Pulmonary hypertension

1. GRAND ROUND PRESENTATION
FIRM II
INTERNAL MEDICINE, LTH Ogbomoso
7/18/2023 1

2. Case presentation 1
7/18/2023 2

3. Biodata
• Name: Ms Z.A
• Age: 22yrs
• Sex: F
• Occupation: student
• Marital Status: Single
• Address: Iseyin, Oyo
• Religion: muslim
• Tribe: Yoruba
• Informant: patient
7/18/2023 3

4. Presenting Complaints
• Recurrent easy fatiguability x ?10years
• Dyspnea on exertion x ? 10years
• Leg swelling x 2/52
7/18/2023 4

5. History
• She was in her usual state of health until about ?10 years ago when she
started noticing easy fatiguability which comes especially on mild exertion.
No dyspnea at rest.
• Associated PND, orthopnea and palpitation but no history of chest pain.
• She developed bilateral leg swelling about 2 weeks ago, therefore
prompting her presentation to this facility. It was insidious in onset and
progressively worsened within two weeks.
• No swelling in any other parts of the body nor associated facial puffiness,
reduction in urine output or history of similar swelling in the past.
7/18/2023 5

6. History
• Positive history of recurrent productive non bloody cough in her childhood
period however aetiology of cough wasn’t disclosed to her following
treatment with antibiotics.
• Positive history of progressive weight loss evidenced by loosening of
previously well fitted clothes.
• Not history of reactive exposure to smoke or dust or pollen.
• No history of drenching night sweats, hemoptysis, exposure to anyone with
chronic cough.
• No fever, history of abdominal pain, vomiting, passage of loose stool.
7/18/2023 6

7. history
• No history of excessive sweating or tremors
• Positive history of blood donations 2-3 times a year but stopped after 4
years when she started feeling headaches with dizziness.
• No history loss of consciousness, seizures or fall nor differential limb
weakness.
• No history of low back pain
• Not a known patient with hypertension, DM, SCD, asthma, PUD or epilepsy.
7/18/2023 7

8. history
• She does not smoke cigarettes nor drink alcoholic beverages.
• She does not abuse psychoactive substances.
• Patient had been to a private facility since onset of illness but when
symptoms failed to improve she therefore presented to this facility for
expert medical care.
7/18/2023 8

9. General examination
• A young woman, conscious, dyspneic, acutely ill looking, not pale,
anicteric, acyanosed, not dehydrated, grade iV finger clubbing, pitting
pedal oedema up to the knees.
7/18/2023 9

10. Cardiovascular examination
PR- 114b/m, regular, small volume, synchronous with contralateral
pulse
TAW0 LCB0
JVP- not raised
Hyperactive praecordium
AB- displaced
Left parasternal heave
Pansystolic murmur in the parasternal region
HS- S1 S2 S3
7/18/2023 10

11. Chest examination
• RR- 38cpm, dyspneic
SPO2- 93% in ambient air
Trachea is central
Dull percussion notes on the left middle and lower lung zones
Bronchial breath sounds posteriorly
Coarse crepitations in the left middle and lower and lateral lung zones
anteriorly and posteriorly
7/18/2023 11

12. Abdominal examination
Full, moves with respiration
Umbilicus is inverted
Epigastric and right hypochondriac tenderness
Liver is enlarged 12cm below xiphisternum and 6cm below the RCM,
smooth, tender
Spleen not palpably enlarged
Kidneys not bimanually palpable
Ascites present demonstrated by shifting dullness
7/18/2023 12

13. Central nervous system examination
Conscious and alert
Oriented in time, place and person
Speech is coherent not slurred
No neck stiffness
Normal tone and reflexes
Moves all limbs spontaneously
7/18/2023 13

14. assessment
• Predominant right ventricular failure secondary to ? Tuberculous
pericarditis (cor pulmonale) r/o chronic pulmonary
thromboembolism.
7/18/2023 14

15. investigations
Echocardiography showed:
• Normal valvular morphology and mobility
• Massively dilated RV and RA
• Right ventricular hypertrophy with severely reduced right ventricular systolic
dysfunction
• Grade 3 right ventricular diastolic dysfunction
• Moderate pericardial effusion with fibrous strands
• Thiuckened pericardial wall
• Severe TR and PR
• Echo evidence of severe pulmonary hypertension
• Spontaneous echo contrast in RA
• No septal wall defect
7/18/2023 15

16. investigations
Conclusion:
Features are consistent with constrictive physiology complicated by
severe pulmonary hypertension.
Possibilities:
1. Constrictive pericarditis secondary to tuberculous pericarditis
2. Secondary pulmonary hypertension ? etiology
7/18/2023 16

17. Investigations
• Abdominopelvic USS:
There’s hepatomegaly with a span of 17.1cm. The outline and echotexture are
preserved. The hepatic vein is dilated almost 9mm and the IVC is dilated and
measures 23mm. The hepatobiliary system, spleen (11.51cm) and pancreas are
preserved.
Both kidneys are normal in size, location, orientation and outline. The right kidney
measures 11.4x6.0x4.5cm while the left measures 12.1x5.8x4.9cm with a volume of
177mls. The parenchymal echo is accentuated however corticomedullary
differentiation is preserved.
Mild ascites is noted. Normal bowel peristalsis is noted.
7/18/2023 17

18. • Findings:
1. Hepatomegally with features of right heart failure
2. Grade II renal parenchymal disease
3. Mild ascites
7/18/2023 18

19. Investigations
• Electrocardiography result
HR: 126bpm
Sinus tachycardia, P-wave- LAE,
PR- 0.16s
RVH
T wave inversion in aVR, lead III, V1-V6
7/18/2023 19

20. Investigations
• FBC:
PCV- 53%
WBC- 4300/cmm
Neut- 49%
Eosin- 2%
Lymphocytes- 49%
ESR- 1mm/hr
7/18/2023 20

21. investigations
• Serology: anti HCV- neg
HBsAg- neg
RVS- negative
D-dimer- 0.64ug/mL (0.1-0.5)
Urinalysis- bilirubin- neg
urobilinogen- normal
ketone- neg
Glucose-neg
protein-neg
blood- neg
nitrite-neg
leu-neg
pH- 6.0
SG- 1.010
7/18/2023 21

22. investigations
• Clotting profile-
• Serum urea- 3.2mmol/L
• Serum creatinine-89 (60-120ug/l)
PT (sec) PTTK (sec)
test 15” 32”
control 14” 38”
ratio 1.07
ISI 1.06
INR 1.07
7/18/2023 22

23. • Cardiomegaly with left middle and left lower zone infiltrates seen on
chest xray
7/18/2023 23

24. Treatment plan
• IV furosemide 60mg stat then 40mg 8 hrly
• IV augmentin 1.2g stat then 600mg 12hrly
• Tab Zithromax 500mg dly x 3/7
• Tab spironolactone 12.5mg dly
• Sc clexane 40mg dly
• Tab warfarin 2.5mg dly
• Tab Tadalafil 20mg dly
• Low salt diet
• Strict I/O charting
7/18/2023 24

25. Day 2
• Patient was regular on medications, not dyspneic, pedal oedema had
subsided, however, patient complained of mild epigastric pain.
• PR- 92bpm
• BP- 102/74mmHg
• HS- S1 S2 S3 with a tricuspid regurgitation murmur
Plan:
1. Tab rabeprazole 20mg bd
2. Syrup gascol 10mls tds
3. Discontinue clexane
4. Consult to consultant pulmonologist on account of diagnosis
7/18/2023 25

26. Day 3
• Seen by consultant pulmonologist
• Clincal examination showed a young woman, small for age, with
severe mucosal cyanosis and reverse digital clubbing (nil finger
clubbing but severe grade IV toe clubbing- Eisenmenger syndrome)
• Assessment- likely congenital cyanotic heart disease ? Mild type
complicated with cor pulmonale.
• Plan: convert antibiotics to oral
continue antifailure regimen
decrease furosemide to 40mg 12hrly
7/18/2023 26

27. Day 4
• Patient had sustained clinical improvement and was discharged on
some medications
7/18/2023 27

28. Follow up
• Patient attended cardiology clinic for two weeks and then
represented at the ER with bilateral leg swelling and abdominal pain.
• Patient claimed to be regular on medications
• She was readmitted.
• Abdominopelvic USS- bilateral grade II renal parenchymal disease
• BP- 88/60mmHg
7/18/2023 28

29. Plan
• IV furosemide 60mg 12hrly
• Tab digoxin 0.125mg dly
• Tab tadalafil 20mg dly
• Tab spironolactone 25mg dly
• Tab lisinopril 5mg daily
• Caps omeprazole 20mg bd
• Tabs warfarin 2.5mg dly
• Nurse in cardiac position
• Monitor I/O closely
7/18/2023 29

30. • Patient was managed for 3 days
• Following resolution of symptoms patient requested to be discharged
• Patient however defaulted clinic visits then presented 3months later
with complaints of severe abdominal pain, increasing pedal oedema,
cough and PND
• BP- 98/60mmHg
7/18/2023 30

31. plan
• Admit to the ward
• IV augmentin 600mg 12hrly
• Iv furosemide 80mg 12hrly
• Tab tadalafil 20mg dly
• Tab aldactone 25mg dly
• Tab digoxin 0.25mg dly
• Tab torsemide 20mg dly
• Tab warfarin 2.5mg dly
• Sc clexane 40iu daily
• No salt diet
7/18/2023 31

32. investigations
• Doppler USS of both legs showed venous thrombosis in the right superficial femoral artery.
• EUCr done was essentially within normal range
• FBC showed
PCV- 53%
WBC- 3,900/cmm
Platelets- 222,000/cmm
Neutrophils- 48%
Eosinophils- 2%
Lymphocytes- 48%
monocytes- 2%
Poikilocytosis- +
Target cells - ++
INR- 4.46
7/18/2023 32

33. • Assessment: chronic refractory heart failure with pulmonary
hypertension
• Plan:
1. Commence dopamine infusion 200mg in 200mls of N/S to run over
4hrs.
2. Discontinue clexane.
3. Continue other medications
7/18/2023 33

34. • Patient was found not to be tolerating dopamine infusion
• Still having hypotension BP- 88/59mmHg
• Still complained of headache, dizziness and severe abdominal pain.
• Still had significant abdominal swelling and leg swelling
• Repeat INR- 1.73
Plan-
1. Change IV dopamine to IV dobutamine 200mls in 200mls of IV NS to
run over 4hrs
2. Continue other medications
7/18/2023 34

35. • Patient however requested to be discharged against medical advise
on account of lack of funds to continue care after 50days on
admission.
• Patient relatives also requested a fully detailed medical report in case
they decide to seek healthcare outside the country.
7/18/2023 35

36. 7/18/2023 36

37. Case presentation 2
7/18/2023 37

38. BIODATA
• Name: Ms F.A
• Age: 30yrs
• Sex: F
• Occupation: trader
• Marital Status: Single
• Address: Ijeru Area,Ogbomosho
• Religion: Christianity
• Tribe: Yoruba
• Informant: patient
7/18/2023 38

39. Presenting Complaints
• Bilateral pedal swelling x 2yrs
• Abdominal swelling x 2yrs
• Facial swelling x 1yr
• Exertional dyspnea x 1yr
7/18/2023 39

40. History of presenting complaints
• Apparently well until about 2 years prior to presentation when she
developed pedal swelling initially intermittent in nature but later
progressed to affect the legs and thighs despite use of drugs
administered at a private hospital.
• As pedal swelling progressed upwards, abdominal distension also
developed, progressive in nature with no associated abdominal pain
or discomfort. No associated history of jaundice, pruritus, or passage
of pale bulky stool, hiccups.
7/18/2023 40

41. • Positive history of early morning facial puffiness and reduction in urine
output. No history of frothiness of urine, haematuria, frequency or
nocturia. No flank pain.
• Positive history of progressively worsening exertional dyspnea which was
insidious in onset and associated with a history of orthopnea but no history
of PND or palpitations.
• No history of multiple sexual partners, sharing of sharps, recurrent
jaundice with fever in the past or consumption of mouldy grains. Positive
history of blood transfusion 12 years ago. Positive history of injection
administration from paramedical health workers and quacks. Positive
history of scarification marks.
7/18/2023 41

42. • Not a known DM, HTN, asthmatic or PUD patient.
• Married in a monogamous setting with 2 children
• Does not smoke cigarette or drink alcohol.
• No known drug allergy.
7/18/2023 42

43. General examination
• A young woman, conscious, and alert, in obvious respiratory distress,
emaciated, afebrile, pale, anicteric, centrally cyanosed, mildly
dehydrated, right axillary lymphnodes enlargement, no finger
clubbing, no asterixes, pitting pedal oedema bilaterally up to the
waist. Hyperpigmentation over the distal half of both LL, Parotid
fullness, sparse axillary hair with fluffy hair noted.
7/18/2023 43

44. • Abdominal examination
Markedly distended
Everted umbilicus
Abdominal girth 110cm
Crepitus over the right upper half of the abdomen consistent with
subcutaneous emphysema
No area of tenderness
Liver is 8cm palpable below RCM, pulsatile, with a blunted edge. Span is about
16cm and it extends into left hypochondrion.
Spleen not palpably enlarged.
Kidneys not bimanually palpable.
Ascites demonstrable by fluid thrill.
Bowel sounds normoactive.
7/18/2023 44

45. • Cardiovascular examination
PR- 110 beats per minute, regular small volume, synchronous with contralateral
pulse
No radiofemoral delay
No TAW or LCM brachialis
BP- 90/60mmHg
Elevated JVP with distended neck veins
Apex beat at 6th LICS 2cm medial to AAL, heaving
Left parasternal heave
No thrills or palpable heart sounds
HS-S1 S2 S3 with MR and TR
?AR murmur
7/18/2023 45

46. • Chest exam:
RR: 40cpm, dyspneic
trachea is central
stony dull percussion notes in the right MLZ anteriorly, RLLZ
laterally.
expiratory rhonci in both MLZ, LLZ.
coarse crepitations in RMLZ
7/18/2023 46

47. • CNS exam:
Conscious and alert
Oriented in TPP
No focal neurological deficit
Pupils are 3mm bilaterally, reactive
No signs of meningeal irritation.
7/18/2023 47

48. diagnosis
• Assessment:
1. Congestive cardiac failure 20 to ? Rheumatic multivalvular heart disease KIV
Endomyocardial Fibrosis ppted by LRTI in NYHA IV
7/18/2023 48

49. Investigations
• Abdominopelvis USS scan
There is massive ascites, the liver echo is slightly accentuated with dilated
hepatic veins. The gallbladder, intrahepatic duet, spleen and both kidneys are
sonographically within normal limits. The uterus is also normal in outline and
parenchymal echoes. There is minimal right-sided pleural effusion
Findings: massive ascites
• Urinalysis:
Nitrite: +
Blood: +++
Protein: ++
pH: 6.0
SG: 1.030
Urobilinogen: normal
Bilirubin, ketone, glucose, leucocyte: negative
7/18/2023 49

50. investigations
• Chest Xray- not done
• E/U/Cr:
Bicarbonate- 22mmol/L
Chloride- 98mmol/L
Sodium: 134mmol/L
Potassium: 4.1mmol/L
Urea: 5.4mmol/L
Creatinine- 93mmol/L
PCV- 37%
• RBS- 7.0mmol/L
7/18/2023 50

51. • Echocardiography result:
There is severe mitral, tricuspid, pulmonary regurgitation. The peak aortic and
pulmonary pressure gradients are reduced. The inferior vena cava is dilated.
There is pulmonary hypertension (PASP 23+15mmHg)
Conclusion: this is combined mitral valve disease (mitral stenosis +
regurgitation) and pulmonary hypertension, likely Rheumatic.
• Electrocardiography result:
HR- 110bpm
Normal sinus rhythm
PR 0.12s, low limb lead voltage, no RAE/LVH/RVH.
Impression: sinus tachycardia, LAE, low limb lead voltages.
consider hyperinflated lung fields, pleural or pericardial fluid
collection.
7/18/2023 51

52. Investigations
• Liver function test
Total Bilirubin- 30mmol/L (<20mmol/l)
Conj bilirubin- 22mmol/L (<5mmol/L)
Protein- 64g/L (58-80g/L)
Albumin – 33 (35-50g/L)
AST- 10 (<12IU/L)
ALT – 2 (<12 IU/L)
ALP- 132 (73-207IU/L)
• Serology- HbsAg- -ve
Anti HCV- -ve
RVS- -ve
• Ascitic fluid protein- 35g/L
7/18/2023 52

53. Plan
• Nurse in cardiac position
• Intranasal oxygen 100% @ 6L/min
• IV furosemide 100mg stat then 40mg 12hrly
• Tab spironolactone 25mg bd
• IV augmentin 1.2 g stat then 600mg 8hrly
• Sc clexane 40mg daily
• Monitor vital signs and input: output closely.
7/18/2023 53

54. Day 1
• Patient was reviewed by the consultant
• Patient was still in respiratory distress
• RR- 36cpm, SPO2- no functioning pulse oximeter at the time on the
ward.
• Still on INO2 6L/min
• Abdomen still enlarged. Girth- 112cm
• BP- 92/60mmHg
Plan:
-therapeutic paracentesis 4L over 5hrs
7/18/2023 54

55. • patient was found to be having recurrent abdominal distension
despite draining about 12 litres of ascetic fluid over 25 days on
admission.
• Still had distended anterior abdominal veins with hepatomegaly
• Was also found to have bibasal crepitations and hypotension.
• Hypotension occurred following overdrainage of ascitic fluid
• Abdominal girth- 86cm
• Ascitic fluid m/c/s wasn’t done at the time.
• Patient was discharged to be seen on outpatient basis but has since
defaulted clinic visit since after visiting for 6 months after discharge.
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56. PULMONARY HYPERTENSION
IN HEART FAILURE
7/18/2023 56

57. OUTLINE
• INTRODUCTION
• DEFINITIONS
• EPIDEMIOLOGY
• CLASSIFICATION
• PATHOGENESIS
• CLINICAL FEATURES
• INVESTIGATIONS
• TREATMENT
• SUMMARY
• REFERENCES
7/18/2023 57

58. INTRODUCTION
• THE PULMONARY CIRCULATION
• The pulmonary circulation is the vascular system that conducts blood
from the right to left side of the heart through the lungs
• Pulmonary arteries are very thin walled, low resistance and highly
distensible vessels
• The pulmonary vascular resistance (PVR) is a measure of the
impedance to flow in the pulmonary vasculature
• PVR depends on pulmonary artery pressure, left atrial pressure and
the cardiac output. Normal pulmonary artery pressure=25/8 mmHg
Normal mean pulmonary artery pressure=15+/-3mmHg
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59. • Pulmonary vascular resistance is about 1/8th of systemic resistance
• During exercise pulmonary vascular flow increase with attendant
decrease in resistance
7/18/2023 59

60. DEFINITIONS
• Pulmonary hypertension (PH) is a spectrum of disease conditions
involving the pulmonary vasculature
• It is defined as an abnormal elevation in pulmonary artery
pressure(PAP). It is a feature of advanced disease.
• The pulmonary artery pressure and pulmonary vascular resistance
progressively rises, leading to right heart failure and death.
• Over the years, improvement in understanding the pathogenesis has
resulted in the development of targeted approaches to the treatment
of PH. Survival advantage has also been shown with some of the
pharmacologic agents.
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61. • Pulmonary hypertension is a haemodynamic and pathophysiological
condition defined as mean PAP ≥ 25mmHg at rest done by right heart
catheterization(RHC) or greater than 30mmHg during exercise
• It may be post capillary, that is the result of an increase in pulmonary
venous pressure in left-sided heart diseases, or precapillary, caused
by pulmonary vascular remodeling leading to increased PVR
• Differentiation between these 2 conditions is based on whether
pulmonary artery wedge pressure (PAWP) or left ventricular (LV) end-
diastolic pressure (LVEDP) is either greater or less than 15 mm Hg.
7/18/2023 61

62. • Pulmonary arterial hypertension (PAH) is a clinical condition
characterized by the presence of pre- capillary PH in the absence of
other causes of pre- capillary PH such as PH due to lung diseases,
chronic thromboembolic PH, or other rare diseases
• It is a progressive, incurable disease of the pulmonary arterioles
characterized by vascular cell proliferation, aberrant remodeling, and
thrombosis in situ
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63. 7/18/2023 63

64. EPIDEMIOLOGY
• E. Romberg, a German doctor in 1891, the description of an autopsy,
showing thickening of the pulmonary artery in the absence of evident
cardiac or lung disease
• In 1951, 39 cases were reported by Dr. D.T. Dresdale in the United
States.
• Between 1967 and 1973, a 10-fold increase in unexplained PH was
reported in central Europe. The rise was subsequently traced to
Aminorex fumarate, an amphetamine-like drug introduced in Europe
in 1965 to control appetite.
7/18/2023 64

65. • In adults, the commonest cause of pulmonary hypertension is lung
disease, especially chronic obstructive pulmonary disease (COPD)
• An estimated 30,000 persons die each year of COPD, many of whom
have pulmonary hypertension and resulting right ventricular failure as
a contributing cause of death.
• Other common causes of pulmonary hypertension/pulmonary heart
disease includes pulmonary tuberculosis, chronic suppurative lung
disease, connective tissue disease, and sickle cell disease.
7/18/2023 65

66. • The incidence of pulmonary arterial hypertension in patients with
collagen vascular disease ranges from 2 to 35% in patients with
scleroderma
• Pulmonary arterial hypertension has also been reported to occur in
23 to 53% of patients with mixed connective tissue diseases and in 1
to 14% of cases of systemic lupus erythematosus
7/18/2023 66

67. • Idiopathic pulmonary arterial hypertension (IPAH), formerly referred
to as primary pulmonary hypertension is uncommon, with an
estimated incidence of two cases per million.
• There is a strong female predominance,
• Most patients presenting in the fourth and fifth decades, although
the age range is from infancy to >60 years.
• 1 to 2% of patients with portal hypertension or human
immunodeficiency virus (HIV) infection have pulmonary arterial
hypertension.
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68. • In Nigeria, pulmonary hypertension-related heart disease accounts
for:
• 0.6-28% of heart diseases
• 1.4-10.1% of echo registries
• 0.9-17% of autopsy/mortality studies.
• Mortality associated with the disease is high. Over 70% die in less
than 6 months after the onset of symptom (Ogah OS. Pulmonary
hypertension in Nigeria. PVRI Review 2010;2:95)
7/18/2023 68

69. • Valentine et al in 2017 at OAUTH studied 94 SCA subjects who had
echocardiography and 6-minute self-paced walking exercise done. PH
was diagnosed by Doppler echocardiography on finding a tricuspid
regurgitant velocity (TRV) of ≥2.5 m/s in 23.9% of them
• Akintunde A.A reported an 86year old woman with cor triatriatum
with pulmonary hypertension (WHO group 2) during preoperative
evaluation. Akintunde AA ,Singapore Med J. 2011 Oct;52(10):e203-5
7/18/2023 69

70. CLASSIFICATION OF PULMONARY
HYPERTENSION
• First version was proposed in 1973 at the first international
conference on PPH by WHO.
• Second and third world meetings on PAH in 1998 and 2003,
respectively.
• Fourth World meet on PH held in 2008 in Dana Point, California,
adopted new clinical classification
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71. 7/18/2023 71

72. GROUP 1. PULMONAY ARTERIAL HYPERTENSION
• Key feature: Elevation in PAP
with normal PCWP
• Idiopathic (IPAH)
• Heritable (BMPR2, ALK1,
endoglin , Unknown)
• Exposure to drugs or toxins
• Persistent pulmonary
hypertension of the newborn
• Associated with (APAH)
• Collagen vascular disease
• Congenital heart diseases
• Portal hypertension
• HIV infection
• Schistosomiasis
• Chronic haemolytic anaemia
• GROUP 1’ Pulmonary veno-
occlusive disease(PVOD) and
pulmonary capillary
haemangiomatosis
7/18/2023 72

73. GROUP 2. LEFT SIDED HEART DISEASE
• Key feature: Elevation in PAP with elevation in PCWP
• Includes:
• Left ventricular systolic dysfunction
• Left ventricular diastolic dysfunction
• Valvular disease
• Specific congenital abnormalities
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74. GROUP 3. PH ASSOCIATED WITH HYPOXEMIC
LUNG DISEASE.
• Key feature: chronic hypoxia with mild elevation of PAP, Includes:
• Chronic obstructive lung disease
• Interstitial lung disease
• Sleep-disordered breathing
• Alveolar hypoventilation disorders
• Chronic exposure to high altitude
• Developmental abnormalities
7/18/2023 74

75. GROUP 4. PH DUE TO CHRONIC
THROMBOEMBOLIC DISEASE
• Key feature: elevation of PA pressure with documentation of
pulmonary arterial obstruction for >3 months. Includes:
• Chronic pulmonary thromboembolism
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76. GROUP 5. WITH UNCLEAR AND/OR
MULTIFACTORIAL MECHANISMS
• Key feature: elevation in PAP in association with a systemic disease
where a causal relationship is not clearly understood. Includes:
• Haematological disorders: myeloproliferative disorder, splenectomy.
• Systemic disorders : sarcoidosis, pulmonary Langerhans cell
histiocytosis, neurofibromatosis, vasculitis
• Metabolic disorders: Glycogen storage disease, Gaucher disease
Thyroid disorders
• Others: Tumoural obstruction, fibrosing mediastinitis, chronic renal
failure on dialysis
7/18/2023 76

77. PATHOPHYSIOLOGY
Pulmonary vasomotor tone controlled by:
• Vasoconstrictors
• Thromboxane
• ET-1
• Leukotrienes
• Platelet activating factor
• Vasodilators
• NO
• PGI2
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78. • Abnormalities in molecular pathways regulating the pulmonary
vascular endothelial and smooth-muscle cells have been described as
underlying PAH.
• These include
• (I) inhibition of the voltage-regulated potassium channel,
• (II) mutations in the bone morphogenetic protein-2 receptor,
• (III) increased serotonin uptake in the smooth-muscle cells,
• (iv) increased angiopoietin expression in the smooth-muscle cells
• (v)and excessive thrombin deposition related to a procoagulant state.
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79. • BMPR2 abnormal: vascular hyperplasia and abnormal
neovascularization.
• Three key pathogeneses:
• Relative decrease in bioavailability of NO
• Relative increase in serum endothelin-1
• Relative deficieny of PGI2/excess of thromboxane A2  platelet dysfunction
• Intense vasoconstriction: abnormal ATP-sensitive K-channels.
• Immune dysfunction: autoimmune etiology in some cases
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80. 7/18/2023 80

81. PATHOGENESIS
• Remodeling of the pulmonary vascular bed
• Intimal and medial hypertrophy with proliferation of smooth
muscle cells and eventual obliteration
• Pulmonary arteries constrict
• Right heart must pump against resistance
• Right heart becomes dilated and less efficient  TR
• Less blood gets out to the lungs and to the body
• Adaptation to stress, increased activity or growth become impossible
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82. • Passive backward transmission of the LA pressure elevation to the
pulmonary vasculature
• The elevation of PVR is due to an increase in vasomotor tone of
pulmonary arteries and fixed structural obstructive remodelling
• The vasoconstrictive reflexes also arise from stretch receptors in the
left atrium and pulmonary veins, and endothelial dysfunction
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83. • Enlarged and thickened pulmonary veins, pulmonary capillary
dilation, interstitial edema ,alveolar hemorrhage with lymph vessel
and lymph node enlargement
• Distal arteries may be affected by medial hypertrophy and intimal
fibrosis. Primary or pathognomic vascular changes in arterial wall may
be absent
• With time when pulmonary venous pressure is ≥ 25mmHg on chronic
basis there would be a disproportionate elevation of PAP occurs due
to intrinsic reactive PA vasoconstriction
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84. 7/18/2023 84

85. • The normal pulmonary vascular bed has a remarkable capacity to
dilate and recruit unused vasculature to accommodate increases in
blood flow.
• In pulmonary hypertension, however, this capacity is lost, and
pulmonary artery pressure is increased at rest and further elevated
during exercise
7/18/2023 85

86. • The right ventricle responds to an increase in resistance within the
pulmonary circulation by increasing RV systolic pressure as necessary
to preserve cardiac output.
• Chronic changes occur in the pulmonary circulation that result in
progressive remodelling of the vasculature, which can sustain or
promote pulmonary hypertension even if the initiating factor is
removed.
• The ability of the RV to adapt to increased vascular resistance is
influenced by several factors, including age and the rapidity of the
development of pulmonary hypertension.
7/18/2023 86

87. • Coexisting hypoxemia can impair the ability of the ventricle to
compensate.
• Several studies support the concept that RV failure occurs in
pulmonary hypertension when the RV myocardium becomes ischemic
due to excessive demands and inadequate right ventricular coronary
blood flow to the RV.
• The onset of clinical RV failure, usually manifest by peripheral edema,
and is associated with a poor outcome
7/18/2023 87

88. SIGNS AND SYMPTOMS OF PH
• SYMPTOMS
• Easy fatigability, lethargy. These symptoms are often ignored unless
the patient has another underlying condition .
• Exertional chest discomfort
• Syncope with exertion
• Cough
• Hemoptysis
• Hoarseness of voice
7/18/2023 88

89. • SIGNS
• Cyanosis
• Clubbing of the digits
• Increased intensity of the pulmonic component of the second heart
sound (P2)
• Systolic ejection murmur from TR suggestive of an advanced Disease.
• Diastolic murmur of PI in severe PH.
• Left parasternal heave
7/18/2023 89

90. • Prominent ‘a’ wave in jugular venous system.
• Signs of RV failure:
• Jugular venous distension
• Hepatomegaly
• Ascites, and/or peripheral edema
7/18/2023 90

91. WHO CLASSIFICATION OF FUNCTIONAL
STATUS OF PATIENTS WITH PH
• Class Description
• I Patients with PH in whom there is no limitation of usual physical
activity; ordinary physical activity does not cause increased dyspnea,
fatigue, chest pain, or presyncope.
• II Patients with PH who have mild limitation of physical activity. There
is no discomfort at rest, but normal physical activity causes increased
dyspnea, fatigue, chest pain, or presyncope.
7/18/2023 91

92. • III Patients with PH who have a marked limitation of physical activity.
There is no discomfort at rest, but less than ordinary activity causes
increased dyspnea, fatigue, chest pain, or presyncope.
• IV Patients with PH who are unable to perform any physical activity at
rest and who may have signs of right ventricular failure. Dyspnea
and/or fatigues may be present at rest, and symptoms are increased
by almost any physical activity.
7/18/2023 92

93. CHEST RADIOGRAPH
• Findings include central pulmonary arterial dilatation, which
contrasts with ‘pruning’ (loss) of the peripheral blood vessels.
• Right atrium and RV enlargement may be seen
• Enlargement of the central pulmonary arteries with attenuation of
the peripheral vessels
7/18/2023 93

94. 7/18/2023 94

95. • Computed Tomography scan
-PA >aorta
-cardiomegaly, enlarged RV
-pericardial effusion
7/18/2023 95

96. PA
A
Enlarged main PA on CT
Standard view Coronal view
7/18/2023 96

97. DIAGNOSTIC TESTS
• ELECTROCARDIOGRAPHY
• ECG has sensitivity(55%) and specificity (70%) detecting significant
PH, may demonstrate
• Right ventricular hypertrophy or strain
• Right axis deviation
• P pulmonale due to right atrial enlargement.
• Ventricular arrhythmias are rare.
• SVT may be present in advanced stages
7/18/2023 97

98. • Electrocardiogram demonstrating the
• Right ventricular hypertrophy with strain
• Increased P-wave amplitude in lead II
7/18/2023 98

99. 7/18/2023 99

100. ECHOCARDIOGRAPHY
• Is performed to estimate the pulmonary artery systolic pressure and
to assess RV size, thickness, and function.
• In addition, left ventricular systolic and diastolic function, and valve
function, while detecting pericardial effusions and intracardiac
shunts.
• PH may have echocardiographic signs of right ventricular pressure
overload, including paradoxical bulging of the septum into the left
ventricle during systole and hypertrophy of the right ventricular free
wall.
• As the right ventricle fails, there is dilation and hypokinesia, septal
flattening, right atrial dilation, and tricuspid regurgitation
7/18/2023 100

101. The classic echocardiographic appearance of a patient with
idiopathic pulmonary arterial hypertension shows
(i) right ventricular and
(ii) right atrial enlargement
(iii) normal or reduced left ventricular size .
7/18/2023 101

102. 7/18/2023 102

103. • Four-chamber
echocardiographic view of a
patient who has severe PAH.
• Note the massively dilated
right ventricle(RV) and right
atrium(RA) that have shifted
the septa and narrowed the
left ventricle (LV) and left
atrium (LA).
7/18/2023 103

104. • VENTILATION-PERFUSION SCANNING
• Is used to evaluate patients for thromboembolic disease.
• A normal V/Q scan accurately excludes chronic thromboembolic
disease with a sensitivity of 90 to 100 percent and a specificity of 94
to 100 percent .
• Pulmonary angiography is necessary to confirm the positive V/Q scan
and to define the extent of disease.
• PULMONARY ANGIOGRAM
• Used to measure circulation in the lungs and to visualize clots in the
lung on x-rays
7/18/2023 104

105. • PULMONARY FUNCTION TESTS
• Pulmonary function tests (PFTs) are performed to identify and
characterize underlying lung disease contributing to PH.
• An obstructive pattern is suggestive of COPD,
• Restrictive disease suggests ILD, neuromuscular weakness, or chest
wall disease.
• In most circumstances, PH should not be attributed to lung disease if
the PFTs are only mildly abnormal
7/18/2023 105

106. • LABORATORY TESTS
• HIV serology to screen for HIV-associated PH
• Liver function tests to screen for porto-pulmonary hypertension
Antinuclear antibody (ANA)
• Thyroid function test
• NT-proBNP is the precursor of BNP in right heart failure .
• Anti-centromere antibodies in scleroderma
• Thrombophilia screening including anti-phospholipid antibodies,
lupus anticoagulant, and anti-cardiolipin antibodies should be
performed in CTEPH
7/18/2023 106

107. • OVERNIGHT OXIMETRY
• Nocturnal oxyhemoglobin desaturation can be identified by overnight
oximetry in patients with PH —obstructive sleep apnea-hypopnea
(OSAH) coexists .
• Polysomnography is the gold standard diagnostic test for OSAH.
• ULTRASONOGRAPHY
• Useful in portal hypertension
7/18/2023 107

108. • EXERCISE TESTING
• Exercise testing is most commonly performed using the six minute
walk test (6MWT)
• Provide benchmarks for disease severity, response to therapy, and
progression.
• In addition to distance walked, dyspnoea on exertion and finger O2
saturation are recorded.
• Walking distances , <250 m and O2 desaturation 10% indicate
impaired prognosis in PAH.
7/18/2023 108

109. • RIGHT HEART CATHETERIZATION
• Right heart catheterization is necessary to confirm the diagnosis of
PH . Accurately determine the severity of the hemodynamic
derangements.
• PH is confirmed if the mean pulmonary artery pressure is greater
than 25 mmHg at rest .
• RHC is required to guide therapy
• An additional benefit of RHC is that the presence and/or severity of a
congenital or acquired left-to-right shunt.
7/18/2023 109

110. • VASOREACTIVITY TEST
• Aim: To detect the residual properties of vasodilatation of small pulmonary
arteries and arterioles .
• It is recommended in patients with group 1 PAH .
• This involves the administration of a short-acting vasodilator and then
measurement of the hemodynamic response .
• Agents commonly used for vasoreactivity testing include epoprostenol,
adenosine, and inhaled nitric oxide .
• Epoprostenol is infused at a starting rate of 1 to 2 ng/kg per min and
increased by 2 ng/kg per min every 5 to 10 minutes until a clinically
significant fall in blood pressure, an increase in heart rate, or adverse
symptoms develop .
7/18/2023 110

111. • Test is positive if mPAP decreases at least 10 mmHg and to a value
less than 40 mmHg, with an increased or unchanged cardiac output,
and a minimally reduced or unchanged systemic blood pressure.
• Patients with a positive vasoreactivity test are candidates for a trial of
CCB therapy.
• Negative vasoreactivity test should be treated with an alternative
agent
7/18/2023 111

112. • LUNG BIOPSY
• Is reserved only in an unusual patient in whom PH is not thought to
be the primary disease.
• In such patients, one always finds abnormalities such as lung
infiltrates or other findings such as pulmonary hemangiomatosis or
pulmonary veno occlusive disease.
7/18/2023 112

113. 7/18/2023 113

114. TREATMENT OF PH
• Early identification and treatment PH is generally suggested because
advanced disease may be less responsive to therapy .
• Treatment begins with a baseline assessment of disease severity,
followed by primary therapy.
• Primary therapy is directed at the underlying cause of the PH.
• Some patients progress to advanced therapy, which is therapy
directed at the PH itself, rather than the underlying cause of the PH.
• It includes treatment with prostanoids, endothelin receptor
antagonists, phosphodiesterase 5 inhibitors, or, rarely, certain calcium
channel blockers.
7/18/2023 114

115. • BASELINE ASSESSMENT
• The baseline severity assessment is essential because the response to
therapy will be measured as the change from baseline.
• The functional significance of the PH is determined by measuring exercise
capacity.
• From the exercise capacity, the patients WHO functional class can be
determined .
• Pulmonary artery systolic pressure and right ventricular function can be
estimated by echocardiography, and then used to make a presumptive
diagnosis of PH.
• Right heart catheterization must be performed to accurately measure the
hemodynamic parameters and confirm that PH exists.
7/18/2023 115

116. PRIMARY THERAPY
• Primary therapy refers to treatment that is directed at the underlying
cause of the PH.
• Group 1 PAH -There are no effective primary therapies for most types
advanced therapy is often needed.
• Group 2 PH — Patients with group 2 PH have PH secondary to left
heart diseases. Primary treatment of the underlying heart disease.
• Group 3 PH — Patients with group 3 PH have PH secondary to various
causes of hypoxemia. Treatment of the underlying cause of
hypoxemia and correction of the hypoxemia with supplement of
oxygen
7/18/2023 116

117. • Group 4 PH — Patients with group 4 PH have PH due to
thromboembolic occlusion .Anticoagulation is primary medical
therapy for patients .
• Surgical thrombo-endarterectomy is primary surgical therapy for
selected patients with thromboembolic obstruction of the proximal
pulmonary arteries .
• Group 5 PH — Group 5 PH is uncommon and includes PH with unclear
multifactorial mechanisms. Primary therapy is directed at the
underlying cause.
7/18/2023 117

118. • GENERAL MEASURES
• All groups — Several therapies should be considered in all patients with PH.
• Diuretics —
• Diuretics are used to treat fluid retention due to PH . Should be
administered with caution to avoid decreased cardiac output , arrhythmias
induced by hypokalemia, and metabolic alkalosis.
• Oxygen therapy —
• Oxygen the cornerstone of therapy in patients with group 3 PH.
• Oxygen is generally administered at 1 to 4 L/min and adjusted to maintain
the oxygen saturation above 90 percent .
• Supplemental oxygen will not significantly improve the oxygen saturation
of patients who have Eisenmenger physiology.
7/18/2023 118

119. • Digoxin —
• Improves the right ventricular ejection fraction of patients with group 3 PH due
to COPD and biventricular failure
• Helps control the heart rate of patients who have SVT associated with RV
dysfunction .
• Anticoagulation —
• increased risk for intrapulmonary thrombosis and thromboembolism, due to
sluggish pulmonary blood flow, dilated right heart chambers, venous stasis, and a
sedentary lifestyle.
• Indicated in patients with IPAH , hereditary PAH , drug- induced PAH , or group 4
PH.
• The anticoagulant of choice is warfarin.
• Goal of an INR of approximately 2.
7/18/2023 119

120. ADVANCED THERAPY
• Advanced therapy is directed at the PH itself, rather than the
underlying cause of the PH.
• It includes treatment with prostanoids, endothelin receptor
antagonists, phosphodiesterase 5 inhibitors, or, rarely, certain calcium
channel blockers.
• Patient selection — Advanced therapy is considered for patients who
have evidence of persistent PH and a World Health Organization WHO
functional class II, III.
7/18/2023 120

121. • CALCIUM CHANNEL BLOCKERS(CCB)
• Patient who may benefit from CCB therapy can be identified by acute
vasodilator response test in PAH.
• The dosages used are quite high; 90–180 mg/day for nifedipine (up to 240
mg/day) and 240–720 mg/day for diltiazem (up to 900 mg/day). or
amlodipine, 20 mg/day
• <20% of patients respond to calcium channel blockers in the long term.
Not effective in patients who are not vasoreactive.
• Patients with BMPR2 receptor mutation do not respond .
• Side effects – constipation, nausea, headache, rash, edema, drowsiness,
dizziness, low blood pressure
7/18/2023 121

122. • Vasoactive medications
• Prostacyclins
• Epoprostenol (synthetic prostacyclin (PGI2) aka Flolan®)
• Treprostinil (Remodulin®), Iloprost (Ilomedin®, Ventavis®)
• Endothelin receptor antagonists
• Bosentan (Tracleer®), Sitaxsentan (Thelin®), Ambrisentan
(Letairis®)
• Phosphodiesterase type 5 inhibitors
• Sildenafil (Revatio®), Tadalafil (Cialis®)
7/18/2023 122

123. • PROSTACYCLIN
• The main product of arachidonic acid in the vascular endothelium
causes relaxation of smooth muscle
• Also results in inhibition of growth of smooth muscle cells.
• Successfully used in the treatment of PH resulting from left to right
shunt, portal hypertension and HIV infection.
7/18/2023 123

124. • ENDOTHELIN RECEPTOR ANTAGONISTS
• Endothelin-1 is a potent vasoconstrictor and smooth muscle
mitogen.
• High concentrations of endothelin-1 have been recorded in the lungs
of patients with group 1 PAH, including scleroderma and congenital
cardiac shunt lesions .
• Emerged as an initial therapy for group 1 PAH in the late 1990s.
7/18/2023 124

125. PHOSPHODIESTERASE INHIBITORS
• SILDENAFIL
• Sildenafil citrate is a selective and potent inhibitor of cGMP-specific
phosphodiesterase type 5 (PDE 5)
• PDE5 is the major subtype in the pulmonary vasculature and is more
abundant in the lung than in other tissues
• Pulmonary vascular cGMP levels can be increased by inhibiting
phosphodiesterases responsible for cGMP hydrolysis
• Relatively selective pulmonary vasodilation with little systemic
hypotension
• Recommended for WHO Class II and III
7/18/2023 125

126. ADVERSE EFFECTS
• Abdominal pain, nausea, diarrhea
• Hypotension, vasodilation, hot flushes
• Dry mouth, arthralgia, myalgia
• HA, abnormal dreams, vertigo
• Dyspnea, abnormal vision, deafness
• Penile erection, UTI, vaginal hemorrhage
• Retinitis of prematurity
7/18/2023 126

127. • NITRIC OXIDE
• Inhaled form.
• Acts as direct smooth muscle relaxant via activation of the guanylate
cyclase system.
• Short therapeutic half life.
• Ameliorates hypoxemia and lowers PVR by direct pulmonary
vasodilatation.
7/18/2023 127

128. RCTs of Approved Agents
Class of Drug Study/
Drug
N
Etiol
Class*
Design PositiveResults Dis-advantages
ET-1
Antagonist
BREATHE-1
Oral Bosentan/
placebo
213
PAH
III,IV
Double-
Blind
16-wk
6 MWD
Symptoms
Clinical Worsening
CPH
Hepatic toxicity (11%;
transient, reversible)
PDE-5 Inhibitor SUPER
Sildenafil Citrate (20, 40
or 80 mg tid)
278
IPAH,CT
CHD
II, III
Double-blind,
placebo
12 wks
6 MWD
CPH
Symptoms
Headache, flushing,
dyspepsia
Prostacyclin
analogue
Inhalational
Iloprost/
Placebo
203
PH
III-IV
Double-blind
12-week
Composite
Endpoint
6 MWD, sx
Administration
6 to 9 times daily
Prostacyclin
analogue
SQ Treprostinil/
SQ placebo
470
PAH
II-IV
Double-blind
12-wk
6 MWD
Symptoms
CPH
Pain, erythema
at infusion site
Side effects
Prostacyclin IV Epoprostenol/
Conventional Rx
81
PPH
III,IV
Open-
Label
12-wk
6 MWD
Symptoms
CPH
Survival
Indwelling central line
Pump
(infection,malf)
Side effects
7/18/2023 128

129. 7/18/2023 129

130. 7/18/2023 130

131. SURGICAL INTERVENTIONS
• Balloon Atrial Septostomy
• Allow R - L shunting to increase systemic output
• In spite of fall in the systemic arterial oxygen saturation, will produce
an increase in systemic oxygen transport.
• Shunt at the atrial level would allow decompression of the RA and RV,
alleviating s/s of right heart failure.
• Considered after short term failure of maximal medical therapy.
• Severe IPAH has been the main indication other include PAH
associated with surgically corrected CHD, CTD, distal CTEPH, PVOD,
and pulmonary capillary haemangiomatosis.
7/18/2023 131

132. • HEART / LUNG TRANSPLANTATION
• 1 year survival of 70%.
• 5 year survival of 50%.
• Effective therapy for patients with end stage pulmonary vascular disease.
• Other areas of research for treatment of PH includes
• Gene therapy
• serotonin transporter
• vasoactive intestinal peptide and tyrosine kinase inhibitors. Angiogenic
factors and stem cells .
7/18/2023 132

133. NATURAL HISTORY AND SURVIVAL
• Median survival 2.8 years, with 1-, 3-, and 5-year survival rates of
68%, 48%, and 34%, respectively.
• Functional class remains a strong predictor of survival
• The prognosis in patients with PAH associated with the scleroderma is
worse than for IPAH.
• CHD have a better prognosis than those with IPAH
• Cause of death is usually RV failure, manifest by progressive
hypoxemia, tachycardia, hypotension, and edema
7/18/2023 133

134. OUTCOMES
• Some improve
• PPHN
• Lung dx—as the dx improves, so does the PHTN
• In the absence of a correctable anatomic lesion, reports of spontaneous remission are very rare
• Some die rapidly
• Pulmonary veno-occlusive disease and CHD leading to cardiovascular collapse within one year
• Alveolar capillary dysplasia
• Congenital pulmonary vein stenosis
• Some get worse slowly
• Seems to be most common and may need lung transplant
• Must stay on top of associated OSA, RAD, chronic aspiration and other triggers
7/18/2023 134

135. PARAMETERS OF WORSE PROGNOSIS IN PAH
• Presence of RV failure
• Rapid progression of symptoms
• WHO –FC IV
• 6 MWT < 300 m
• Pericardial effusion
7/18/2023 135

136. SUMMARY
• Pulmonary arterial hypertension is a progressive disease with
significant morbidity and mortality
• Right heart failure is an important development which clearly
prognosticates and marks disease progression
• Treatment of right heart failure is essential
• Therapies with proven benefit in transpulmonary hemodynamics,
functional class and exercise tolerance include ET-1 receptor
antagonism (bosentan), prostanoids, and oral sildenafil.
7/18/2023 136

137. REFERENCES
• Cecil’s Medicine 23rd Edition
• Harrison’s Principle of Medicine
• Kumar and Clark’s Clinical Medicine
• European Society of Cardiologists , Guideline for the diagnosis and
treatment of pulmonary hypertension
(European Heart Journal (2009) 30, 2493–2537)
7/18/2023 137

138. •THANK YOU
7/18/2023 138