This presentation covers the methodology of evaluating CTEPH (chronic thromboembolic pulmonary hypertension) case. It starts from the basic concepts of Pulmonary hypertension.

1. Evaluation of CTEPH
ABHIJIT JOSHI
NH

2. PULMONARY HYPERTENSION
• HC). PH was previously known as an orphan disease, that is, a
condition that affects few individuals and is overlooked by the
medical profession, health care systems, and pharmaceutical
companies. Although PH is indeed rare, one can no longer say that it
is being overlooked.
• Pulmonary hypertension (PH) is defined as an increase in mean
pulmonary arterial pressure (mPAP) of 25 mm Hg or greater at rest,
as assessed by right heart catheterization (RHC).

3. • the population resting mPAP is approximately 14 mm Hg, and a value
of 20 mm Hg encompasses two standard deviations above the
mean; a value of 25 mm Hg is therefore definitively above the normal
distribution of values; and (3) the value of 25 mm Hg has, by
consensus, been used to identify candidates for participation in
clinical trials and registries.

4. Clinical presentation - History
• The most common initial symptoms of PH include exertional dyspnea or
reduced exercise tolerance, chest pain, fatigue, and light-headedness.
• Manifestations of more advanced disease include syncope, abdominal
distention, and lower extremity edema attributable to right ventricular
failure.
• Delay in diagnosis occurs in ~20% patients.
• A delay in diagnosis was most frequently observed in patients whose
symptoms occurred at a younger age (< 36 years) and in those with
chronic obstructive pulmonary disease (COPD) or obstructive sleep
apnea. It appears that young people in whom cardiopulmonary disease is
considered less likely to be present or patients thought to have an
alternative explanation for the symptoms are most at risk for a delayed
diagnosis.

5. • In some patients the clinical presentation may be related to mech-
anical complications of PH and the abnormal distribution of blood
flow in the pulmonary vascular bed.
• These include haemoptysis re- lated to rupture of hypertrophied
bronchial arteries, as well as symptoms attributable to pulmonary
arterial dilatation such as hoarseness caused by compression of the
left recurrent laryngeal nerve, wheeze caused by large airway
compression and angina due to myocardial ischaemia caused by
compression of the left main coronary artery. Significant dilation of
the PA may result in its rupture or dissection, leading to signs and
symptoms of cardiac tamponade.

6. Clinical findings
Accentuated pulmonary component of
S 2 (audible at the apex in > 90%)
High pulmonary pressure that increases force of
pulmonic valve closure
Early systolic click Sudden interruption of opening of the pulmonary valve
into a high-pressure artery
Midsystolic ejection murmur Turbulent transvalvular pulmonary outflow
Left parasternal lift High right ventricular pressure and hypertrophy present
Right ventricular S 4 (in 38%) High right ventricular pressure and hypertrophy present
Increased jugular A wave Poor right ventricular compliance

7. Moderate to severe pulmonary hypertension
Holosystolic murmur that
increases with inspiration
Tricuspid regurgitation
Increased jugular V waves
Pulsatile liver
Diastolic murmur Pulmonary regurgitation
Hepatojugular reflux High central venous pressure

8. Advanced pulmonary hypertension with right ventricular failure
Right ventricular S 3 (in 23%) Right ventricular dysfunction
Distention of jugular veins Right ventricular dysfunction or tricuspid
regurgitation, or both
Hepatomegaly Right ventricular dysfunction or tricuspid
regurgitation, or both
Peripheral edema (in 32%)
Ascites
Low blood pressure, diminished
pulse pressure, cool extremities
Reduced cardiac output, peripheral
vasoconstriction

9. • Wheeze and crackles are usually absent.
• inspiratory crackles may point towards interstitial lung disease
• An accentuated pulmonic component of the second heart sound is
present in most patients with PAH because of the high pulmonary
pressure, which results in more forceful closure of the pulmonic valve.
If a split S 2 is audible at the apex, P 2 may be accentuated and the
possibility of PAH should be further investigated.

10. • Common electrocardiographic findings include right atrial
enlargement, right axis deviation, and right ventricular enlargement,
often with a strain pattern
• Chest radiograph : enlarged main and hilar pulmonary artery
shadows with “pruning” or attenuation of the peripheral
vasculature and right ventricular enlargement, which is best
appreciated on the lateral view. Other findings on the chest
radiograph may point to an associated diagnosis, such
as hyperinflation with flat diaphragms (COPD) or pulmonary
venous congestion (left-sided heart disease)

11. • So, by now, with history and physical examination we have made a
diagnosis of Pulmonary Hypertension.
• Next is to zero down the cause.

12. Pathophysiological types
PH
PRE CAPILLARY POST CAPILLARY
PRE AND POST
CAPILLARY

14. PRE CAPILLARY
• Precapillary PH is defined as an
mPAP of 25 mm Hg or more; a
pulmonary capillary wedge
pressure (PCWP) of 15 mm Hg
or less; and a pulmonary
vascular resistance (PVR) of
more than 3 Wood units.
POST CAPILLARY
• Postcapillary PH is present when
the mPAP is 25 mm Hg or more
and the PCWP is 15 mm Hg or
more.

15. • Recent guidelines have updated the characterization of postcapillary
PH and now rely on the DPG (diastolic PAP–mean PCWP) gradient to
determine the presence of pulmonary vascular disease as opposed
to passive congestion.
• PCWP represents LA pressures, which will rise in cardiac causes : and
DPG will drop.
• A DPG of less than 7 mm Hg and/or a PVR of less than 3 Wood units
reflects isolated postcapillary PH, whereas a DPG of more than
7 mm Hg and /or a PVR of more than 3 Wood units is
considered combined postcapillary and precapillary PH .

16. Aetiological classification

17. Overview of the PH groups
• The prevalence of PAH associated with CTDs is greatest in those with the scleroderma
spectrum of diseases, although PAH can occur in the setting of any of the connective tissue
diseases.
• Because PAH has a high prevalence in patients with scleroderma, scleroderma patients
constitute a high-risk group in whom screening can be done; early therapy can be instituted
if a diagnosis of PAH is then made in a patient.

18. All these have unknown mechanisms
• PAH is a rare, but well-established, complication of human
immunodeficiency virus (HIV) infection. Population studies of
individuals infected with HIV suggest that the incidence of PAH is
approximately 0.5% and is independent of the CD4 + cell count or
previous opportunistic infections. The prevalence of HIV-associated
PAH has not changed with the widespread use of highly active
antiretroviral therapy.

19. • The development of PAH in association with elevated pressure in the
portal circulation is known as portopulmonary hypertension. Portal
hypertension, as opposed to the underlying liver disease, is the risk
factor. Neither the severity of the liver disease nor the degree of
portal hypertension predicts the presence or severity of
portopulmonary hypertension.
• The presence of PAH increases the risk associated with liver
transplantation.
• Diagnosed most commonly in endemic areas of South America and
sub-Saharan Africa, PH associated with schistosomiasis has clinical
and histologic features similar to those of IPAH. PAH develops in
approximately 5% of patients with hepatosplenic schistosomiasis,
making it one of the most prevalent causes of PAH worldwide.

20. Drug- and Toxin-Induced Pulmonary Arterial
Hypertension
• An association between anorexigens (appetite-suppressant drugs that increase,
release, and block the reuptake of serotonin) and PAH was initially observed in
the 1960s, when an epidemic of IPAH (then termed PPH) was noted in Europe
after the introduction of aminorex fumarate. Structurally related compounds
such as fenfluramine, dexfenfluramine, and benfluorex were also demonstrated
to be associated with the development of PAH in the 1980s, 1990s, and 2000s,
and have since been withdrawn from the market. 16 Epidemiologic studies have
also linked the development of PAH to rapeseed oil, l -tryptophan, interferon
alpha and beta, and illicit drugs such as methamphetamines. More recently, the
tyrosine kinase inhibitor dasatinib has been associated with the development of
PAH. 17 From the approval of dasatinib in November 2006 to September 30,
2010, nine incident cases of PAH in patients treated with dasatinib were
identified in the French National Registry, which corresponds to an estimated
incidence of 0.45% in patients exposed to dasatinib in France. Improvement is
usually observed after cessation of the use of dasatinib.

21. pathology
• In PAH the pathologic lesions involve
mainly the distal pulmonary arteries
(< 500 µm in diameter) and are
characterized by medial hypertrophy,
intimal proliferative and fibrotic
changes (concentric, eccentric),
adventitial thickening with moderate
perivascular inflammatory infiltrates,
complex lesions (plexiform, dilated
lesions), and thrombotic lesions .
• PAH patients may show significant
bronchial arterial remodeling. Such
changes in the systemic vasculature
may cause episodes of hemoptysis

22. Left-sided heart disease is probably the most frequent cause of PH

23. • Primary or pathognomonic vascular changes in the arterial wall may
be absent in group 2 PH. Capillary and arterial remodeling develop as
a result of backward transmission of increased pulmonary venous
pressure. The pathologic changes are characterized by enlarged and
thickened pulmonary veins, pulmonary capillary dilation, interstitial
edema, alveolar hemorrhage, and lymphatic vessel and lymph node
enlargement. The distal pulmonary arteries may be affected by
medial hypertrophy and intimal fibrosis.
• The pulmonary vasculature tries to adapt by vasoconstricting the
arteries and increasing forward flow. But this increases PVR and
adversely affects the RV

25. Mild PH is common in both severe interstitial lung disease and
severe chronic obstructive pulmonary disease (COPD), while
severe PH is uncommon.
Severe PH can be seen in the combined emphysema/ fibrosis
syndrome, where the prevalence of PH is high

26. • Group 4: CTEPH spectrum, to be discussed in detail later.
• Group 5: Pulmonary hypertension with unclear and/or multifactorial
mechanisms

28. How do you investigate – for CTEPH?
• Aim is to establish whether it is pre-capillary or post capillary: I.e. rule
out the left heart as the cause.
• Next is in the pre-capillary causes, rule out the lung, as lung pathology
would be the most common differential.

30. The Echocardiogram
• PAH vs PVH – echo has indirect indicators to differentiate these,
needs Cath to make a definitive diagnosis
• Relative size of left vs right heart chambers
• E/A ratio
• Atrial Septal bowing
• Pre vs Post capillary PAH
• Evaluate for signs of elevated PVR – definitive measurement by cath
• Severity of disease:
• RV function - TAPSE
• Pericardial effusion

32. PASP : pulmonary artery systolic pressure
• PASP is NOT the criterion to define PAH, however it is an important
predictor of PH. Also useful for follow up .
• Mean PA pressures and diastolic PA pressures are not reliably
recorded on echo and need Cath.
• PLAX view is used to obtain a coaxial TR jet.
• V-max of the TR jet is used in conjuction with RA pressure
estimate(again an indirect measurement), to obtain PASP.
• Modified Bernoulli's equation is used to compute

37. RV on echo
• Signs of RV enlargement (apical 4-chamber view): RV shares apex
with LV; RV bigger than LV; RV basal diameter > 4.2 cm
• RV hypertrophy (subcostal view): RV end-diastolic wall thickness >
5 mm
• RV systolic dysfunction: RV fractional area change < 35%;
• TAPSE < 1.6 cm;
• RV tissue Doppler s′ velocity < 10 cm/s at base of RV free wall
(tricuspid annulus)
• Septal flattening: in systole = RV pressure overload and in diastole =
RV volume overload

38. High PVR on echo
• Normal pulmonary vasculature with high compliance produces a
reflected wave that propagates slowly, reaching the RVOT after the
completion of the systolic phase.
• In contrast, in the presence of decreased pulmonary vascular
compliance, reflected waves propagate more rapidly, with less
attenuation, arriving at the RVOT during systole and causing mid-
systolic notching.

39. A: no notching
B: mid systolic notch , followed by a second
acceleration (high PVR but good RV function)
C: no acceleration after the mid systolic notch (RV is
poor along with high PVR)

41. Now what??
• So , till now, we have reached a point where:
• We have a detailed, but still not definitive evaluation of the heart.
• We know the status of the LV and can surmise whether or not the left heart is
the culprit for the patient's PAH
• Now, we are looking for:
• A definitive diagnosis of pre vs post capillary PAH = Right Heart Cath
• Evaluation of the Lung – after the heart, the lung is the next possible culprit =
V/Q and CT

42. RIGHT HEART CATHETERISATION
• Invasive hemodynamic assessment by RHC is pivotal in the evaluation
of any patient with suspected PAH.
• RHC is typically performed after the noninvasive testing for PH
described earlier. Some patients initially suspected of having PAH will
not require RHC because they have had an alternative diagnosis
established by noninvasive testing.
• However, all patients who are still suspected of having PAH after
noninvasive evaluation should undergo RHC before the initiation of
therapy.

43. Essential measurements during RHC
• Oxygen saturation (superior and inferior vena cavas, pulmonary and systemic arteries)
• Right atrial pressure
• Right ventricular pressure
• Pulmonary artery pressure
• Left-sided filling pressure (PAWP, left atrial pressure, or left ventricular end-
diastolic pressure [LVEDP])
• CO/cardiac index
• PVR
• Systemic blood pressure
• Heart rate
• Response to acute vasodilators

44. APPRECIATE THE DIASTOLIC PRESSURE GRADIENT = PA DIASTOLIC PRESSURE – MEAN WEDGE
PRESSURE

45. COMBINATION OF DIASTOLIC PRESSURE GRADIENTS AND PVR DATA ARE USED TO
RELIABLY DISTINGUISH PRE AND POST CAPILLARY PAH

46. • CATH data is also used to know operability and severity of disease,
discussed later
• So, now we have established whether the Patient has Pre capillary or
Post capillary PAH. Let us go ahead with a diagnosis of pre capillary
PAH
• Next, we have 2 possible culprits:
• 1. ARTERIES
• 2. LUNGS

47. V/Q SCAN, PFT, ABG, CT
• A Ventilation – Perfusion Scintigram is the screening method of choice
to rule out CTEPH. ALL patients with unexplained dyspnoea + PAH
need CTEPH screening.
• PFTs and ABGs help rule out lung pathology
• CT pulmonary angiogram shows both lung and vascular pathology,
but lacks the sensitivity of a v/q. It is difficult to appreciate cteph
lesions, the radiologist has to be told specifically to look for the same.
• A conventional pulmonary angiogram is almost never needed

48. V/Q SCAN
• Most common gas used is XENON for ventilation scanning
• Tc-99m macroaggregated albumin (MAA) is the radio-
pharmaceutical used to perform most perfusion lung scans
• Normal ventilation scans have homogeneous radiopharmaceutical
distribution throughout all lung fields on all three phases of the scan,
initial breath, equilibrium, and washout. A subtle base-to-apex
gradient may be seen
• Normal half-time for xenon washout is less than 1 minute. Washout is
complete within 3 minutes. Retention (trapping) of xenon in the lungs
in a focal or in a diffuse pattern is an indication of obstructive lung
disease

49. • Normal perfusion scans show well-defined margins of both lungs on
all views with sharply defined costophrenic angles. A mild base-to-
apex count activity gradient is present due to the physical difference
in lung thickness of the base compared with the apex. Tracer
distribution should otherwise be homo- geneous
• A v/q cannot differentiate acute from chronic PE.

53. • Now, we are in a position to say we are dealing with Pulmonary
embolism.
• But we are yet to know whether it is acute or chronic.
• Let us discuss pathology of pulmonary embolism first.

54. The organised thrombus and vascular
remodelling
• INTIMAL THICKENING is a stereotyped response to vascular injury.

55. Organization and recanalization. Older thrombi become organized
by the ingrowth of endothelial cells, smooth muscle cells, and
fibroblasts . Capillary channels eventually form that reestablish the
continuity of the original lumen, albeit to a variable degree.
Continued recanalization may convert a thrombus into a smaller
mass of connective tissue that becomes incorporated into the vessel
wall. Eventually, with remodeling and contraction of the
mesenchymal elements, only a fibrous lump may remain to mark the
original thrombus.

57. Bands & Webs

59. Webs : A typical
display of an
organised and
recanalised
thrombus
New vascular channels were
formed within individual
bands,but they were much
more prominent in the webs

60. Mosaic perfusion

61. Acute vs chronic embolus on CT
ACUTE (inside-out)
• show filling defects within the
pulmonary vasculature with
acute pulmonary emboli.
When the artery is viewed in
its axial plane the central filling
defect from the thrombus is
surrounded by a thin rim of
contrast, which has been called
the Polo Mint sign (mint with a
hole!)
CHRONIC(outside in)
• webs or bands, intimal irregularities
• abrupt narrowing or complete obstruction of
the pulmonary arteries
• “pouching defects” which are defined as
chronic thromboembolism organised in a
concave shape that “points” toward the vessel
lumen
Indirect signs include :
• mosaic perfusion
• vascular calcification
• bronchial or systemic collateralisation

62. Multidetector CT
showing
intravascular filling
defects in the left
lower lobe artery.

63. Right-sided
pulmonary
angiography
showing partly and
completely occluded
vessels.

64. Webs & Bands – CT and angio

65. webs

66. Bands -
circumferential
constrictions

68. CT AND CTPA
• CT can raise suspicion of
pulmonary hypertension : PA or RV
enlargement
• increased PA diameter (≥29 mm)
and pulmonary:ascending aorta
diameter ratio (≥1.0). A segmental
artery:bronchus ratio .1 : 1 in three
or four lobes
• Contrast CT angiography of the PA
is helpful in determining whether
there is evidence of surgically
accessible CTEPH. It can delineate
the typical angiographic findings in
CTEPH, such as complete
obstruction, bands and webs and
intimal irregularities, as accurately
and reliably as digital subtraction
angiography. With this technique,
collaterals from bronchial arteries
can be identified.

69. CTEPH
• Diagnosis of CTEPH requires ⩾3 months of effective anticoagulation
and a mean pulmonary arterial pressure (mPAP) >25 mmHg with a
pulmonary capillary wedge pressure ⩽15 mmHg, and at least one
(segmental) perfusion defect .

70. Aetiology in brief
• CTEPH has been reported as a long-term complication of pulmo- nary
embolism (PE) with a cumulative incidence between 0.1% and 9.1% after
symptomatic PE
• Traditional risk factors for VTE include antithrombin deficiency, protein C
deficiency, protein S deficiency, factor V Leiden, plasminogen deficiency,
and anticardiolipin antibodies.
• The ABO locus is a known susceptibility locus for VTE,and non-O blood
group carriers share a higher risk for VTE than O carriers.
• Previous splenectomy, the presence or history of infected ventriculoatrial
shunts for the treatment of hydrocephalus, indwelling catheters and leads,
• thyroid replacement

71. • cancer, and chronic inflammatory disorders, such as osteomyelitis and
inflammatory bowel diseases
• Patients suffering from moderate hypothyroidism are at an increased
risk of thrombosis.
• In addition, treatment with levothyroxin increases von Willebrand
factor levels and shortens in vitro platelet plug formation

72. UCSD SURGICAL CLASSIFICATION

73. Surgical specimens from OT 1

74. STRATIFYING RISK

78. RISK PREDICTORS FOR PEA
• PVR IS THE NUMBER 1 RISK PREDICTOR, with risk increasing sharply
beyond a PVR of 1200.
• A difficult issue in the preoperative assessment of patients with
CTEPH is definition of the extent of small-vessel disease. Patients with
CTEPH and defects in the main, lobar, or proximal segmental level
have proximal disease and are best suited for surgery. In contrast,
patients with significant PH but little or no obstruction are considered
poor candidates for surgery. This latter group is believed to display
significant pulmonary arteriopathy.

80. Other therapies
• Medical
• CCBs
• Prostanoids – prostacyclin
• Endothelin receptor antagonists – bosentan
• PDE inhibtors – sildenafil
• Guanacyl cyclase stimulators – riociguat
• Interventional
• Balloon pulmonary angioplasty