Pathophysiology of the respiratory system III –
Pulmonary blood flow
Pulmonary circulation
Pulmonary hypertension definition  classification
– role of hypoxic pulmonary vasoconstriction and vascular
remodelling
Pulmonary embolism
Pulmonary oedema
ARDS
Pulmonary vs. systemic circulation
• Lungs are the only organ through which entire blood passes!!!
– the volume equals to the cardiac output (CO)
• The pressure is generated by the right ventricle (RV)
– increased CO (e.g. physical activity) must by adopted by pulmonary circulation without a significant
increase of the work of RV
• see recruitment and distension of pulmonary vessels (capillaries)
– therefore, given the differences in pressure and volume parameters in pulmonary bed, the
morphology of pulmonary vessels is different
• smaller amount of smooth muscle, larger distensibility by pressure and increased flow
• however, smooth muscle of pulmonary arteries is very important – see hypoxic pulmonary vasoconstriction
• Pulmonary vascular resistance (PVR) varies between imperium and expirium, i.e. with
changing lung volume (see further)
• Lungs have a dual blood supply
– deoxygenated blood from RV via pulmonary artere (PA)
– systemic (nutritional) supply of conductive zone airways via bronchial circulation
• branching from descendent aorta
• bronchial veins drain in small extent post capillary to pulmonary veins and are responsible for a physiological
R-L shunt
• 4 main pulmonary veins drain into LA
The pulmonary capillary network
• The PA splits into left and right branches,
further to smaller arteries an arterioles and
finally to capillary network
– this is a low-pressure system that can expand two
to three times the normal size before a
significant increase in pulmonary capillary
pressures is detectable
• normal PAP in a healthy adult 22-25/8-10 mmHg
(mPAP 15 mmHg)
• normal SAP in a healthy adult  120/80 mmHg (mSAP
96 mmHg)
– under normal resting conditions, some pulmonary
capillaries are closed and not perfused
• The pulmonary circulation has two
mechanisms for lowering PVR when vascular
pressures are increased because of increased
blood flow
– (1) recruitment = opening of previously closed
capillary vessels
– (2) distention = widening of capillary vessels
Recruitment and distension of pulmonary capillaries
Pulmonary vs. systemic circulation
• Pulmonary circulation
–  P /  resistance /  compliance
• lower pressure gradient is sufficient to cover the distance between RV and LA
– paradoxical response to  PAO2
(i.e. alveolar hypoxia) – vasoconstriction
• with the aim to optimise VA/Q mismatch by redistribution of blood to well ventilated parts
of the lungs
• Systemic circulation
–  P /  resistance /  compliance
• massive pressure gradient necessary to cover large distance between LV and RA
– typical response to  PaO2
(i.e. hypoxemia) – vasodilation
• with the aim to increase perfusion and oxygen delivery
Pulmonary vascular resistance
Pulmonary alveolar and extra-alveolar vessels
• alveolar vessels
– capillaries of alveolar septs exposed to alveolar pressure
(changing during inspiration and expiration)
• they become compressed by inspiring
• extra-alveolar vessels
– arteries and veins in interstitium paralleling branching of
airways
• together they create a „broncho-vascular bundle“
– they are distended by radial traction of elastic elements of
interstitium
• therefore they become opened by inspiring
– this is a compartment
initially collecting fluid
in lung oedema
Pulmonary vascular resistance - minimal at FRC
Relation between lung volume and PVR
• PVR is the main determinant of RV afterload and can increase
significantly at both extremes of lung inflation
– as lung volume increases from residual volume (RV) to total lung capacity (TLC),
the “alveolar” vessels (red) become increasingly compressed by the distending
lung units, and so their resistance increases
– whereas the resistance of the “extra-alveolar” vessels (blue) falls as they
become less tortuous and dilate with lung inflation
• During healthy conditions, these opposing effects of inflation normally
optimize at functional residual capacity (FRC), assuming patency of all
lung units
„Starling resistor“ – effect of alveolar pressure on vessel diameter
Koncept plicních zón
• zóna 1
– u normální plíce (ve vzpřímeném postoji)
prakticky neexistuje
– patologicky se zvětšuje u
• hypotenze/hypovolemie (např. krvácení)
• mechanická ventilace plic s pozitivním
přetlakem
• zóna 2
– průtok je určen rozdílem Pa a PA a ne
tlakovým gradientem Pa – Pv
– patologicky se zvětšuje u
• hypoventilace a dýchání s malým DO
• zóna 3
– průtok je určen rozdílem Pa – Pv, protože
oba jsou větší než alveolární tlak (PA)
– patologicky se zvětšuje u
• PH a atelektázy
PULMONARY HYPERTENSION
Pulmonary hypertension (mPAP >25 mmHg) – diagnosis
• PH consists of a group of diseases with a
resting mPAP ≥25 mmHg (≥25 mmHg during
exercise)
– initial diagnosis (or screening) by
echocardiogram, however, Doppler estimates
of PAP are inaccurate in many patients, and
cannot be used to quantify RA, pulmonary
venous, LA or LV pressures reliably
• PAP measured with right heart catheterization
• other parameters are necessary to classify
and prognosticate patients appropriately
– right ventricular end-diastolic pressure
(RVEDP)
– left ventricular end-diastolic pressure (LVEDP)
• left heart catheterisation only in some patients
(measurements of PV and LA pressure)
– congenital heart defects or structural heart diseases
• typically pulmonary blood flow and end-expiratory
pulmonary artery wedge pressure (PAWP)
commonly used as a surrogate of LVEDP
Right heart (PA) catheterization
• precise assessment of pressure waves
generated by the different cardiac chambers
• performed by pulmonary artery catheter
(frequently referred to as a Swan-Ganz
catheter) following local anaesthesia via the
femoral, jugular, brachial or subclavian vein
access
Pulmonary hypertension (mPAP >25 mmHg) – pathogenesis
• pathogenesis is driven by the triad
of vasoconstriction,
microthrombosis and remodelling
of small pulmonary arteries
Pulmonary hypertension (MPAP >25 mmHg) – classification
• A–G level of the haemodynamic obstruction/problem:
– A pulmonary arteries and arterioles
• pulmonary arterial hypertension (group I)
• pulmonary hypertension associated with lung diseases (group III)
– B pulmonary venules: pulmonary veno-occlusive disease
– C pulmonary veins: PV stenosis
– D left atrium: stiff LA
– E mitral valve: mitral stenosis, mitral regurgitation
– F left ventricle: heart failure with reduced ejection fraction,
heart failure with preserved ejection fraction
– G left ventricular outflow tract: aortic stenosis
Group 1: Pulmonary arterial hypertension (PAH)
• mPAP ≥ 25 mmHg, PAWP ≤ 15 mmHg (i.e. pre-capillary) and PVR > 3
Wood Units
• types of PAH
– idiopathic (iPAH) comprising the majority of cases
• iPAH has been found to be strongly associated with female gender, family
history and genetic variants, especially bone morphogenetic protein receptor
type 2 (BMPRII) mutations
– secondary to
• connective tissue diseases (CTD)
• congenital heart disease - hyperkinetic
– at the end might lead to Eisenmenger’s syndrome
• drugs, toxins, HIV, schistosomiasis, portal hypertension, …
• pre-capillary arterioles are affected by an angioproliferative
vasculopathy that increases the PVR, thereby increasing the RV
afterload with the resulting right heart failure being the ultimate
cause of mortality
• management of PAH has advanced rapidly in recent years due to
improved understanding of the pathophysiology revealing a
disruption of three key signalling pathways
– nitric oxide (NO)
• phosphodiesterase 5 inhibitors (PDE-5i)
• guanylate cyclase (GC) stimulators
– prostacyclin (PGI2) - thromboxane A2 (TXA2)
• prostacyclin analogues and receptor agonists
– endothelin-1 (ET-1)
• endothelin receptor antagonists (ERAs) available as ETA selective or dual-action
on ETA and ETB receptors
PAH due to CHD – Eisenmenger’s syndrome
• PAH develops in CHD patients as a result of
increased pulmonary blood flow due to
the presence of a left-to-right shunts
– simple
• atrial septal defect (ASD)
• ventricular septal defects (VSD)
• patent ductus arteriosus
– complex
• complete atrioventricular septal defect (AVSD)
• truncus arteriosus
• single ventricle
• transposition of the great arteries with
• Eisenmenger’s syndrome = reversal of the
initial L-R shunt to the right-to-left
(pulmonary-to-systemic) shunt due to
remodelling of pulmonary vasculature
Group 2: PH due to left heart disease (PH-LHD)
• mPAP ≥ 25 mmHg, PAWP > 15
mmHg (i.e. post-capillary) and PVR
normal (< 3 Wood Units)
• causes
– adult population
• systolic or diastolic heart failure (HFpEF or
HFrEF)
– pulmonary vascular complications of heart
failure with preserved ejection fraction
• valvular disease
– paediatric population
• anatomical left-sided obstruction (e.g.,
valvar aortic stenosis, coarctation of the
aorta, obstructive hypertrophic
cardiomyopathy and others
The Journal of Physiology, Volume: 597, Issue: 4, Pages: 1143-1156, First published: 13 December 2018, DOI: (10.1113/JP275858)
Progression left heart disease to congestive heart failure
The Journal of Physiology, Volume: 597, Issue: 4, Pages: 1143-1156, First published: 13 December 2018, DOI: (10.1113/JP275858)
Lung congestion can lead to oedema in LHD
The Journal of Physiology, Volume: 597, Issue: 4, Pages: 1143-1156, First published: 13 December 2018, DOI: (10.1113/JP275858)
Fluid balance in the lungs
• determined by
– capillary hydrostatic pressure
• low but still higher than pressure in the
interstitium
– colloid osmotic pressure
• higher in capillaries than in interstitium,
therefore opposes the hydrostatic pressure
– capillary permeability (leakiness)
• in total, very small amount of fluid leaks
into interstitial space and this amount is
drained by lymphatics
Pulmonary lymphatics
• lymphatics start in
the interstitial space
between the alveolar
cells and the capillary
endothelium of the
pulmonary arterioles
– the tracheobronchial
lymph nodes are
arranged in five main
groups:
• paratracheal, superior
tacheobronchial,
subcarinal,
bronchopulmonary
and pulmonary
Alveolar fluid clearance
• The alveolar epithelium is composed of
squamous Alveolar Type I (AT I) and
cuboidal Alveolar Type II (AT II) cells
• Both AT I and AT II cells contain
amiloride-sensitive epithelial Na
channels as well as Na+/K+-ATPase
which are involved in alveolar
transepithelial sodium transport
• In addition, AT I cells have aquaporin 5,
which contributes to either water or gas
exchange
• AT II cells have the Cystic Fibrosis
Transmembrane conductance Regulator
(CFTR) and Chlorine (Cl-) channels, which
mediate apical Cl- transport
• The tight junctions (a chain in grey
between Alveolar Epithelial Cells (AECs))
and adherens junctions (in red between
AECs) between adjacent alveolar
epithelial cells provide a physical barrier
from paracellular solute transport
Lung oedema
• interstitial or alveolar oedema
• cardiogenic
– result of acute decompensation of left sided heart failure
• commonly precipitated by fluid overload, rise in BP (hypertensive
emergency), myocardial infarction, acute valvular disease,
tachyarrhythmia, acute renal injury
• non-cardiogenic = direct injury to alveoli (inflammation)
increasing capillary permeability
– serious clinical form is denoted as acute respiratory distress syndrome
(ARDS)
– causes
• external
– pulmonary infection
– inhalation of toxic substances or aspiration
– chest trauma
• internal
– sepsis
– low oncotic pressure
• consequences – an impaired gas exchange
– diffusion impairment
– change of lung compliance – intrinsic restrictive ventilation disease
Group 3: PH due to lung disease and/or chronic hypoxia
• causes - chronic
– COPD
– interstitial lung disease
• scarring and inflammation in the lungs
– overlap syndromes
– conditions that cause hypoxemia
• obstructive sleep apnea
• alveolar hypoventilation disorders
– chronic exposure to hypoxia – high
altitude
• mechanisms (thin air = thick vessels)
– acute hypoxia leads to vasoconstriction
occurring due to alterations in redox and
NO signaling and release of vasoactive
mediators
– vessel remodeling in the context of
sustained hypoxic exposure due to HIFdependent
processes
Hypoxic pulmonary vasoconstriction (HPV)
• a physiological phenomenon in which small pulmonary arteries
constrict in the presence of alveolar hypoxia (low oxygen levels)
– as in hypoventilation and low VA/Q ratio
• typically in obstructive diseases (since these are chronic) resistant to
compensatory hyperventilation such as chronic bronchitis
• a homeostatic mechanism that is intrinsic to the pulmonary
vasculature
– intrapulmonary arteries constrict in response to alveolar hypoxia, diverting
blood to better-oxygenated lung segments, thereby optimizing
ventilation/perfusion matching and systemic oxygen delivery
• chronically happens with low V/Q ratio (and event. in long-lasting
hypoventilation)
• mechanisms involve (in brief)
– in response to alveolar hypoxia, a mitochondrial sensor dynamically
changes reactive oxygen species and redox couples in pulmonary artery
smooth muscle cells (PASMC)
– this inhibits potassium channels, depolarizes PASMC, activates voltagegated
calcium channels, and increases cytosolic calcium, causing
vasoconstriction
– sustained hypoxia activates rho kinase, reinforcing vasoconstriction, and
hypoxia-inducible factor (HIF)-1α, leading to adverse pulmonary vascular
remodelling and pulmonary hypertension (PH)
– this pre-capillary PH leads to right heart remodelling – cor pulmonale
Mechanism of HPV The current model of the
cellular mechanism of hypoxic
pulmonary vasoconstriction in
a rat pulmonary artery (PA).
Relevant ion channels are
displayed. Under normoxia,
the membrane potential of
the smooth muscle of the PA
is held at approximately −50
mV because of the TASK-like
background current of a K +
channel. Hypoxic conditions
initially decrease TASK activity.
When combined with TXA 2 ,
activation of NSC induces
membrane depolarization up
to the threshold voltage for
activation of K v channels
(Step 1). In addition to the
NSC activation, hypoxic
inhibition of the K v current
further depolarizes the
membrane potential (Step 2).
As the membrane potential
depolarizes above −40 mV, the
activation of VOCC L
eventually allows for Ca 2+
influx for contraction of
smooth muscles. K v , voltagegated
K + channel; NSC,
nonselective cation channel;
TASK-1, background-type K +
channel with a two-pore
domain (K2P); TXA 2 ,
thromboxane A 2 ; VOCC L ,
voltage-gated L-type Ca 2+
channels.
Primary role in non-ventilated foetal lung where HPV diverts blood to
the systemic vasculature
• at birth
– lung inflation and reaching stable
volumes
• surfactant
– pulmonary blood flow
• increase of alveolar PAO2 relieves
HPV and leads to vasodilation
– subsequent circulatory changes
(closure of foetal shunts)
– resorption of fluid from alveoli
• role of pneumycytes
Group 4: Chronic thromboembolic PH (CTEPH)
• 50% of CTEPH patients never have had a
specific episode of thrombosis that they recall
• meaning typically deep vein thrombosis (DVT)
event. followed by pulmonary embolism
– DVT frequency: calf, popliteal, femoral, pelvic, portal,
hepatic (Budd-Chiari sy), renal vein in nephrotic sy
– PE frequency: femoral (and other above knee)
• dg. venous duplex US + d-dimers (active
fibrinolysis)
• superficial thrombophlebitis might co-exist with
DVT!
– PE severity
• acute – small, sub-massive and massive
(haemodynamic instability)
– saddle PE
• chronic
• it is therefore important to rule out CTEPH on
every PH patient as it is a potentially curable
disease
• pulmonary angiogram
• perfusion (V/Q) scan
Virchow’s
triad
CETPH
• 3%-5% of all PE cases due to
organised blood clot following
– acute PE
– recurrent PE (successive)
• treated invasively by
– pulmonary
thromboendarterectomy (PTE)
– percutaneous balloon
angioplasty
– lifelong anticoagulation