PULMONARY HYPERTENSION FOCUS SPECIALLY ON GROUP 3 PHTN . (WITH RECENT UPDATES)

1. Pulmonary Hypertension
Dr Govind Desai
III Year Post Graduate Student

2. TOPICS UNDER DISCUSSION
 DEFINITION OF PH
 CLASSIFICATION
 PATHOPHYSIOLOGY
 CLINICAL APPROACH
 TREATMENT
 PROGNOSIS

4. DEFINITION
 PH is defined as a mean pulmonary artery pressure (mPAP) ≥20 mmHg
at rest, measured by right heart catheterization.
 PH is considered severe if mPAP is ≥35 mmHg or the mPAP is ≥20
mmHg with an elevated right atrial pressure and/or the cardiac index
is <2 L/min/m
Ref : 6th WSPH ( April 2019)

5. Classification of PH

6. DETERMINANTS OF PAP AND PVR
 The pulmonary circulation is normally a HIGH flow and LOW resistance
LOW pressure system that carries blood into the pulmonary
microcirculation where the blood undergoes oxygenation and unloads
excess Carbon-dioxide.
 From early childhood to till late 50s the PAP is approximately around 20
mmHg
 PAP = CO* x [(PVR art + PVR cap + PVR veins)]

7. PULMONARY VASCULAR STRUCTURAL AND
FUNCTIONAL CHANGES IN PH

8.  A rise in the Cytosolic Ca levels is the major trigger for vasocontriction and a
key stimulus for pulmonary arterial smooth muscle cell proliferation and
migration which contributes to vascular remodelling .
 Hypoxic Pulmonary Vasoconstriction is an adaptive mechanism important for
redirecting blood flow away from poorly ventilated areas to areas of better
ventilated to maximise V/Q and hence optimizing oxygenation of blood.
 In chronic hypoxia two factors contribute to increased PAP (GROUP 3 PH)
a) Vascular Remodelling due to arterial smooth muscle cell proliferation.
b) Sustained vasoconstriction
SUSTAINED VASOCONSTRICTION

9. VASCULAR REMODELLING
 The Thickness and tissue mass of the pulmonary arterial walls are maintained
at an appropriate level by a fine balance between proliferation and apoptosis
of fibroblasts.
 Thickening of the wall occurs if the balance is tipped in favour of cell
proliferation
 Resting Calcium is seen to be increased in proliferating pulmonary arteries
compared to growth arrested cells.
 Plexiform Lesions: These are aneurysmatic dilatation of a muscular
artery that can occur in very small arteries and arterioles

10. INSITU THROMBUS
 Thrombosis is frequently seen within the small vessels of patients with PAH.
This occurs without evidence of a remote(embolic) source of the thrombus
suggesting a local imbalance of pro and anticoagulant forces
 Local Causes
1)Endothelial damage due to sheering force
2)Platelet derived growth factors
3)TGF-β
4)VEGF
Ref: Fishmans textbook on Pulmonary Disorders 5th Edition

11. PATHOGENIC MECHANISM OF PH

12. CELLULAR MEDIATORS *
 IMBALANCE OF VASOACTIVE MEDIATORS
NO* , Prostacyclin , VIP
 INCREASE IN VASOCONSTRICTIVE MEDIATORS
Thromboxane , 5-HT , Endothelin-1*
 INCREASED EXPRESSION OF GROWTH FACTORS
 INCREASED CYTOKINES AND INFLAMMATION

13. INTRACELLULAR MEDIATORS
 IPAH is associated with abnormally low levels of the potent pulmonary
arterial smooth muscle cellrelaxant NO. In pulmonary arterial endothelial
cells, NO produced by eNOS freely diffuses across the cell membrane to
pulmonary arterial smooth muscle cells and activates intracellular soluble
guanylate cyclase (sGC), which catalyzes the conversion of guanosine 5′-
triphosphate (GTP) to cyclic guanosine monophosphate (cGMP).
 cGMP then activates cGMP-dependent kinases, which can reduce [Ca2+]
cyt, inhibit Rho signaling, and inhibit phosphorylation of myosin-binding
protein, all of which lead to smooth muscle relaxation.In the lung,
metabolism of cGMP is controlled by phosphodiesterase 5 (PDE-5). PDE-5
inhibitors block the breakdown of cGMP, leading to vasodilation due to an
accumulation of cGMP in the tissue.

14. CYCLIC GMP PATHWAY

15. PREVALENCE
 Group 3 PH appears to be more
prevalent in older adults. In one
series of patients ≥65 years with
PH, group 3 PH occurred in 14
percent, while 28 percent had
group 2 PH and 17 percent had
mixed group 2/3 PH

16. IN COPD
In one study of 374 patients with advanced lung disease (transplant
candidates), most of whom had COPD, the prevalence of PH was 25 percent by
RHC .
Almost half of the study population were misclassified as having PH by
echocardiography (sensitivity and specificity of 85 and 55 percent,
respectively) suggesting that echocardiography may be less useful
diagnostically in those with severe lung disease.

17. One retrospective review of 156 patients with advanced lung disease, most of whom had
COPD, reported that two-thirds had right ventricle (RV) dysfunction . PH was in the mild
range with a mean mPAP of 25 mmHg, but was markedly lower than that seen in those
with group 1 PAH, in whom the mean mPAP was 50 mmHg.

18. IN ILD
PH although spirometric abnormalities correlate poorly .Idiopathic pulmonary fibrosis (IPF) –
An mPAP of ≥25 mmHg is present in 8 to 15 percent at initial evaluation of IPF, in 30 to 50
percent of advanced cases, and in over 60 percent of end-stage IPF patients (mPAP mostly
assessed by RHC).
In the largest of these studies, 46 percent of patients with advanced ILD had mPAP ≥25
mmHg but only 9 percent had mPAP >40 mmHg (ie, severe PH) .
A decreased diffusing capacity may predict.

19.  Suspecting group 3 pulmonary hypertension — A high index of suspicion is
needed for the detection of PH in patients with pulmonary disorders since
many of the symptoms of the lung disease itself mimic those of PH (eg,
exertional dyspnea, fatigue, lethargy).
CLINICAL EVALUATION

20. PATIENT HISTORY IN
PULMONARY
HYPERTENSION

21. 1. Dyspnea on exertion is by far the most common presenting complaint. Often,
because of the lack of other signs or symptoms, it is attributed to physical
deconditioning or anxiety. Other initial complaints, particularly easy fatigability
and chest discomfort, are often similarly dismissed.
2. Angina-like or nonspecific Chest pain is common in patients with severe
pulmonary hypertension and generally attributed to right ventricular overload and
myocardial ischemia. Chest pain might also occur due to the extrinsic
compression of the left main coronary artery by an enlarged pulmonary artery.
3. Hoarseness,due to paralysis of the left recurrent laryngeal nerve, may result
from trapping of the nerve between the aorta and the dilated left pulmonary
artery (a form of Ortner syndrome)
4. Symptoms of right ventricular failure and the presence of syncopal events are
associated with a worse prognosis

23. WHEN TO SUSPECT
On History
 Long standing dyspnea that has not been responded to treatment for other
common disorders
 In younger individuals who have frequently been told the symptoms are due
to asthma yet failed to improve with significantly aggressive anti-
inflammatory and bronchodilator therapy.
 In older individuals COPD
 History of collagen vascular diseases, sleep apnea, drug usage, HIV infection,
Liver Diseases.

24. ON PHYSICAL
EXAMINATION

25. INVESTIGATIONS

27. ON ECG
 Findings suggestive of the presence of pulmonary hypertension include
1. right axis deviation
2. right atrial enlargement
3. right ventricular hypertrophy

28. ON ECHOCARDIOGRAM

29. MANAGEMENT
 GENERAL MANAGEMENT
 SPECIFIC MANAGEMENT

30. SPECIFIC MANAGEMENT
 Group 1 PAH
 Patients with group 1 pulmonary arterial hypertension (PAH) have idiopathic
pulmonary arterial hypertension (IPAH, formerly called primary pulmonary
hypertension), hereditary PAH, or PAH due to diseases that localize to small
pulmonary arterioles, such as connective tissue diseases, HIV infection, portal
hypertension, congenital heart disease, schistosomiasis, and drug use.
 There are no effective primary therapies for most types of group 1 PAH. As a
result, PH-specific therapy is often needed

31.  Group 2 PH — Patients with group 2 PH have PH secondary to left heart
disease with chronic left atrial and pulmonary venous hypertension, including
systolic dysfunction, diastolic dysfunction, and valvular heart disease
 Primary therapy for group 2 PH consists of treatment of the underlying heart
disease

32.  Group 3 PH — Patients with group 3 PH have PH secondary to various
causes of hypoxemia, such as chronic obstructive pulmonary disease,
interstitial lung disease, other pulmonary diseases with a mixed restrictive
and obstructive pattern, sleep-disordered breathing, or alveolar
hypoventilation disorders
 Primary therapy for group 3 PH consists of treatment of the underlying cause
of hypoxemia and correction of the hypoxemia with supplemental oxygen
 Oxygen is the only modality with proven mortality benefit in some patients
with group 3 PH. This has been established by two large trials studying
patients with COPD, the most common cause of group 3 PH.

33.  Oxygen is the only modality with proven mortality benefit in some patients with
group 3 PH. This has been established by two large trials studying patients with
COPD, the most common cause of group 3 PH:
 ●A trial randomly assigned 87 patients with COPD, a history of right ventricular
dysfunction, and a PaO2 below 60 mmHg to receive either oxygen therapy for 15
hours per day or no oxygen therapy . Oxygen therapy decreased five-year mortality
(46 versus 67 percent), but the survival advantage did not appear until after 500
days of therapy. Pulmonary vascular resistance did not increase in the oxygen
group,but increased in the group without oxygen .
 ●The Nocturnal Oxygen Therapy Trial (NOTT) compared continuous (19 hours per
day) to nocturnal (12 hours per day) oxygen administration. The three-year
mortality rate was lower with continuous oxygen than nocturnal oxygen (22 versus
42 percent) . Oxygen therapy was also associated with a slight reduction of
pulmonary vascular resistance.
 Thus, continuous oxygen therapy improves survival in patients with COPD and a
PaO2 below 55 mmHg. While the trial suggested seemingly mild effects on
pulmonary hemodynamics, in our experience, some patients with chronic hypoxia
experience a marked reduction in pulmonary artery pressure with continuous
oxygen therapy.

34.  Group 4 PH — Patients with group 4 PH have PH due to thromboembolic or
other occlusion of the proximal or distal pulmonary vasculature (eg, chronic
thromboembolic disease
 Anticoagulation is primary medical therapy for patients with group 4 PH. The
value of anticoagulant therapy for group 4 PH is an extrapolation of the
clinical evidence that anticoagulation prevents recurrent pulmonary
embolism. Data suggesting that anticoagulation is beneficial in patients with
group 4 PH are lacking.
 Surgical thromboendarterectomy is primary surgical therapy for selected
patients with thromboembolic obstruction of the proximal pulmonary
arteries. Perioperative mortality for this procedure is less than 10 percent
when performed in selected centers and the hemodynamic response may be
dramatic and sustained.

35. GENERAL MEASURES
 Exercise and the Avoidance of Deconditioning

36.  In a meta-analysis of five randomized trials that included mostly patients with group 1
PAH, exercise programs ranging from 3 to 15 weeks resulted in improved exercise capacity
(increase by 60 meters in the six-minute walk distance [6MWD]) peak oxygen uptake
(increase 2.4 mL/kg/minute), and health-related quality of life.
 In a randomized crossover trial, 15 weeks of exercise training resulted in an
improved 6MWD when compared with sedentary controls (+96 versus -15 meters)
 Following crossover, the sedentary group also improved their mean 6MWD (+74 meters).
Exercise training improved the World Health Organization (WHO) functional class and peak
oxygen consumption. However, exercise training did not improve hemodynamic
abnormalities, measured as the Doppler-derived pulmonary artery systolic pressure.

37. DIURETICS
Spironolactone is often used to manage mild fluid retention. It may also have
beneficial effects in heart failure by modulating neurohormones.
Loop diuretics are often required to prevent more significant fluid retention
and right
heart failure.
Indeed, high doses and combinations of diuretics are often required to
maintain appropriate fluid balance

38. DIGOXIN
 Digoxin — Digoxin therapy has been shown to have both beneficial effects and
drawbacks:
 ●Digoxin improves the left ventricular ejection fraction of patients with group 3 PH
due to COPD and biventricular failure. However, these patients may be more
sensitive than most patients to digitalis toxicity and require close monitoring.
 ●Digoxin helps control the heart rate of patients who have supraventricular
tachycardias associated with right ventricular dysfunction.
 Ref:Effect of digoxin on right ventricular function in severe chronic airflow
obstruction. A controlled clinical trial.Mathur PN, Powles P, Pugsley SO, McEwan
MP, Campbell EJ

39. VACCINATIONS
 Immunizations against influenza and pneumococcal pneumonia are important
preventive measures in all patients with pulmonary hypertension and cor
pulmonale.
 Influenza vaccination should occur annually,
 Administration of the 23-valent polysaccharide pneumococcal vaccine should
occur once at the time PH is diagnosed and again when the patient turns 65.

40. PH SPECIFIC THERAPY
 Group 3 PH — We suggest that for most patients with PH secondary to or
associated with significant lung disease, PH-targeted therapy should not be
used since it may be harmful. PH-specific therapy for this population may
only be considered in patients with severe PH who may be eligible for a
clinical trial setting in a specialized center.

41. SELECTIVE DRUGS FOR TYPE 1 PAH
 CCB therapy can be initiated with either long
acting nifedipine (30 mg/day) or diltiazem (120 mg/day), then increased to the
maximal tolerated dose. Short-acting nifedipine should NOT be used.
 Epoprostenol ( PGI I 2 ANALOGUE) I.V.
Doses of 1 to 2 ng/kg per min and increased by 1 to 2 ng/kg per min every one to two
days as tolerated. most patients require dose increases of 1 to 2 ng/kg per min every two
to four weeks to sustain the clinical effect

42. ENDOTHELIN ANTAGONISTS
 Endothelin-1 (ET-1) is a potent vasoconstrictor and smooth muscle mitogen. High
concentrations of ET-1 have been recorded in the lungs of patients with both
idiopathic PAH and other etiologies of group 1 PAH, including scleroderma and
congenital cardiac shunt lesions .
 There are two receptors (endothelin receptor A and B) that are targeted by
endothelin receptor antagonists (ERAs). ERAs that have been tested in clinical
trials include:
●Nonselective dual action receptor antagonists – bosentan and macitentan
●Selective receptor antagonists of endothelin receptor A – ambrisentan and
sitaxsentan

43. PROGNOSIS

44. TAKE HOME MESSAGE
 ALWAYS RULE OUT PH IN UNEXPLAINED DYSPNEA
 DEFINITION CHANGE
 COPD AND OTHER PULMONARY CAUSES ARE ASSOCIATED MOSTLY WITH MILD TO
MODERATE PH
 THE ONLY EFFECTIVE Rx TILL DATE FOR GROUP 3 PH IS O2 THERAPY
 NO DRUG SHOULD BE GIVEN IN CASE OF DIAGNOSED GROUP 3 PH
 OVERLAP EXISTS BETWEEN GROUP 2 AND GROUP 3

45. THANK YOU