality in high risk PAH patientsalso asmonotherapy.
d
Consider also balloonatrialseptostomy.
64. Failure of Medical Therapy: Consider Atrial Septostomy
⢠Improved left-sided filling
⢠Decreased right-sided pressures
⢠May serve as bridge to transplant
65. Failure of Medical Therapy: Indications for Lung Transplant
⢠New York Heart Association (NYHA) functional
class III or IV
⢠Mean right atrial pressure >10 mmHg
⢠Mean pulmonary arterial pressure >50 mmHg
⢠Failure to improve functionally despite medical
therapy
⢠Rapidly progressive disease
66. Following Response to Therapy
⢠Six minute walk test
⢠Echocardiogram
⢠Right heart catheterization
⢠BNP
⢠Functional class
67. What we can doâŚ
ďą High index of suspicion
ďą Electrocardiography, Radiography, Echocardiography, Lung
function testing, HRCT, Angiography, Exercise testing
ďą Easily available â CCBs, Sildenafil
ďą Educate suitable candidates about catheterization
68. Recommendations for paediatric pulmonary
hypertension
PH diagnostic algorithm workup is recommended for diagnosis and
definition of the specific aetiology group in paediatric PH patients
PAH-specific therapeutic algorithm is recommended in paediatric
PH patients
Combination therapy should be considered in paediatric PH patients
Specific paediatric determinants of risk should be considered
69. Recommendations for pulmonary arterial hypertension
associated with congenital heart disease
Bosentan is recommended in WHO-FC III patients with Eisenmenger syndrome
Other ERAs, PDE-5is and prostanoids should be considered in patients with Eisenmenger syndrome
In the absence of significant haemoptysis, oral anticoagulant treatment may be considered in
patients with PA thrombosis or signs of heart failure
The use of supplemental O2 therapy should be considered in cases in which it produces
a consistent increase in arterial O2 saturation and reduces symptoms
If symptoms of hyperviscosity are present, phlebotomy with isovolumic replacement should be
considered, usually when the haematocrit is .65%
The use of supplemental iron treatment may be considered in patients with low ferritin plasma
levels
Combination drug therapy may be considered in patients with Eisenmenger syndrome
The use of CCBs is not recommended in patients with Eisenmenger syndrome
70. Recommendations for pulmonary arterial hypertension
associated with connective tissue disease
In patients with PAH associated with CTD, the same treatment algorithm as
for patients with IPAH is recommended
Resting echocardiography is recommended as a screening test in
asymptomatic patients with SSc, followed by annual screening with
echocardiography, DLCO and biomarkers
RHC is recommended in all cases of suspected PAH associated with CTD
Oral anticoagulation may be considered on an individual basis and in the
presence of thrombophilic predisposition
71. Recommendations for pulmonary arterial hypertension
associated with portal hypertension
Echocardiographic assessment for signs of PH is recommended in symptomatic patients with
liver disease or portal hypertension and in all candidates for livertransplantation
It is recommended that patients affected by PAH associated with portal hypertension should be
referred to centres with expertise in managing both conditions
It is recommended that the treatment algorithmfor patients withother forms of PAH should be
applied to patients with PAH associatedwith portal hypertension, taking into account the severity
of liver disease
Anticoagulation is not recommended in patients with PH associated with portal hypertension
Liver transplantation may be considered in selected patients responding well to PAH therapy
Liver transplantation is contraindicated in patients with severe and uncontrolled PAH
72. Recommendations for pulmonary arterial hypertension
associated with human immunodeficiency virus infection
Echocardiographic screening in asymptomatic HIV patients to detect PH is not recommended
In patients with PAH associated with HIV infection, the same treatment algorithm used for
patients with PAH should be considered, taking into consideration co-morbidities and drugâ
drug interactions
Anticoagulation is not recommended because of a lack of data on the efficacy: risk ratio
73. Recommendations for pulmonary veno-occlusive disease and
pulmonary capillary haemangiomatosis
A combination of clinical findings, physical examination, bronchoscopy and radiological
findings is recommended to diagnose PVOD/PCH
Identification of a bi-allelic EIF2AK4 mutation is recommended to confirm a diagnosis of
heritable PVOD/PCH without histological confirmation
Referral of eligible patients with PVOD/PCH to a transplant centre for evaluation is
indicated as soon as the diagnosis is established
Patients with PVOD/PCH should be managed only in centres with extensive experience in PH
due to the risk of lung oedema after the initiation of PAH therapy
74. Management of pulmonary hypertension in left heart
disease
Optimization of the treatment of the underlying condition is recommended beforeconsidering
assessment of PH-LHD (i.e. treating structural heart disease)
It is recommended to identify other causes of PH (i.e. COPD, sleep apnoea syndrome, PE, CTEPH)
and to treat them when appropriate before considering assessment of PH-LHD
It is recommended to perform invasive assessment of PH in patients on optimized volume status
Patients with PH-LHD and a severe Pre-capillary component as indicated by a high DPG and/or high
PVR should be referred to an expert PH centre for a complete diagnostic workup and an individual
treatment decision
The importance and role of vasoreactivity testing is not established in PH-LHD, except in patients
who are candidates for heart transplantation and/ or LV assist device implantation
The use of PAH-approved therapies is not recommended in PH-LHD
75. Recommendations for chronic thromboembolic pulmonary
hypertension
In PE survivors with exercise dyspnoea, CTEPH should be considered
Life-long anticoagulation is recommended in all patients with CTEPH
It is recommended that in all patients with CTEPH the assessment of operability and decisions
regarding other treatment strategies should be made by a multidisciplinary team of experts
Surgical PEA in deep hypothermia circulatory arrest is recommended for patients with CTEPH
Riociguat is recommended in symptomatic patients who have been classified as having
persistent/recurrent CTEPH after surgical treatment or inoperable CTEPH by a CTEPH team
including at least one experienced PEA surgeon
Off-label use of drugs approved for PAH may be considered in symptomatic patients who have
been classified as having inoperable CTEPH by a CTEPH team including at least one experienced
PEA surgeon
76. Recommendations for pulmonary hypertension due to lung
diseases
Echocardiography is recommended for the non-invasive diagnostic assessment of suspected PH in
patients with lung disease
Referral to an expert centre is recommendedd in patients with echocardiographic signs of severe PH
severe right ventricular dysfunction
The optimal treatment of the underlying lung disease, including long-term O2 therapy in patients with
chronic hypoxaemia, is recommended in patients with PH due to lung diseases
Referral to PH expert center should be considered for patients with signs of severe PH/severe RV failure for
individual-based treatment
RHC is not recommended for suspected PH in patients with lung disease, unless therapeutic consequences
are to be expected (e.g. lung transplantation, alternative diagnoses such as PAH or CTEPH, potential
enrolment in a clinical trial)
The use of drugs approved for PAH is not recommended in patients with PH due to lung diseases
77. 2015 ESC/ERS Guidelines for the diagnosis and
treatment of pulmonary hypertension
The Joint Task Forceforthe Diagnosis and Treatment of Pulmonary
Hypertension of the European Society of Cardiology (ESC) and the
European Respiratory Society (ERS)
Endorsedby:AssociationforEuropeanPaediatricandCongenital Cardiology
(AEPC), International Society for Heart and Lung Transplantation (ISHLT)
Authors/Task Force Members: NazzarenoGalie`* (ESC Chairperson)
(Italy), Marc Humbert*a (ERS Chairperson) (France), Jean-Luc Vachieryc
(Belgium),
Simon Gibbs (UK), Irene Lang (Austria), Adam Torbicki (Poland), Ge´rald
Simonneaua (France), Andrew Peacocka (UK), Anton Vonk Noordegraafa (The
Netherlands), Maurice Beghettib (Switzerland), Ardeschir Ghofrania (Germany),
MiguelAngelGomezSanchez(Spain),GeorgHansmannb(Germany),Walter
Klepetkoc (Austria), Patrizio Lancellotti (Belgium), Marco Matuccid (Italy),Theresa
McDonagh (UK),Luc A. Pierard (Belgium),Pedro T. Trindade (Switzerland),
Maurizio Zompatorie (Italy) and Marius Hoepera (Germany)