“a study of etiological profile of non cardiogenic

“A STUDY OF ETIOLOGICAL PROFILE OF NON CARDIOGENIC

PULMONARY HYPERTENSION AT A TERTIARY CARE

HOSPITAL”

BY

SURGEON LIEUTENANT COMMANDER (DR) AMIT SHARMA

DISSERTATION SUBMITTED TO THE

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE

IN PARTIAL FULLFILLMENT OF THE REQUIREMENT FOR THE DEGREE OF

DOCTOR IN MEDICINE

IN

MEDICINE

Under the guidance of

GROUP CAPTAIN (DR) AJAY HANDA

GROUP CAPTAIN (DR) ASHISH CHAUHAN

DEPARTMENT OF MEDICINE

COMMAND HOSPITAL (AIR FORCE)

BANGALORE 560007

2014-2017

Rajiv Gandhi University of Health Sciences Karnataka,

Bangalore

i

CERTIFICATE

ii

Rajiv Gandhi University of Health Sciences

Bangalore

DECLARATION BY THE CANDIDATE

I hereby declare that this dissertation/thesis entitled “A study of etiological

profile of Non Cardiogenic Pulmonary Hypertension at a Tertiary Care Hospital” is

a bonafide and genuine research work carried out by me under the guidance of Group

Captain (Dr.) Ajay Handa, M.D (Med), D.M. (Pulmonary Medicine), Professor,

Department of medicine, Command Hospital, Air Force, Bangalore

Place : Bangalore-07 Surg Lt Cdr (Dr.) Amit Sharma

Date : PG student in Medicine

Department of Medicine

Command Hospital,

Air Force

Bangalore-07

iii


Bangalore

CERTIFICATE BY THE GUIDE

This is to certify that the dissertation entitled “A STUDY OF ETIOLOGICAL

PROFILE OF NON CARDIOGENIC PULMONARY HYPRTENSION AT A

TERTIARY CARE HOSPITAL” is a bonafide and genuine research work carried out

by Surgeon Lieutenant Commander (Dr.) Amit Sharma in partial fulfilment of the

requirement for the degree of Doctor in Medicine in Medicine.

Place : Bangalore-07 Group Captain (Dr.) Ajay Handa

Date : M.D., D.M. (Pulmonary Medicine),

Professor


Command Hospital Air Force

Bangalore-07.

iv


Bangalore

ENDORSEMENT BY THE HOD, PRINCIPAL/HEAD OF THE

INSTITUTION

This is to certify that the dissertation/thesis entitled “A STUDY OF

ETIOLOGICAL PROFILE OF NON CARDIOGENIC PULMONARY

HYPRTENSION AT A TERTIARY CARE HOSPITAL” is a bonafide and genuine

research work carried out by Surgeon Lieutenant Commander (Dr.) Amit Sharma under

the guidance of Group Captain (Dr.) Ajay Handa, M.D., D.M. (Pulmonary

Medicine), Professor, Department of Medicine, Command Hospital, Air Force,

Bangalore.

Brig (Dr.) Krishnan Narayanan

M.D., PDCC (Rheumatology), Dean Academics

Consultant Medicine & Rheumatology,

Head of Department of Medicine

Command Hospital Air Force

Bangalore-07

Place: Bangalore-07 Place: Bangalore-07

Date: Date:

v

COPYRIGHT

DECLARATION BY THE CANDIDATE

I hereby declare that the Rajiv Gandhi University of Health Sciences, Karnataka

shall have the rights to preserve, use and disseminate this dissertation/thesis in print or

electronic format for academic / research purpose.


Date : PG student in Medicine


Command Hospital, Air Force

Bangalore-07.

© Rajiv Gandhi University of Health Sciences, Karnataka

vi

ACKNOWLEDMENTS

vii

ACKNOWLEDGEMENTS

Dedication towards the Command hospital Air Force, Bangalore, sincerity in work and

organizational practicalities was absorbed by me from Air Vice Marshal (Dr.) MV

Singh, Commandant and Principal, Command Hospital Air Force, Bangalore.

I express my sincere thanks to my guide for this dissertation work Group Captain

(Dr.) Ajay Handa, Professor Medicine and Senior Advisor Pulmonology and co-guide

Group Captain Ashish Chauhan, Senior Advisor Cardiology, CHAF, Bangalore for

their kindness and guidance throughout this study.

The credit of inspiration goes to Brigadier (Dr.) Krishnan Narayanan, Head of the

Department, Department of Medicine, CHAF, Bangalore for his support to fulfil this

course.My sincere gratitude to my teachers Gp Capt SC Mishra; Gp Capt S Shankar;

Gp Capt Salil Gupta; Col KS Brar, VSM; Gp Capt Vishal Singh; Lt Col R Saxena;

Wg Cdr AS Prasad; Wg Cdr TVSVGK Tilak; Lt Col S Srinivasa and Wg Cdr

Kumar Abhisheka and all the other teaching and administrative staff, who guided,

molded and infused in me a sense of confidence with their knowledge and experience. I

also thank cooperation of my colleagues Dr. Dinesh and Dr. Lakshmi for their valuable

support. My special thanks to the patients of this study for their valuable cooperation

without whom I would not have completed my study.

Finally, I am grateful to my wife Mrs. Shubhi and daughter Miss Nishita for

their constant support which helped me to pursue my course.


Date :

viii

ABSTRACT

ix

ABSTRACT

of the Dissertation on


PULMONARY HYPERTENSION AT A TERTIARY CARE HOSPITAL”

Background and Objectives: Pulmonary hypertension results from several

etiologies, of which underlying cardiac diseases constitute the major group and other

etiologic entities such as respiratory diseases, drugs, and connective tissue diseases

being relatively less common. In all these diseases, Pulmonary Hypertension has

adverse prognostic effects on the disease progression and outcomes. The Etiological

profile and prevalence of Pulmonary Hypertension in various non-cardiac disorders

has not been given adequate attention and there is paucity of data from our country.

This study was conducted to describe the etiological profile of Non Cardiac

Pulmonary Hypertension and to evaluate the severity of Pulmonary Hypertension

with respect to various clinical parameters.

Methodology: We screened a total of 66 patients with features suggestive of

Pulmonary Hypertension. Total 35 subjects with evidence of Pulmonary Hypertension

and with no underlying heart disease were included in the study.

Results: The mean age of patients with Pulmonary Hypertension was 59.54 ±

14.45 years. Cumulatively prevalence of Pulmonary Hypertension was highest in

patients of age group of 51-60 years. Male gender preponderance was noted with

male to female ratio of 2.1. Chronic Obstructive Pulmonary Disease (COPD) was

found as the commonest cause (51.43%) followed by idiopathic Pulmonary Artery

Hypertension (iPAH) in 22.86% and Interstitial Lung Disease (ILD) in 17.14% of all

patients. The mean Right Ventricular Systolic Pressure was 55.94 ± 15.46 mmHg.

Maximum number of patients (54.29%) were found to be in the WHO functional class

x

II. Spirometry showed Obstructive pattern in 51% of our patients. The mean arterial

partial pressure of oxygen was 53.01 ± 18.05 mm of Hg.

Interpretation and Conclusion: The prevalence of Pulmonary Hypertension

increases after the age of 50 years. The most common etiology was COPD followed

by iPAH and ILD. We recommend regular screening of the above patients for

Pulmonary Hypertension if there are symptoms disproportionate to underlying

disease.

Key Words: Pulmonary Artery Hypertension; Pulmonary hypertension, Right

Ventricular Systolic Pressure, Chronic Obstructive Pulmonary Disease.

Written by

Surg Lt Cdr (Dr.) Amit Sharma

PG student in Medicine


Command Hospital, Air Force

Bangalore-07.

xi

ACRONYMS

xii

ACRONYMS (in alphabetical order)

2D Echo 2-Dimensional Echocardiography

6MWD 6-Minute Walk Distance

ABG Arterial Blood Gas

ALK1 Activin Receptor like Kinase 1 gene

ANA Anti Nuclear Antibodies

BiPAP Bilevel Positive Airway Pressure non-invasive

Ventilation

BMPR2 Bone Morphogenetic Receptor Protein 2

BNP Brain Natriuretic Peptide

CAV1 Caveolin 1

CCB Calcium Channel Blocker

cGMP cyclic Guanosine Monophosphate

COPD Chronic Obstructive Pulmonary Disease

CPAP Continuous Positive Airway Pressure Ventilation

CTD Connective Tissue Disease

CTEPH Chronic Thromboembolic Pulmonary Hypertension

DLCO Diffusing Capacity of the Lung for Carbon Monoxide

xiii

ECG Electrocardiogram

ELC Endothelial like Cells

ENG Endoglin

ET Endothelin

FEV1 Forced Expiratory Volume in First Second

GOLD Global initiative for Obstructive Lung Disease

HHT Hereditary Haemorrhagic Telangiectasia

HIV Human Immunodeficiency Virus

HPV Hypoxic Pulmonary Vasoconstriction

HRCT High Resolution Computed Tomography

ILD Interstitial Lung Disease

iPAH Idiopathic Pulmonary Artery Hypertension

IVC Inferior Vena Cava

LTOT Long Term Oxygen Therapy

mPAP mean Pulmonary Artery Pressure

mRNA messenger Ribo Nucleic Acid

NO Nitric Oxide

NT pro BNP N-Terminal pro Brain Natriuretic Peptide

PAH Pulmonary Artery Hypertension

xiv

PaO2 Partial Pressure of Oxygen in Arterial Blood

PAVM Pulmonary Arterio-venous Malformation

PCWP Pulmonary Capillary Wedge Pressure

PDE 5 Phosphodiesterase type 5

PFT Pulmonary Function Test

PH Pulmonary Hypertension

PVR Pulmonary Vascular Resistance

RAP Right Atrial Pressure

RCT Randomised Controlled Trial

RHC Right Heart Catheterisation

RHF Right Heart Failure

RVSP Right Ventricular Systolic Pressure

SaO2 Oxygen Saturation in Arterial Blood

SDB Sleep Disordered Breathing

SMLC Smooth Muscle like Cells

TGF β Transforming Growth Factor β

TTE Trans Thoracic Echocardiography

WHO World Health Organisation

xv

TABLE OF CONTENTS

xvi

TABLE OF CONTENTS

S No.

TOPIC

Pg No.

1. Introduction 1

2. Aims and Objectives 3

3. Literature review 5

4. Methodology 37

5. Results 41

6. Discussion 54

7. Conclusion 60

8. Summary 62

9. Bibliography 65

10. Annexures 75

xvii

LIST OF FIGURES

S No.

FIGURES

Pg No.

1. Role of BMPR2 as factor associated with idiopathic Pulmonary Artery Hypertension

14

2. A hypothetical mechanism underlying the pulmonary vascular remodeling in highlanders, chronic obstructive pulmonary disease (COPD) patients and idiopathic pulmonary arterial hypertension (iPAH) patients

17

3. ECG representing features of Pulmonary Hypertension 24

4. Representative Chest X Ray showing findings of pulmonary hypertension

25

5. Echocardiography showing features of Pulmonary Hypertension

28

6. Diagnostic Approach to Pulmonary Hypertension 31

xviii

LIST OF TABLES

S No.

TABLES

Pg No.

1. Updated Clinical Classification of pulmonary hypertension

8

2. World Health Organization Classification of Functional Status of Patients With Pulmonary Hypertension

22

3. Echocardiographic probability of pulmonary hypertension in symptomatic patients with a suspicion of pulmonary hypertension

29

4. Age wise Distribution of Cases with Pulmonary Hypertension

43

5. Gender wise distribution of cases with Pulmonary Hypertension

44

6. Etiological Diagnosis of cases with Pulmonary Hypertension

45

7. Distribution of Severity of Pulmonary Hypertension on the basis of Right Ventricular Systolic Pressures

47

8. Distribution of Severity of Pulmonary Hypertension on the basis of WHO Function Status Classification

48

9. Distribution of Pattern of Spirometry in cases with Pulmonary Hypertension

49

10. Distribution of Pulmonary Hypertension cases with Obstructive Airway Disease on the basis of GOLD Classification

50

11. Pulmonary Hypertension and level of hypoxemia on ABG analysis

51

12. Modalities of Treatment in cases of Pulmonary Hypertension

52

xix

LIST OF CHARTS

S No.

CHARTS

Pg No.

1. Age wise distribution of cases with Pulmonary Hypertension

43

2. Gender wise distribution of cases with Pulmonary Hypertension

44

3. Etiological Diagnosis of cases with Pulmonary Hypertension

46

4. Distribution of Severity of Pulmonary Hypertension on the basis of Right Ventricular Systolic Pressures

47

5. Distribution of Severity of Pulmonary Hypertension on the basis of WHO Function Status Classification

48

6. Distribution of Pattern of Spirometry in cases with Pulmonary Hypertension

49

7. Distribution of Pulmonary Hypertension cases with Obstructive Airway Disease on the basis of GOLD Classification

50

8. Pulmonary Hypertension and level of hypoxemia on ABG analysis

51

9. Modalities of Treatment in cases of Pulmonary Hypertension

53

1

INTRODUCTION

2

INTRODUCTION

Pulmonary Hypertension (PH) is defined as a mean pulmonary artery pressure

(mPAP) ≥ 25 mmHg with a pulmonary capillary wedge pressure ≤ 15 mmHg, as

measured by cardiac catheterization(1).

With most of the public health attention being focused on atherosclerotic

cardiovascular disease, the problem of pulmonary hypertension is largely overlooked. The

aetiology of pulmonary hypertension is diverse and most of the underlying causes of

Pulmonary Hypertension are prevalent in the developing world in a much larger

magnitude as compared to the western world(2)

Pulmonary hypertension results from several etiologic factors (3).Among them

underlying cardiac diseases constitute the major group and other etiologic entities such as

drugs, connective tissue diseases and respiratory diseases being less common in

practice(4). In all these diseases, the development of Pulmonary Hypertension has

adverse prognostic effects on the disease progression and outcomes(5). Few studies have

described the aetiology of Pulmonary Hypertension from India; and it is not clear

whether there is an association between aetiology and severity of pulmonary

Hypertension(6).

The Etiological profile and prevalence of Pulmonary Hypertension in various non-

cardiac disorders has not been given adequate attention and there is paucity of data from

our country on this aspect. This study was undertaken to find out the etiological and

clinical profile of Pulmonary Hypertension due to non-cardiac causes at a Tertiary Care

Hospital.

3

AIMS AND OBJECTIVE

4

AIMS AND OBJECTIVES

Aim of the Study:

To study the etiology, clinical profile, and functional capacity in patients with non-cardiac

Pulmonary Hypertension.

Objective of the Study:

1) To describe the etiological profile of non-cardiac Pulmonary Hypertension in a

Tertiary Care Hospital

2) To describe the severity of disease in these cases of non-cardiac Pulmonary

Hypertension with parameters including measured RVSP on Echocardiography,

WHO functional class, spirometry, and partial pressure of oxygen in arterial blood.

5

LITERATURE REVIEW

6

LITERATURE REVIEW

Definition:

Pulmonary Hypertension (PH) is defined as a mean pulmonary artery pressure

(mPAP) ≥ 25 mmHg with a pulmonary capillary wedge pressure ≤ 15 mmHg, measured

by cardiac catheterization(1). 2D Echocardiography is used as a screening tool for most

cases with suspected PH(7). Doppler is used to measure the maximum velocity (V) of the

Tricuspid regurgitant jet, the systolic pressure gradient (AP) between right ventricle and

right atrium is calculated by the modified Bernoulli equation (AP = 4V2). Adding the

trans-tricuspid gradient to the mean right atrial pressure (which is estimated by IVC

collapsibility and is generally in the range of 3-5 mm of Hg in healthy adults) gives

predictions of right ventricular systolic pressure that correlates well with catheterization

values(7). The right ventricular systolic pressure of ≥35 mm Hg measured by

echocardiography is suggestive of Pulmonary Hypertension as this pressure correlates

well with mean pulmonary artery pressure of ≥ 25 mmHg measured by invasive right

heart catheterisation(8, 9).

Clinical Classification of Pulmonary Hypertension:

The classification of pulmonary hypertension (PH) has gone through a series of

changes since the first classification was proposed in 1973 at an international conference

on primary PH (PPH) endorsed by the World Health Organization. The initial

classification designated only 2 categories, PPH or secondary PH, depending on the

presence or absence of identifiable causes or risk factors. Twenty-five years later, the 2nd

World Symposium on Pulmonary Arterial Hypertension (PAH) was held in Evian,

7

France. The “Evian classification” attempted to create categories of PH that shared

pathologic and clinical features and the available therapeutic options (3).

During the 5th World Symposium held in Nice, France, in 2013, the consensus

was reached to maintain the general scheme of previous clinical classifications. However,

modifications and updates especially for Group 1 patients (pulmonary arterial

hypertension [PAH]) were proposed. The main change was to withdraw persistent

pulmonary hypertension of the new born (PPHN) from Group 1 because this entity

carried more differences than similarities with other PAH subgroups. In the current

classification, PPHN is now designated number 1’’. Pulmonary hypertension associated

with chronic haemolytic anaemia has been moved from Group 1 PAH to Group 5 i.e.

unclear/multifactorial mechanism. In addition, it was also decided to add specific items

related to paediatric pulmonary hypertension in order to create a comprehensive, common

classification for both adults and children. Therefore, congenital or acquired left-heart

inflow/outflow obstructive lesions and congenital cardiomyopathies were added to Group

2, and segmental pulmonary hypertension was added to Group 5. Last, there were no

changes for Groups 3 and 4. The prognosis and management of each type of PH depends

on the cause and underlying associated condition. The current updated classification of

PH given by WHO in 2013 is depicted in Table 1 below (3).

8

Table 1 Updated Clinical Classification of pulmonary hypertension

1. Pulmonary arterial hypertension (PAH)

1.1 Idiopathic PAH

1.2 Heritable PAH

1.2.1 BMPR2 (Bone Morphogenetic Receptor Protein)

1.2.2 ALK-1 (Activin Receptor like Kinase 1 gene), ENG (Endoglin) , SMAD9,

CAV1 (Caveolin 1), KCNK3

1.2.3 Unknown

1.3 Drug and toxin induced

1.4 Associated with:

1.4.1 Connective tissue disease

1.4.2 HIV infection

1.4.3 Portal hypertension

1.4.4 Congenital heart diseases with intracardiac Lt Rt shunt like ASD, VSD or

PDA

1.4.5 Schistosomiasis

1’ Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis

1’’. Persistent pulmonary hypertension of the new born (PPHN)

9

2. Pulmonary hypertension associated with left heart diseases

2.1 Left ventricular systolic dysfunction

2.2 Left ventricular diastolic dysfunction

2.3 Valvular disease

2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital

cardiomyopathies

3. Pulmonary hypertension associated with lung respiratory diseases and/or hypoxia

3.1 Chronic obstructive pulmonary disease

3.2 Interstitial lung disease

3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern

3.4 Sleep-disordered breathing

3.5 Alveolar hypoventilation disorders

3.6 Chronic exposure to high altitude

3.7 Developmental lung diseases

4. Chronic thromboembolic pulmonary hypertension (CTEPH)

5. Pulmonary hypertension with unclear multifactorial mechanisms

5.1 Hematologic disorders: chronic haemolytic anaemia, myeloproliferative disorders,

post splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis,

10

lymphangioleiomyomatosis

5.3Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders

5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure,

segmental PH

Epidemiology:

Disorders in Group 1 are classified as Pulmonary Arterial Hypertension (PAH),

which is a distinct disease entity with pathological changes in pulmonary arteries causing

increased pulmonary vascular resistance resulting in PAH. Commonest among the group

1 is Idiopathic Pulmonary Artery Hypertension (iPAH) which is a rare and progressive

disease seen in younger patients (10)

There is paucity of data regarding the exact prevalence of Pulmonary

Hypertension both in Western and Indian Literature. The limited data available shows the

prevalence of PAH is about 15 per million and Idiopathic PAH is 6 per million. Familial

PAH is found in 6–10% of PAH. The incidence of PAH in human immunodeficiency

virus (HIV) infection is 0.5% which is 6–12 times that in general population. The

prevalence of PAH in patients of cirrhosis is 2–6%. The prevalence of PAH in sickle cell

disease is about 30%. The prevalence of PAH in systemic sclerosis is 32%(4). From

India, Mehrotra et al studied 57 patients with PH and reported Group-I as the most

common (72%) and Group-II the second most (16%) cause of PH in their registry. Group-

III and Group-IV were less common (5 and 7% respectively) whereas no patient was

found in Group-V PH(11).

11

Pulmonary hypertension (PH) is increasingly being recognized in the elderly

population; however, the causes and characteristics of PH in the elderly population are

not well established. In a study Pugh et al found that PAH is an uncommon cause of PH

in elderly patients, most frequently associated with connective tissue disease. WHO group

2 PH and mixed disease were common, highlighting a need for careful phenotyping of

elderly patients with PH prior to initiating therapy (12).

Etiopathogenesis of Pulmonary Hypertension:

Pulmonary Hypertension (PH) is a heterogeneous disease with different

hemodynamic parameters and complex patho-physiology depending upon the underlying

etiology. PH is found throughout the world, but the disease burden is thought to be

greater in India and in other developing countries(10). It is a disease characterized by

vascular obstruction and vasoconstriction leading to progressive increase in pulmonary

vascular resistance and right ventricular failure(10).

Pulmonary arterial hypertension (PAH) has a multifactorial pathogenesis.

Vasoconstriction, remodelling of the pulmonary vascular bed, and thrombosis contribute

to increased pulmonary vascular resistance in PAH. The process of pulmonary vascular

remodelling involves all layers of the vessel wall and is complicated by cellular

heterogeneity within each compartment of the pulmonary arterial wall. Various

constituents of the blood vessel are incriminated such as endothelial, smooth muscle, and

fibroblast, along with inflammatory cells and platelets, are thought to play a significant

role in genesis of PAH. Disordered proteolysis of the extracellular matrix is also evident

in PAH. Pulmonary vasoconstriction is believed to be an early component of the

pulmonary hypertensive process. Excessive vasoconstriction has been related to abnormal

function or expression of potassium channels and due to endothelial dysfunction.

12

Endothelial dysfunction leads to chronically impaired production of vasodilators such as

nitric oxide and prostacyclin along with overexpression of vasoconstrictors such as

endothelin (ET-1). Many of these abnormalities elevate pulmonary vascular tone and

promote vascular remodelling and are being used for developing potent pharmacological

agents to treat PAH. Various genetic and pathophysiologic studies have emphasized the

relevance of several mediators in this condition, including prostacyclin, nitric oxide, ET-

1, angiopoietin-1, serotonin, cytokines, chemokines, and members of the transforming-

growth-factor-beta super-family. (13).

The etiopathogenesis of each group causing PH mentioned in classification of

Pulmonary Hypertension are discussed in subsequent paragraphs.

a) Group 1: Pulmonary Artery Hypertension: Idiopathic Pulmonary

Artery Hypertension is a chronic disease which is characterised by progressive

remodelling of the pulmonary arterial vasculature which if untreated leads to right

heart failure and subsequently death (14). Idiopathic pulmonary arterial

hypertension was perceived as a progressive disease with a poor outcome. The

natural course of the disease has been altered by advances in medical therapies

such as Prostacyclin analogues (epoprostenol), Sildenafil, Bosentan and advanced

cases who are refractory to medications , heart lung transplantation has proven to

be lifesaving (15).

While PAH clearly can be inherited as an autosomal dominant disorder, it

is much more likely that a patient who have idiopathic PAH, have a spontaneous

mutation, or other co-existent disease as the underlying cause of PAH. Familial

disease is related to germ-line mutations in genes encoding transforming growth

factor β (TGF-β) receptor superfamily, namely endoglin 1, the activin-receptor-

13

like kinase-1 (ALK 1), and the BMPR2. There are 144 distinct BMPR2 mutations

found in PAH patients, which affect multiple loci in the gene, including the

ligand-binding domain, the serine-threonine kinase domain, or the cytoplasmic

tail. About 70% of mutations are nonsense or frame-shift mutations, which result

in nonsense-mediated mRNA decay of the BMPR2 mutant transcripts, thus

leading to haplo-insufficiency. Roughly 30% of mutations have mis-sense

cysteine substitutions within the ligand-binding or the kinase domain of BMPR2,

which lead to impaired trafficking of BMPR2 to the cell membrane (16).

BMPR2 is expressed on pulmonary artery smooth muscle cells and is the

master regulator in remodeling of pulmonary arteries. Upon binding of ligands,

BMPR2 and BMPR1 dimerize and activate pro-apoptotic genes through the action

of the transcription factors SMAD and Id (inhibitor of differentiation).

Dysregulation of this pathway, for example due to mutations inBMPR2, results in

a pro-proliferative state. Inflammatory cytokines (e.g. interleukin-6 [IL-6])

phosphorylate the transcription factor STAT3 and induce the expression of micro

RNAs. Micro-RNAs act as gene silencers and down regulate BMPR2, which

directly inhibits cell cycle regulators. Ion channels, serotonin transporters and

receptors associated with tyrosine kinase signaling are also involved in mediating

vasoconstriction and remodeling and thus cause PAH(17).

14

Fig 1:Role of BMPR2 as factor associated with idiopathic Pulmonary

Artery Hypertension

PAH associated with connective tissue diseases (CTD) represents an

important clinical subgroup, among them systemic sclerosis represents the major

cause of CTD associated PAH. Drugs causing PAH includes Aminorex,

fenfluramine derivatives and toxic rapeseed oil as the only identified “definite”

risk factors for PAH. It has been demonstrated that this subgroup of PAH shares

Gene expressed on Pulmonary Artery Smooth Muscles

BMPR2 Gene

BMPR1 Gene

B

Pro Apoptotic genes

SMAD

Inhibitor of Differentiation

Dysregulation of the pathway

15

clinical, functional, hemodynamic, and genetic features with idiopathic PAH,

suggesting that fenfluramine exposure represents a potential trigger for PAH

without influencing its clinical course. Other drugs which are likely to cause

similar clinical picture with PAH are Amphetamines, L-tryptophan,

Methamphetamines and Dasatinib. The drugs which have possible linkage to PAH

includes Cocaine, Phenylpropanolamine, St John’s Wort, Chemotherapeutic

agents, Selective serotonin reuptake inhibitors and Pergolide(3).

HIV-associated PAH has clinical, hemodynamic, and histologic

characteristics broadly similar to those seen in idiopathic PAH. Porto-pulmonary

hypertension (POPH) is a rare association and is defined by the development of

PAH associated with increased pressure in the portal circulation in cirrhosis (18).

Pulmonary arterio-venous malformations (PAVMs) are structurally

abnormal vessels that provide direct capillary-free communication between the

pulmonary and systemic circulations, and hence an anatomic “right-to-left” shunt.

The most common cause of PAVMs is hereditary haemorrhagic telangiectasia

(HHT) affects 1 in 5,000 - 8,000 persons, is transmitted from parent to child as

autosomal dominant trait, and is most commonly caused by mutations in ENG,

endoglin (HHT1), ACVLI/ALK1 (HHT2), or Smad4 (HTJP) (19).

b) Group 2: Pulmonary hypertension associated with left heart diseases:-

Left heart diseases may produce an increase of left atrial pressure leading to a

backward transmission of the pressure and a passive increase of pulmonary

arterial pressure. Left heart disease represents the most frequent cause of PH in

clinical practice .This group include three distinct diseases: left heart systolic

dysfunction, left heart diastolic dysfunction, and left heart valvular disease(20).

16

c) Group 3: Pulmonary hypertension associated with lung respiratory

diseases and/or hypoxia: In this group, the predominant cause of PH is hypoxia

as a result of either chronic lung disease, impaired control of breathing, or

exposure to high altitude areas. However, the precise prevalence of PH in all these

conditions has not been studied and remains mostly unknown(18).

Highlanders (High Altitude Residents at > 2500 meters or 10000 feet

above mean sea level) have exposure to long-term alveolar hypoxia which can

cause pulmonary vascular alterations, including medial wall thickening and

proliferation of smooth muscle-like cells (SMLCs). These are caused by the high

fluid shear stress owing to hypoxic pulmonary vasoconstriction (HPV), resulting

in an elevated pulmonary arterial pressure. In the patients with COPD, both

vascular injuries caused by toxic agents and airborne particulates, including

tobacco smoke, and the hemodynamic changes induced by the hypoxic condition

resulting from the parenchymal destruction and the decreased vascular bed, may

have a role in inducing the neo-intimal lesions consisting of proliferation of

SMLCs in the pulmonary muscular arteries. These lesions are different from the

pulmonary vascular alterations seen in highlanders and in the pulmonary

hypertension models induced by chronic hypoxic exposure alone. In patients with

Idiopathic PAH (iPAH), the defining pulmonary vascular alterations are complex

vascular lesions consisting of phenotypically altered and proliferating endothelial-

like cells (ELCs) called plexiform lesions of Pulmonary Arteries. The distinction

between the pathological features in iPAH and COPD seems to largely be the

presence or absence of complex vascular lesions with phenotypically altered and

proliferating ELCs. The following figure depicts the pathophysiologic mechanism

underlying the pulmonary vascular remodeling in highlanders, chronic obstructive

17

pulmonary disease (COPD) patients and idiopathic pulmonary arterial

hypertension (iPAH) patients(21).

Fig 2: A hypothetical mechanism underlying the pulmonary vascular

remodeling in highlanders, chronic obstructive pulmonary disease

(COPD) patients and idiopathic pulmonary arterial hypertension

(iPAH) patients.

EC: endothelial cell; SMC: smooth muscle cell

RV dysfunction is common in patients with COPD and is more

pronounced in the presence of PH. Advanced COPD is complicated by

development of Cor Pulmonale and if untreated often progresses to Right Heart

High Altitude Residents COPD Idiopathic PAH

Toxic agents and airborne

particulates including tobacco

smoke

Emphysema (Alveolar destruction) Vascular Injury

Hypoxic pulmonary

vasculature Hypoxic pulmonary

vasculature

Phenotypically altered

and proliferating ELCs

High Altitude Residents COPD Idiopathic PAH

Toxic agents and airborne

particulates including tobacco

smoke

Emphysema (Alveolar destruction) Vascular Injury

Hypoxic pulmonary

vasculature Hypoxic pulmonary

vasculature

Phenotypically altered

and proliferating ELCs

18

Failure (RHF). Mechanisms may differ in various disorders and may include

pulmonary vasoconstriction, pulmonary vascular remodelling, small vessel

destruction due to emphysema and parenchymal fibrosis.

In patients with COPD, vascular injury caused by toxic agents and

airborne particulates, including tobacco smoke, and haemodynamic changes

induced by hypoxic conditions resulting from parenchymal destruction and lung

vessel loss are factors that influence regional lung blood flow behaviour(21).

There are no specific therapies approved for management of PH in COPD

except long term oxygen therapy (LTOT)(22).Therefore, treatment is aimed at

treating the underlying lung disorder with standard drugs and correcting hypoxia

with long-term oxygen therapy which has been shown to attenuate the

hemodynamic abnormalities and slows the progression of pulmonary

hypertension(23). Conversely, few patients, in spite of long-term oxygen therapy,

have severe pulmonary hypertension (23). In these patients a cause of pulmonary

hypertension other than chronic obstructive pulmonary disease should be sought.

If no other causes of pulmonary hypertension are detectable, these patients

frequently exhibit a distinctive clinical pattern which shares similarities with other

pulmonary vasculopathies, such as idiopathic pulmonary arterial hypertension.

These cases are called ‘‘out-of-proportion’’ pulmonary hypertension a distinct

entity which may require use of anti PH drugs along with LTOT(23).In patients

with COPD-associated PH, sildenafil improves pulmonary hemodynamics at rest

and during exercise. This effect is accompanied by the inhibition of hypoxic

vasoconstriction, which impairs arterial oxygenation at rest and can cause

worsening of respiratory failure in these patients. Therefore, the use of sildenafil

19

in COPD with PH should be done cautiously and under close monitoring of blood

gases (24).

Chronic obstructive pulmonary disease (COPD) has considerable effects

on cardiac functions, including those of the right ventricle, left ventricle, and

pulmonary blood vessels. Most of the increased mortality associated with COPD

is due to cardiac involvement. Echocardiography provides a rapid, non-invasive,

portable, and accurate method to evaluate the cardiac changes(25).

Interstitial lung diseases (ILDs) comprise heterogeneous group of diseases

with common functional characteristics (restrictive physiology and impaired gas

exchange) eventually leading to irreversible fibrosis. PH is detected in a

significant proportion of patients with advanced ILDs and, if present, PH is an

independent predictor of mortality(26). Hypoxic pulmonary vasoconstriction is

probably the major cause of vascular medial hypertrophy. Another possible cause

of vascular medial hypertrophy is the response of remaining vasculature to the

mild pulmonary hypertension from vascular obliteration secondary to the fibrosis

and honeycombing seen in ILD. After pulmonary hypertension develops from

vascular destruction, the remaining normal pulmonary arterioles undergo

hypertrophy as a protective mechanism to the higher pulmonary artery

pressures(27).

Sleep Disordered Breathing (SDB) encompasses conditions which range

from habitual snoring to obstructive sleep apnea hypopnea syndrome (OSA) and

may be associated with considerable morbidity and mortality. Increasing evidence

indicates the significant association between SDB and PH. Available evidence

indicates that the development of pulmonary hypertension in patients with SRBD

20

involves the complex interplay of multiple factors and correlates strongly with the

severity and duration of nocturnal desaturations as well as associated risk factors.

Early recognition and treatment of SDB may effectively reduce these

complications(28).

d) Group 4: Pulmonary hypertension due to chronic thrombotic and/or

embolic disease: CTEPH is a rare but serious complication of pulmonary

thromboembolism that must be excluded in any case of pulmonary hypertension

of unknown origin more so because not all patients with this condition have

history of venous thromboembolism. The timely diagnosis of CTEPH, followed

by referral to a specialized centre for pulmonary endarterectomy is important as it

completely reversible in early stages and reduces the morbidity and mortality (29).

e) Group 5: Miscellaneous:- PH has been reported in chronic

myeloproliferative disorders including polycythaemia vera, essential

thrombocythemia, and chronic myeloid leukaemia(30). As described above,

Dasatinib use may be a cause of PH, particularly in chronic myeloid leukaemia

and needs to be stopped to prevent irreversible PAH if echocardiography shows

PH (31).

PH is a well recognized complication of sarcoidosis, with a reported

prevalence of 1–28%. PH is multifactorial and usually attributed to the destruction

of capillary bed by the fibrotic process and/or the result of chronic

hypoxemia(32). Pulmonary Langerhans cell histiocytosis is an uncommon cause

of infiltrative and destructive lung disease. Severe PH is a common feature in

patients with end stage disease and PH in these patients is usually related to

chronic hypoxemia and/or abnormal pulmonary mechanics(33).

21

Lymphangioleiomyomatosis is a rare multisystem disorder mostly

affecting women, characterized by cystic lung destruction, lymphatic

abnormalities, and abdominal tumors. PH is relatively rare in patients with this

disease. A series of 20 cases of lymphangioleiomyomatosis associated PH has

shown that PH is usually moderate in this setting and associated with pulmonary

function impairment(34).

A progressive obstruction of proximal pulmonary arteries leading to PH

may be observed in tumor obstruction when a tumor grows into the central

pulmonary arteries with or without additional thrombosis. Fibrosing mediastinitis

which is mainly reported in tuberculosis, histoplasmosis and after radiotherapy

may be associated with severe PH due to compression of both pulmonary arteries

and veins(35).

Clinical Features of Pulmonary Hypertension:

The symptoms of Pulmonary Hypertension (PH) are nonspecific and there is

considerable delay the diagnosis. The earliest symptoms are effort related like exertional

dyspnea, and cough. When right ventricular failure sets in, patients start having lower

extremity edema due to venous congestion. Angina is an uncommon symptom,

representing more advanced disease due to right ventricular ischemia. Orthopnea and

paroxysmal nocturnal dyspnea (PND) may be seen in patients with PH due to underlying

cardiac disease. Presence of dyspnea which is disproportionate to the severity of the

underlying cardio-pulmonary disease should be clue for evaluating for PH(36).

The Physical examination in Patients of Pulmonary hypertension reveals

prominent ‘a’ wave in jugular venous pressure (JVP),peripheral edema, Left parasternal

22

heave, accentuated pulmonary component of Second heart sound (S2), tricuspid

regurgitation murmur, pulmonary early diastolic murmur, right ventricular third heart

sound (S3), hepatomegaly, and ascites(4).

The severity of PH can be evaluated based on determinations of functional class

based on the WHO classification of symptoms and limitation in activities. Exercise

capacity assessed in PH clinics by the 6-min walk test. The WHO functional class is also

used as a measure of prognosis, response to therapy, and assessment during follow up

(37).

Table 2: World Health Organization Classification of Functional Status of Patients

With Pulmonary Hypertension(37)

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.

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

fatigue may be present at rest, and symptoms are increased by almost any

physical activity.

Diagnosis of Pulmonary Hypertension:

The screening requires investigations that are able to detect presence of PH in

patients presenting with clinical features or with underlying systemic diseases having

23

increased relative risk of developing Pulmonary Hypertension. They include

electrocardiogram (ECG), chest radiograph and transthoracic Doppler echocardiography

(38). The presence of underlying lung disease causing PH can be identified by tests such

as pulmonary function tests, arterial blood gases, ventilation and perfusion lung scan,

high resolution computed tomography (HRCT) of the chest and pulmonary angiography.

Additional investigations which are required for assessing the severity of PH includes

exercise testing and hemodynamics. Finally, right heart catheterisation should be done to

confirm the diagnosis of PH and measure mPAP especially if definitive therapy is

planned in cases with severe PH(39).

Blood tests: Serological tests for HIV, hepatitis B or C serology should be

performed to screen for cause of cirrhosis in porto-pulmonary hypertension. The thyroid

hormone assays may reveal either hyperthyroid dysfunction or autoimmune thyroiditis,

which are rarely associated with PH.

Electrocardiogram (ECG): The ECG may provide suggestive or supportive

evidence of PH by demonstrating right ventricular hypertrophy and strain, and right atrial

dilation. Right ventricular hypertrophy and right axis deviation are present in respectively

87% and 79% of patients with idiopathic PAH. Unfortunately, the ECG has low

sensitivity and specificity as a screening tool for detecting PH(40). A sample ECG

showing right axis deviation, right ventricular hypertrophy with right ventricular strain

pattern and P-Pulmonale is depicted in figure 3(41):

24

Chest radiography: In most of the patient with idiopathic PAH patients, chest

radiography is abnormal at the time of diagnosis. Findings include central pulmonary

arterial dilatation which contrasts with loss of the peripheral blood vessels. Right atrial

and ventricular enlargement may be seen in more advanced cases. Chest radiography may

help in identifying underlying lung disease or pulmonary venous hypertension due to

cardiac diseases(40).

Fig 3: ECG representing features of Pulmonary Hypertension.

P-Pulmonale

25

(a) (b)

Fig 4: Representative Chest X Ray showing findings of pulmonary

hypertension. (a) Frontal chest radiograph shows a prominent main

pulmonary artery, dilated right interlobar artery, and pruning of peripheral

pulmonary vascularity. (b) Lateral chest radiograph shows filling of the

retrosternal airspace, a result of right ventricular dilatation. The right ventricle

is in contact with more than one-third of the distance from the sterno-

diaphragmatic angle to the point where the trachea meets the sternum(42).

Abdominal ultrasound scan: Abdominal ultrasound should be performed in

patients of PH who have underlying liver disease to exclude portal hypertension(43).

Pulmonary function test and arterial blood gases: Pulmonary function tests

(PFT) helps to assess presence of underlying lung disease. Spirometry is used to assess

presence of obstructive or restrictive defect in lung diseases. Presence of a post-

bronchodilatorFEV1/FVC < 0.70 confirms the presence of persistent airflow limitation

indicating obstructive airway disease. Spirometry is the most reproducible and objective

measurement of airflow limitation like in Obstructive Airway Diseases like Bronchial

Asthma, COPD and Bronchiectasis(44). The severity of obstruction in airflow according

to Global initiative in Obstructive Lung Disease is classified based on post bronchodilator

26

FEV1 i.e., GOLD 1 is Mild which is classified as FEV1 ≥ 80% predicted, GOLD 2 is

Moderate which is defined as FEV1 < 80% predicted, GOLD 3 is Severe which is FEV1

≤ 50%, and GOLD 4 is Very Severe which is FEV1 of < 30% predicted(44).Forced

expiratory volume in one second (FEV1) and total lung capacity (TLC) in idiopathic PAH

are usually normal.

Low diffusing capacity of the lung for carbon monoxide (DLCO) has been

reported in PAH patients with associated ILD, but is more pronounced in Pulmonary

Venous Occlusive Disease (PVOD) patients with often severe reductions under 50% of

the predicted value(45).

Results of arterial blood gases usually shows hypoxemia in patients with ILD and

PVOD(45). Severe hypoxemia may be present in advanced chronic lung disease(45).If

the patient is hypoxemic, the low oxygen content in his blood will cause progression of

PH. Mild hypoxemia is defined as a PaO2 of 60 to 79 mmHg; moderate hypoxemia, 40 to

59mm Hg; and severe hypoxemia less than 40 mm Hg(46). These would be relevant for

planning prescription of LTOT in these patient with PH with PaO2 < 59 mm of Hg or

SpO2 < 88%(44).

High resolution computed tomography of the chest: High resolution computed

tomography of the chest (HRCT) gives detailed information about underlying lung

parenchyma disease, such as pulmonary emphysema or interstitial lung disease. It can

also suggest the presence of pericardial effusions and pulmonary artery enlargement,

defined by the ratio of the diameter of main pulmonary artery to that of the ascending

aorta >1(47).

Pulmonary angiography: In CTEPH, CT pulmonary angiography may be helpful

to determinate surgically accessible form. Typical angiographic findings in CTEPH are

27

complete vessel obstruction, vessel cut-offs, intimal irregularities, incorporated thrombus,

band and webs as well as intimal irregularities. Pulmonary angiography may be also be

helpful in the setting of fibrosing mediastinitis(48).

Echocardiography: Echocardiography with Doppler study is non-invasive,

portable tools and most widely used tool for the screening of Pulmonary Hypertension

(PH). It provides both estimates of pulmonary artery pressure and an assessment of

cardiac diseases, valvular lesions, intra-cardiac shunts, wall motion abnormality and

systolic or diastolic dysfunction along with left ventricle ejection fraction. These features

amplify its application as the most commonly used screening tool in patients with

suspected PH(49).Many studies have confirmed that echocardiography derived estimates

of pulmonary arterial pressure co-relate closely with pressures measured by right heart

catheterisation (r > 0.7)(7-9, 25, 39).

Pulmonary arterial systolic pressure can be determined by measuring the peak

systolic pressure gradient from the right ventricle to right atrium. This is calculated by

modified Bernoulli equation. The formula that is used is 4V2, where V is the maximum

velocity of the tricuspid regurgitant jet measured by continuous wave Doppler. This is

added to the mean right atrial pressure (RAP). A commonly used method to measure the

right atrial pressure is to determine the variation in the size of the inferior vena cava with

inspiration. Complete collapse of the IVC indicates a right atrial pressure of 5 mm

mercury, partial collapse indicates 10 mm mercury pressure and absence of collapse

indicates more than 15 mm mercury(6).

28

Fig 5: Echocardiography showing features of Pulmonary Hypertension: The

figure above depicts the features which can be seen on Echocardiography in

cases of Pulmonary Hypertension. Panels A show marked right ventricular

dilatation (left: end-diastole, right: end-systole). Panel B demonstrates flat

interventricular septum in the cross-sectional view, and Panel C demonstrates

hypertrophied right ventricular free wall in the apical four chamber view.

Panel D shows that the peak velocity of tricuspid regurgitation is 4.7 m/s,

suggesting an estimated right ventricular systolic pressure of 98.4 mmHg(50).

The severity of Pulmonary Hypertension on the basis of measured Right

Ventricular Systolic Pressure can be classified as Mild if the RVSP is between 35-50 mm

of Hg, Moderate if the measured RVSP is between 51-65 mm of Hg and as Severe if the

measured RVSP is > 65 mm of Hg(51).

It has several limitations such as need for adequate thoracic window selection

which is poor in thick chested individuals (obese patients and females) or underlying

Emphysema and operator experience in performing the study. Despite these problems

echocardiography remains the most clinically useful non-invasive method allowing for

29

multidimensional assessment of pulmonary circulation. However, detection of tricuspid

regurgitation for tricuspid jet velocity is mandatory for calculating RVSP for the

diagnosis of PH. Hence, in patients who have features suggestive of PH but no tricuspid

regurgitation in echocardiography, RHC is warranted for diagnosis of PH. The prognostic

value of certain echocardiographic parameters like mean Pulmonary Artery Pressures and

Tricuspid Jet Velocity is well recognised for assessment in patients who are on drug

therapy. It is a critical tool to monitor the progression of PH and the response of patients

to specific treatment(37).A table showing echocardiographic probability of pulmonary

hypertension in symptomatic patients with a suspicion of pulmonary hypertension is

given below and can be used for clinical decision making in PH:-

Peak Tricuspid Jet Velocity

(in m/s)

Presence of other PH

clinical signs

Echocardiographic

probability of PH

≤ 2.8 or not measurable No Low

≤ 2.8 or not measurable Yes Intermediate

2.9 to 3.4 No

2.9 to 3.4 Yes High

> 3.4 Not required

Table 3: Echocardiographic probability of pulmonary hypertension in symptomatic

patients with a suspicion of pulmonary hypertension

Right Heart Catheterisation (RHC): Invasive hemodynamic assessment with

right heart catheterization showing a resting mPAP of ≥25 mmHg and a normal PCWP is

the gold standard test and is required to confirm the diagnosis of PH. Measurement values

obtained by RHC are PAP (diastolic, mean and systolic), right atrial pressure (RAP),

PCWP, right ventricular pressure, cardiac output and pulmonary vascular resistance

(PVR). The assessment of PCWP allows the distinction between pre-capillary (normal

30

PCWP ≤15 mmHg) and post capillary PH (PCWP >15 mm Hg)(18). The overall rate of

complications in right heart catheterisation is approximately very low at 1.1%. The most

frequent complications are related to venous access (hematoma), pneumothorax followed

by arrhythmias and hypotensive episodes related to vaso-vagal reactions or pulmonary

vaso reactivity testing (52).

The rationale for vaso reactive testing in the diagnostic evaluation of group I PAH

patients is based on 2 factors: 1) acute vasodilator responsiveness identifies patients with

a better prognosis; and 2) responders are more likely to have a sustained beneficial

response to oral calcium channel blockers than non-responders and could be treated with

these less expensive drugs. The ideal vasodilator agent for PAH is selective for the

pulmonary circulation and has rapid onset and offset of effect. Acute vasodilator testing is

most commonly performed using inhaled Nitric Oxide, intravenous epoprostenol, or

intravenous adenosine (52).

The diagnostic step wise approach to case with Pulmonary Hypertension

recommended in various guidelines is depicted in Fig 6 below:

31

Fig 6: Diagnostic Approach to Pulmonary Hypertension

Management of Pulmonary Hypertension:

The optimal therapeutic approach must be individualized for every patient, taking

into account factors including the etiology of PH, severity of illness, route of

administration of therapy, side effect profile, co-morbid illnesses, treatment goals and

clinician experience.

General Measures:

a) Physical activities: Peripheral vasodilatation or increased cardiac demand

increases PAH patient’s risk of acute cardiac failure and syncope. Thus, the

patients with severe PH or who are in WHO functional class III/IV are advised

32

against extreme physical activity. Patients are counselled to stay active and

perform activities according to their functional class.

b) Pregnancy and contraception: The hemodynamic and hormonal changes

occurring during pregnancy and peripartum period may lead to severe, and at

times fatal, right heart failure. Pregnancy is considered to be strong risk factor for

high rate of mortality (30-50%) in PH patients. Hence, pregnancy is

contraindicated in women with severe PH. Therefore, contraception is strongly

recommended in PH women of childbearing age(53).

c) Prescribed drugs: Vasoconstrictors used in cold medication should be

avoided in PAH patients. Beta-blockers have been shown to be deleterious to

PAH patients as they prevent the important adaptive physiologic response that

allows preservation of adequate cardiac output. Discontinuation of such drugs in a

patient with PAH may lead, by itself, to important clinical and hemodynamic

improvement(54).

Miscellaneous drugs:

a) Diuretics: Diuretics are one of the most important treatments in the setting

of PAH because right heart failure leads to fluid retention, hepatic congestion,

ascites and peripheral edema. Right ventricular overload is part of clinical

symptoms and has been associated with a poor prognosis in PAH(55).

b) Calcium channel blockers: Calcium channel blockers (CCB) are

vasodilators and were initially introduced in the 1980’s as part of PAH therapy to

counteract vasoconstriction that has traditionally been assumed to be a

preponderant mechanism in PAH. The choice of CCB is based upon the patient’s

heart rate; nifedipine and amlodipine were preferred in the presence of relative

33

bradycardia and diltiazem in the presence of tachycardia(56). Very few patients

(<7%) with iPAH do well over the long-term on calcium-channel blockers(57).

Specific Pulmonary vasodilator agents:

a) Prostanoids: Prostacyclin synthase expression is reduced in endothelial

cells from PAH patients, resulting in inadequate production of prostaglandin I2

(i.e., prostacyclin), a vasodilator with anti-proliferative effects. Administering

prostanoids has been a mainstay of PAH therapy for nearly 2 decades. There are

currently multiple prostanoids commercially available: epoprostenol (continuous

IV infusion by pump), treprostinil (continuous subcutaneous, continuous IV,

intermittent inhaled, and oral) and iloprost (intermittent inhaled). The common

side effects of Prostanoids includes headache, nausea, diarrhea, and jaw pains(58).

b) Endothelin receptor antagonists: Endothelin receptor antagonists act by

selectively blocking endothelin-A receptors or by dual blockage of endothelin-A

and -B receptors; furthermore, they constituted the first class of drugs orally

administered in PAH. Bosentan, a nonselective endothelin-A and B receptor

antagonist has been studied in multiple placebo-controlled trials in PAH. Bosentan

has been evaluated in PAH (idiopathic, associated with CTD, and Eisenmenger’s

syndrome) in five RCT’s (Pilot, BREATHE-1, BREATHE-2, BREATHE-5, and

EARLY) that have shown improvement in exercise capacity, functional class,

haemodynamic, echocardiographic and Doppler variables, and time to clinical

worsening(59).

Ambrisentan, a selective endothelin-A receptor antagonist, has been

studied in 2 phase III multicentre, randomized, placebo-controlled trials in

34

394PAH patients and demonstrated an improvement in 6MWD and time to

clinical worsening(59).

Macitentan, a nonselective endothelin-A and B receptor antagonist has

increased tissue penetration and more sustained receptor blockade compared with

bosentan. It has been studied in a phase III long term morbidity and mortality trial

(n ¼ 742) in which the primary endpoint was the time from initiation of treatment

to the first occurrence of a composite endpoint of death, atrial septostomy, lung

transplantation, initiation of treatment with parenteral prostanoids, or worsening

PAH. There were 30%and 45%riskreductionsinthe primary endpoint with the 3-

and 10-mg doses, respectively(59).

c) Nitric oxide pathway: Nitric oxide (NO) is a potent vasodilator of the

pulmonary circulation, acting through the increase in cyclic guanosine

monophosphate (cGMP), and cleared mainly as a result of degradation by

Phosphodiesterase type 5 (PDE-5). Reduction in the expression of NO synthase

has been described as a mechanism associated with the pathogenesis of PH(60).

Currently, there are 2 therapeutic classes of drugs interacting in the NO pathway,

aiming to increase the direct action of cGMP: PDE-5 inhibitors, which decrease

cGMP degradation, and soluble guanylate cyclase stimulators, which increase

cGMP production.

Phosphodiesterase type 5 inhibitors – Sildenafil has been studied in a 12-

week multicentre, randomized, placebo-controlled trial in cases of PAH and was

found to improve6MWD and hemodynamics, but not the secondary endpoint of

time to clinical worsening(61). Tadalafil was studied in a 16-week multicentre,

randomized, placebo-controlled trial and demonstrated an improvement in the

primary endpoint of 6 Minute Walk Distance (62).

35

Soluble guanylate cyclase stimulators - Riociguat is a first-in-class soluble

guanylate cyclase stimulator. It directly stimulates soluble guanylate cyclase

independent of nitric oxide, and increases the sensitivity of soluble guanylate

cyclase to nitric oxide. 2 Randomised controlled trials in inoperable CTEPH or

persistent PH after pulmonary endarterectomy and PAH patients (44% previously

treated with endothelin receptor antagonists and 6% with nonparenteral

prostanoids) demonstrated an improvement in the primary endpoint of 6MWD as

well as multiple secondary endpoints including PVR, N-terminal pro BNP,

functional class, and time to clinical worsening with riociguat(63, 64).

Lung Transplantation and Bridge to Transplantation with Extracorporeal

Life Support:

Despite recent advances in medical therapy, lung and heart-lung

transplantation remains lifesaving treatment option for Idiopathic and familial

PAH patients who are refractory to medical management. Lung transplantation is

a life-saving procedure in severe PAH with survival rates after1,5,10, and 15years

of70%, 50%, 39% and 26% (heart-lung transplantation) and 79%, 52%, 43%, and

30% (double-lung transplantation), respectively(65).

Now why this study:

The etiological profile and prevalence of Pulmonary Hypertension in various non-

cardiac disorders has not been evaluated adequately in Indian population there is paucity

of data from western world on this aspect.

A number of underlying diseases are associated with the development of PH

which increases the morbidity and mortality of the disease. It is important to screen

36

patients with disproportionate dyspnea by echocardiography to evaluate for Pulmonary

Hypertension so as to institute timely therapy to reduce the morbidity and mortality.

37

METHODOLOGY

38

METHODOLOGY

(i) Study Design: The study was a cross sectional observational study.

(ii) Subjects: Patients presenting to this hospital outpatient department or as inpatient

who were diagnosed to have Pulmonary Hypertension with Echocardiographic right

ventricular systolic pressure (RVSP) or pulmonary artery systolic pressure (PASP)

measured by right heart catheterisation >35 mmHg or mean Pulmonary Artery Pressure

(mPAP) > 25 mm of Hg on right heart catheterisation (RHC) with normal cardiac

structure and functions were included in the study for analysis.

Inclusion Criteria:

• Subject age> 18 years

• Diagnosed with echocardiographic/ RHC evidence of Pulmonary Hypertension

• Willingness to participate in the study

Exclusion Criteria:

• Patients with Echocardiographic evidence of Pulmonary Hypertension due to

underlying Heart diseases were excluded

(iii) Sample size: A total of 35 Patients diagnosed with non-cardiac Pulmonary

Hypertension were studied

39

(iv) Methodology:

a) Subjects were enrolled after informed written consent (Appendix A). Their

detailed history and physical examination was carried out and documented in

proforma (Appendix B). The patients were then classified according to WHO

Functional class as per their symptoms and exercise limitation.

b) All patients initially underwent complete transthoracic echocardiographic study

including two-dimensional, M-Mode, color flow and spectral Doppler

echocardiography. The echocardiographic mean pulmonary artery pressure was

assessed by Tricuspid Regurgitation jet velocity for confirmation of the diagnosis of

Pulmonary Hypertension (PASP was considered equivalent to RVSP in the absence of

pulmonary outflow obstruction). The RVSP was approximated by measurement of the

systolic regurgitant tricuspid flow velocity v and an estimate of right atrial pressure

(RAP) applied in the formula: RVSP = 4v2 + RAP). The patients were classified as

suffering from mild, moderate or severe Pulmonary Hypertension as per calculated

RVSP.

c) All patients were subjected to Complete Blood Count (CBC), Renal Function Test

(RFT), Liver Function Test (LFT), Thyroid Function Test (TFT), HIV (by ELISA),

Anti-Nuclear Antibodies ANA (by ELISA), Chest X Ray, USG Abdomen and

Pulmonary Function Testing (PFT), and Arterial Blood Gas (ABG) analysis. They

were then classified normal, Restrictive or Obstructive pattern on the basis of the

Spirometry. The Obstructive pattern was further sub classified according to GOLD

classification. They were also classified as normal, mild, moderate or severe

hypoxemia on ABG analysis.

40

d) Specialized tests such as High Resolution Computed Tomography of the Chest

(HRCT), CT Pulmonary Angiography, Diffusion Capacity for Carbon-Monoxide

(DLCO), N Terminal pro- Brain Natriuretic Peptide (NT pro BNP) levels,

Polysomnography, and Right Heart Cardiac Catheterization were carried out in

selected cases as indicated due to financial burden and ethical issues.

e) Etiological diagnosis was arrived in all patients based on data from history,

systemic examination and various tests to confirm the cause of pulmonary

hypertension.

f) The subjects were also assessed on the basis of various therapeutic modalities they

were using for Pulmonary Hypertension.

(v) Statistical Methods: The statistical analyses were performed by STATA 11.2

(College Station TX USA) and Microsoft Office Excel. Descriptive analysis was

performed separately for Age, Gender, WHO functional class, RVSP values on

echocardiography/ RHC, ABG analysis, Spirometry, GOLD classification for Obstructive

pattern, final Aetiology of Pulmonary Hypertension, and various therapeutic modalities

being used by all subjects.

41

RESULTS

42

RESULTS

1. A total of 66 patients were screened for evidence of Pulmonary Hypertension

during the period of study from September 2014 to May 2016. Total 35 subjects with

echocardiographic evidence or by right heart catheterisation showing presence of

Pulmonary Hypertension and with no underlying heart disease were included in the study

for analysis. Out of these 35 patients, 33 patients were diagnosed on the basis of

Echocardiography showing RVSP of > 35 mm of Hg, and 02 patients were diagnosed on

the basis of mean PAP > 25 mm of Hg measured by Right Heart Catheterisation.

2. The age of all patients included in study ranged from 28 years to 90 years with

mean age of 59.54 years, median of 59 years and standard deviation of 14.45 years. The

majority of the patients were in age group of 51-60 years (28.57%), next common age

group was 70-90 years (25.71%) followed by age group of 61-70 (22.86%). Cumulatively

prevalence of Pulmonary Hypertension in patients of age >51 years was77.14% of total

patients diagnosed with disease. 17.14% of patients were in age group of 41-50 years.

Subjects in the age group of 18-40 year constituted only 5.72% of total number of patients

(Table 4, Chart 1).

43

Table 4: Age wise Distribution of Cases with Pulmonary Hypertension

Chart 1: Age wise distribution of cases with Pulmonary Hypertension

2.86 2.86

17.14

28.57

22.8625.71

0

5

10

15

20

25

30

35

20-30 31-40 41-50 51-60 61-70 70-90

Per

cen

tage

Age (in Years)

Percentage (%)

Age (in Years) No. of Cases Percentage (%)

18-30 1 2.86

31-40 1 2.86

41-50 6 17.14

51-60 10 28.57

61-70 8 22.86

70-90 years 9 25.71

Total Number of Cases 35 100

Mean (in Years) 59.54

Median (in Years) 59

SD 13.61

Range 28-90

44

3. Out of total 35 subjects, male gender preponderance was noted with 69% of

patients being males and 31% of females. The male to female ratio was 2.1:1 (Table 5,

Chart 2).

Number of Cases Percentage (%)

Male 24 69

Female 11 31

Total 35 100

Table 5: Gender wise distribution of cases with Pulmonary Hypertension

Chart 2: Gender wise distribution of cases with Pulmonary Hypertension

Male, 69

Female, 31

GENDER PERCENTAGE (%)

Male

Female

45

4. On the basis of all collected data and investigations which were carried out as per

the study protocol, etiological diagnosis was given to all subjects. 18 patients (51.43%)

were diagnosed to have Obstructive airway disease {which included 16 patients of

Chronic Obstructive Pulmonary Disease (COPD), 01 patient of Asthma COPD Overlap

Syndrome (ACOS) and another patient of Allergic Broncho Pulmonary Aspergillosis

(ABPA)}. Interstitial Lung Disease (ILD) due to various underlying Connective Tissue

Disorders was identified in 06 patients (17.14%), and Obstructive Sleep Apnea and/or

Obesity Hypoventilation Syndrome was detected in 02 patients (prevalence of 5.71%).

One patient (2.86%) was detected with Hereditary Haemorrhagic Telangiectasia with

Pulmonary Arterio-venous Malformation. No underlying systemic disease could be

identified in 08(22.86%) patients and they were given a diagnosis of idiopathic

Pulmonary Artery Hypertension (iPAH) (Table 6, Chart 3).

Etiology Number of Cases Percentage (%)

Obstructive Airway Disease 18 51.43%

Idiopathic PAH (iPAH) 8 22.86%

Interstitial Lung Disease (ILD) 6 17.14%

Obstructive Sleep Apnea (OSA) 2 5.71%

Pulmonary AV Malformation (HHT) 1 2.86%

Total 35 100

Table 6: Etiological Diagnosis of cases with Pulmonary Hypertension

46

Chart3: Etiological Diagnosis of cases with Pulmonary Hypertension

51.43%

22.86%

17.14%

5.71%

2.86%

0.00% 10.00% 20.00% 30.00% 40.00% 50.00% 60.00%

Percentage (%)

Etilo

gy

Pulmonary AVM OSA ILD Idiopathic PAH Obstructive Airway Disease

47

5. Out of the total 35 cases, 16 cases (46%) had mild Pulmonary Hypertension with

RVSP ranging from 36 to 50 mm of Hg. Total 6 cases (17%) had moderate RVSP ranging

from 51 to 65 mm of Hg and 13 cases (37%) had severe Pulmonary Hypertension with

RVSP of more than 65 mm of Hg (Table , Chart ). The mean RVSP was 55.94 + 15.46

(Table 7, Chart 4).

Severity on the basis of

RVSP in

Echocardiography

Range

(in mm of Hg)

Number of Cases Percentage

Mild (36-50) 36-50 16 46%

Moderate (51-65) 51-65 6 17%

Severe (> 65) >65 13 37%

Total 35 100

Table7: Distribution of Severity of Pulmonary Hypertension on the basis of Right

Ventricular Systolic Pressures

Chart4: Distribution of Severity of Pulmonary Hypertension on the basis of Right

Ventricular Systolic Pressures

Mild

46%

Moderate

17%

Severe

37%

Mild Moderate Severe

48

6. Based on the symptoms of the patients, they were classified as per WHO

Functional Classification. Maximum number i.e. 19 cases (54.29%) were found to be in

WHO class II. There were 10 cases (28.57%) in WHO Class III and 05 cases (14.29%) in

WHO class IV. There was only 01 (2.86%) case in WHO class I (Table 8, Chart 5).

WHO Class Number of Cases Percentage (%)

Class I 1 2.86%

Class II 19 54.29%

Class III 10 28.57%

Class IV 5 14.29%

Total 35 100

Table8: Distribution of Severity of Pulmonary Hypertension on the basis of WHO

Function Status Classification

Chart 5: Distribution of Severity of Pulmonary Hypertension on the basis of WHO

Function Status Classification

Class I, 2.86%

Class II, 54.29%

Class III, 28.57%

Class IV, 14.29%

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

Per

cen

tage

WHO Functional Class

Class I Class II Class III Class IV

49

7. All patients underwent measurement of their lung functions by spirometry. The

Spirometry data showed normal function in 11 cases (31%) and Restrictive pattern in 06

cases (17%). Majority of cases 18 cases (51%) showed obstructive pattern with FEV1

ranging from 26 to 68 % with a mean FEV1 of 39% + 11.35% of the predicted FEV1 for

the cases (Table 9, Chart 6).


Normal 11 31%

Restrictive 6 17%

Obstructive 18 51%

Total 35 100%

Table9: Distribution of Pattern of Spirometry in cases of Pulmonary Hypertension

Chart 6: Distribution of Pattern of Spirometry in cases of Pulmonary Hypertension

Normal, 31%

Restrictive, 17%

Obstructive, 51%

0%

10%

20%

30%

40%

50%

60%

Per

cen

tage

Normal Restrictive Obstructive

50

8. On further classifying the patients with Obstructive pattern of spirometry on the

basis of GOLD Classification for assessing the severity of Obstructive Airway Disease,

maximum number of cases 12 (66.67%) cases were in GOLD class III whereas GOLD

class II had 02 cases (11.11%) and GOLD class IV had 04 cases (22.22%). There were no

patient in GOLD class I (Table 10, Chart 7).

GOLD Classification (%

Predicted FEV1)


GOLD I (> 70%) (Minimal) 0 0%

GOLD II (50 – 69%) (Mild) 2 11.11%

GOLD III (30 – 49%) (Moderate) 12 66.67%

GOLD IV (< 30%) (Severe) 4 22.22%

Total 18 100%

Table10: Distribution of Pulmonary Hypertension cases with Obstructive Airway

Disease on the basis of GOLD Classification

Chart 7: Distribution of Pulmonary Hypertension cases with Obstructive Airway

Disease on the basis of GOLD Classification

0%

11.11%

66.67%

22.22%

0%

10%

20%

30%

40%

50%

60%

70%

Per

cen

tage

GOLD CLASS

Gold I (> 70%) (Minimal) Gold II (50 – 69%) (Mild)

Gold III (30 – 49%) (Moderate) Gold IV (< 30%) (Severe)

51

9. All subjects underwent Arterial Blood Gas (ABG) analysis and were classified

into four classes on the basis of level of hypoxemia which was defined on the basis of

Partial Pressure of Oxygen in blood (PaO2) on ABG. Normal level of Arterial Oxygen

was defined as PaO2 of >80 mm of Hg. Mild, Moderate and Severe Hypoxemia was

defined as PaO2 levels between 60 -79 mm of Hg, between 40 – 59 mm of Hg and PaO2

< 40 mm of Hg respectively. Analysis of data showed Normal PaO2 in 04 cases (11%),

Mild Hypoxemia was seen in 08 cases (23%), Moderate Hypoxemia in 10 cases (29%)

and Severe Hypoxemia in 13 cases (37%) (Table 11, Chart 8).

Severity of Hypoxemia

(PaO2 in mm of Hg)


Normal (> 80) 4 11%

Mild (60-79) 8 23%

Moderate (40-59) 10 29%

Severe (< 40) 13 37%

Total 35 100%

Table 11: Pulmonary Hypertension and level of hypoxemia on ABG analysis

Chart 8: Pulmonary Hypertension and level of hypoxemia on ABG analysis

Normal, 11%

Mild, 23%

Moderate, 29%

Severe, 37%

0%

10%

20%

30%

40%

Per

cen

tage

Severity of Hypoxemia in Arterial Blood Gas

PaO2 in mm of Hg

Normal (> 80) Mild (60-79) Moderate (40-59) Severe (< 40)

52

10. For the treatment of PH, 08 patients (23%) were not on any therapy. 03 patients

(09%) in the study were prescribed only home based Long Term Oxygen Therapy

(LTOT) for Pulmonary Hypertension. 02 patients (06%) were using Bi-level Positive

Airway Pressure (BiPAP) ventilator without LTOT, and 10 patients (29%) were using

BiPAP with home based LTOT. 02 (06%) patients were using Continuous Positive

Airway Pressure (CPAP) ventilator.07 (20%) patients were on only drug therapy with

Sildenafil and/or Bosentan and 03 patients (09%) were on drugs along with home based

LTOT for Pulmonary Hypertension (Table 12, Chart 9).

Therapeutic Modalities Number of cases Percentage

No Therapy 8 23%

Long Term Oxygen Therapy

(LTOT) 3 9%

BiPAP 2 6%

LTOT + BiPAP 10 29%

CPAP 2 6%

Sildenafil/Bosentan or both

(Drugs) 7 20%

LTOT + Drugs 3 9%

Total 35 100%

Table 12: Modalities of Treatment in cases of Pulmonary Hypertension

53

Chart 9: Modalities of Treatment in cases of Pulmonary Hypertension

23%

9%

6%

29%

6%

20%

9%

0%

5%

10%

15%

20%

25%

30%

Per

cen

tage

Therapy

Therapeutic Modalities

No Therapy Long Term Oxygen Therapy BiPAP

LTOT + BiPAP CPAP Sildenafil/Bosentan or both

LTOT + Drugs

54

DISCUSSION

55

DISCUSSION

Pulmonary hypertension (PH) is a complex, multi-factorial disorder and is defined

as mean pulmonary artery pressure (mPAP) greater than 25 mmHg; a pulmonary capillary

wedge pressure (PCWP), left atrial pressure, or left ventricular end-diastolic pressure

(LVEDP) less than or equal to 15 mm Hg. PH is a rare and potentially life-threatening

disease which if left untreated progresses and leads to poor quality of life and

significantly increased mortality.

Multiple pathogenic pathways have been implicated in the development of PH

including those at molecular and genetic levels, in the smooth muscles, endothelial cells

and adventitia. The imbalance in the vasoconstrictor and vasodilator milieu has served as

the basis for current medical therapies. Easy availability of echocardiography has led to

increased recognition and advances in therapies have made it more treatable. There are

many areas in non group 2 PH that have been inadequately explored and need more work.

Echocardiographic assessment as part of a goal-oriented approach to therapy is

essential for the effective management of PH patients. Many uncertainties however exists

regarding the diagnosis and treatment of patients with PH that are particularly pertinent

for the management of patients with idiopathic pulmonary arterial hypertension and

pulmonary hypertension associated with underlying diseases. Hence it is important to

diagnose the exact cause of the Pulmonary Hypertension in a patient and clearly define

the clinical and laboratory parameters of a patient for appropriate, adequate and timely

therapy.

We studied 35 patients with evidence of Pulmonary Hypertension with no

underlying cardiac cause of PH. The study group consisted of patients coming to the out-

56

patient department or admitted as in-patient at Command Hospital, Air Force, Bangalore

which is a Tertiary Care Centre in Indian Armed Forces Medical Services

1. Out of 35 patients, 33 patients were diagnosed with PH by echocardiographic

measurement of tricuspid jet velocity and RVSP. 02 patients underwent right heart

catheterisation due to inability to detect tricuspid regurgitation for measuring tricuspid

regurgitant jet velocity and calculating the RVSP. These patients had clinical presentation

and signs of PH and were confirmed to have PH on RHC.

2. Mean age of patients in our study was 59.54 + 13.61 which is similar to the study

conducted by Patel et al from Ahmedabad in India which shows the cumulative

prevalence of disease to be 82% in age of > 41 years and maximum prevalence of 30% in

age group of 51-60 years(66). However, the earlier studies have reported lower mean age

of patients presenting with pulmonary hypertension. In a study by Hasan et al conducted

at Aligarh, the mean age of the patients was 43.47±17.44 years(67). The western studies

done by Shapiro et al, Burger et al and the REVEAL registry 2010 have reported a mean

age of 49±18 years, 53±14 years and 50.4±16.8 years respectively (68-70). Thus the mean

age was relatively higher in our study, compared to earlier studies. This could be

explained by the fact that, the most of the subjects in our study were retired soldiers of

Indian Armed Forces who are healthier than corresponding general population when they

are young due to their regular exercise regime and also because of mandatory Annual

Medical Examination during their service tenure. Also most of the previous studies cited

above have included patients of underlying structural heart disease including valvular

heart Diseases and Congenital Heart Diseases which is generally seen in relatively

younger population.

57

3. In the current study, males preponderance was noted with male to female ratio of

2.1 which was relatively comparable to study by Patel et al and Rich S et al which

showed ratio of 1.5 and 1.7 respectively(66, 71). However, another study by Hasan et al

showed the ratio to be 1.07 which was lesser than various other studies(67).

4. In present study, Chronic Obstructive Pulmonary Disease was found as the

commonest cause (51.43%) of pulmonary hypertension which is comparable to the

studies of Patel et al and Hasan et al which showed COPD as the most common cause of

Pulmonary Hypertension in 66% and 36% of their study population respectively(66, 67).

This finding was in contrast to the western literature possibly due to higher incidence of

Respiratory diseases specially COPD in Indian population due to increased use of

biomass fuel for heating and cooking in rural India.

5. In our study we found mean Right Ventricular Systolic pressure (RVSP) to be

55.94 ± 15.46 mmHg. This is comparable to measured mean Pulmonary Artery Pressures

of 50 ± 14 and 48 ± 16 in REVEAL registry 2010 and Korean registry 2011

respectively(70, 72). The other study of Burger et al also showed mean PAP to be in same

range i.e. 50.7 ± 13.6(69). Also our study showed maximum patients to be suffering from

mild Pulmonary Hypertension (46%) followed by Severe Pulmonary Hypertension

(37%). The only Indian study which assessed severity of Pulmonary Hypertension by

RVSP was by Hasan et al and they found higher severity of PH in Indian population with

mean PAP of 69.77 ± 21.2.

58

6. In our study, 19 (54.29%) patients were found to be in WHO functional class II,

10 (28.57%) were found to be in WHO functional class III and 5 (14.29%) were found to

be in WHO functional class IV. There was only one patient in WHO functional class I.

Thus, the maximum number of patients was seen in the WHO functional class II. This is

in contrast to the other studies by Hasan et al, Burger et al, REVEAL registry 2010 and

Korean registry 2011 in which they found maximum number of patients to be in

functional class II. This difference in finding is probably because of early diagnosis of PH

in our study by actively screening for patients with Pulmonary Hypertension in patients

with diseases of respiratory system and other causes of group 1 PAH.

7. As mentioned above, out of the 35 patients in our study, the most common cause

of non-cardiac Pulmonary Hypertension in our study was Chronic Obstructive Pulmonary

Hypertension. The spirometry showed obstructive pattern in 51% of our patients. On

further analysing these patients according to GOLD classification of COPD, we found the

mean FEV1 percent of predicted to be 39 ± 11.35% and also observed that out of these 18

patients maximum number of patients i.e. 12 (66.67%) patients had moderate obstruction

(GOLD III). This is comparable to the findings in the studies of Keller et al and Kessler et

al which showed mean FEV1 of 33 ± 14% and 40.6 ± 12.3% respectively in patients of

Pulmonary Hypertension(73, 74).

8. In our study we found that mean arterial partial pressure of oxygen (PaO2) was

53.01 ± 18.05 mm of Hg with maximum number of patients i.e. 37% were suffering from

severe hypoxemia (PaO2 < 40 mm of Hg). This finding is similar to the observations in

the studies by Keller et al and Kessler et al which showed mean PaO2 of 59 ± 8 mm of

Hg and 60.3 ± 9.3 mm of Hg in the patients who had Pulmonary Hypertension(73, 74).

59

9. There are certain limitations inherent in this study because of the study design,

which includes its descriptive and observational nature and that no clinical and

echocardiographic follow up of the patients was done. In addition, the sample size was

small in each disease category because of which it was not possible to find any significant

correlation between the etiology of Pulmonary Hypertension and the severity of the

disease based on Right Ventricular Systolic Pressure, WHO Functional Class and the

PaO2 levels in Arterial Blood Gas which requires to be examined in further research

works with larger study groups.

60

CONCLUSION

61

CONCLUSION

A total of 35 patients with evidence of Pulmonary Hypertension with no

underlying cardiac cause of PH were studied for demographic, clinical, etiological and

echocardiographic data. The prevalence of Pulmonary Hypertension was maximum in the

age group of 51-60 years (28.57%) and increases after the age of 50 years (77.14%).

Males outnumbered females with a ratio of 2.1. The most common etiology was COPD

(51.43%) followed by idiopathic Pulmonary Artery Hypertension (iPAH) and Interstitial

Lung Disease (ILD).In our study Echocardiographic measured RVSP showed most of the

patient had mild Pulmonary Hypertension (46%) and were in WHO functional class II

(54.29%).

We conclude that, non-cardiac causes of Pulmonary Hypertension are prevalent in

day to day practices and it is important to screen patients for Pulmonary Hypertension in

disease like Chronic Obstructive Pulmonary Disease, Interstitial Lung Disease,

Obstructive Sleep Apnea hypopnea syndrome and/or Obesity Hypoventilation Syndrome

and idiopathic Pulmonary Artery Hypertension as timely diagnosis of Pulmonary

Hypertension and institution of therapy is known to improve quality of life and decreases

morbidity & mortality associated with the disease.

62

SUMMARY

63

SUMMARY

Pulmonary artery hypertension (PAH) is defined as a mean pulmonary artery

pressure (mPAP) ≥ 25 mmHg with a pulmonary capillary wedge pressure ≤ 15 mmHg,

measured by cardiac catheterization. The right ventricular systolic pressure of ≥35 mm

Hg calculated by echocardiographic estimates of tricuspid regurgitant jet velocity and

mean right atrial pressures correlates well with mean pulmonary artery pressure of ≥ 25

mmHg measured by invasive right heart catheterisation.

Pulmonary hypertension results from several etiologies, among them underlying

cardiac diseases constitute the major group. However, the etiological profile and

prevalence of Pulmonary Hypertension in various non-cardiac disorders has not been

given adequate attention and there is paucity of data from our country on this aspect. In

all these diseases, the development of Pulmonary Hypertension has adverse prognostic

effects on the disease progression and outcomes. Hence it is important to diagnose this

condition early on the basis of high clinical suspicion so as to reduce the morbidity and

mortality caused by it.

We screened a total of 66 patients with clinical features suggestive of Pulmonary

Hypertension. Total 35 subjects with echocardiography or direct PA pressure

measurement by right heart catheterisation showing evidence of Pulmonary Hypertension

and with no underlying structural heart disease were included in the study for analysis and

were studied for demographic, clinical, etiological and echocardiographic data.

The age of all patients included in study ranged from 28 years to 90 years with

mean age of 59.54 years, median of 59 years and standard deviation of 14.45 years. The

majority of the patients were in age group of 51-60 years (28.57%) and the cumulatively

prevalence of Pulmonary Hypertension in patients of age >51 years was77.14% of total

64

patients diagnosed with disease. Male gender preponderance was noted with male to

female ratio of 2.1.

Chronic Obstructive Pulmonary Disease (COPD) was found as the commonest

cause (51.43%) followed by idiopathic Pulmonary Artery Hypertension (iPAH) in

22.86% and Interstitial Lung Disease (ILD) in 17.14% of patients of Pulmonary

Hypertension.

The mean Right Ventricular Systolic pressure (RVSP) to be 55.94 ± 15.46 mmHg.

Most of our patients had mild Pulmonary Hypertension (46%) followed by Severe

Pulmonary Hypertension in 37% of all patients. Maximum number of patients were found

to be in the WHO functional class II (54.29%). 28.57% were in WHO functional class III

and 14.29% in WHO functional class IV. There was only one patient in WHO functional

class I.

Spirometry showed Obstructive pattern in 51% of our patients. On classifying

them according to GOLD classification of COPD, we found the mean FEV1 percent of

predicted to be 39 ± 11.35% and also observed that out of these 18 patients maximum

number of patients i.e. 12 (66.67%) patients had moderate obstruction (GOLD III). The

GOLD class IV had 04 cases (22.22%) and GOLD class II had 02 cases (11.11%). There

were no patient in GOLD class I. The mean arterial partial pressure of oxygen (PaO2)

was 53.01 ± 18.05 mm of Hg with maximum number of patients i.e. 37% were suffering

from severe hypoxemia (PaO2 < 40 mm of Hg).

At the end of the study we concluded that, it is important to screen patients for

Pulmonary Hypertension in disease like COPD, ILD and OSA/OHS as timely diagnosis

of Pulmonary Hypertension and institution of therapy improves quality of life and

decreases morbidity & mortality associated with the disease.

65

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66

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75

ANNEXURES

76

ANNEXURE I

INFORMED CONSENT FORM

CONSENT FORM

Patient information sheet for participation in the study

Read the following carefully You are being requested to participate in a research study. Make sure that you understand what your

participation will involve. Ask as many questions you may have to your doctor, before you sign this

document.

In case of an emergency or any other problems with the study kindly contact: Surgeon Lieutenant Commander (Dr) Amit Sharma 9632174511

Background information In the research field, Pulmonary Artery Hypertension has emerged as the most prolific topic in the last

decade with work connecting it with overall improvement in the functional status of the patient

depending upon the etiology of the disease. It has suggested that etiology plays an essential role in the

functional status of patient in Pulmonary Artery Hypertension

We propose to carry out a study to assess the cause, and your functional status in your disease of

Pulmonary Artery Hypertension. THE STUDY IS PURELY BASED ON DIAGONOSTIC TESTS. HENCE YOU/ YOUR PATIENT ARE NOT

AT ANY RISK.

Procedures If you agree to participate in the study, the events described below will take place.

1. When presenting to Medical Department, you will be put through a battery of non-invasive

tests including HIV test (which is one of the common cause of Pulmonary Hypertension) to know the

cause of your disease, and your functional capacity.

2. Grading of your Disease (Pulmonary Hypertension) would be recorded on the basis of

Echocardiography and your functional status.

You will be assigned to group according to your Echocardiographic findings and your functional status

to evaluate the relation between the cause and Disease severity. Your findings after the battery of tests

will be informed to you.

Potential side effects Nil, as study does not interfere with your treatment and is meant only to gather data.

You will not be identified in any published reports on this study. Within the study, you will be

identified only by a numerical code for identification. Confidentiality of your participation will be

maintained to the extent provided by existing law.

Refusal or withdrawal of participation Your participation in this study is voluntary. You may refuse to participate in, or withdraw from the

study at any time without penalty or loss of benefits or right to medical care to which you may

otherwise be entitled. Your agreement to participate does not waive any of your rights.

77

Questions/ patient rights You will be completely free to make inquiries. If you have any other questions about the study you

should contact anyone of the investigators.


PULMONARY HYPERTENSION AT A TERTIARY CARE HOSPITAL”

INFORMED CONSENT FORM

I confirm that Surg Lt Cdr Amit Sharma has explained to me the purpose of the research, the study

procedure and I am willing to undergo in this study. Alternatives to my participation in the study have

also been discussed. I have read and I understand this consent form. I agree to give my consent to

participate as a subject in this study.

……………………… ………………………… ………….. ….……….

Patient Name Patient’s Signature Date Time

I acknowledge the receipt of a copy of this consent form

……………………… ………………………… ………….. ….……….

Patient Name Patient’s Signature Date Time

……………………… ………………………… ………….. ….……….

Name of Legally Acceptable LAR’s signature Date Time

Representative

I have explained to ………………………………………….. the purpose of this research

……………………… ………………………… ………….. ….……….

Investigator’s Name Investigator’s Signature Date Time

……………………… ………………………… ………….. ….……….

Witness Name Witness Signature Date Time

78

ANNEXURE II

“A STUDY OF ETIOLOGICAL PROFILE OF PATIENTS OF NON

CARDIOGENIC PULMONARY ARTERY HYPERTENSION AT A

TERTIARY CARE HOSPITAL”

STUDY PROFORMA

NAME_______________________________________ AGE_______________SEX_________ ADDRESS_____________________________________________________________________ TELE: ________________________________ MOBILE: _______________________________ Chief Presenting Complaints: Clinical Findings WHO Functional Class: 2D Echocardiographic Findings: Complete Blood Count (CBC) Renal Function Test (RFT) Liver Function Test (LFT) Thyroid Function Test (TFT) HIV (ELISA) Anti-Nuclear Antibodies ANA (ELISA)

79

Chest X Ray: Lung Parenchyma: Cardiac Size Pulmonary Artery Rt: Lt: USG Abdomen Pulmonary Function Testing (PFT) Arterial Blood Gas (ABG) analysis N Terminal pro- Brain Natriuretic Peptide (NT pro BNP) levels (if done): Diffusion Capacity for Carbon-Monoxide (DLCO) (if done): High Resolution Computed Tomography of the Chest (HRCT) findings (if done) CT Pulmonary Angiography (if done) Polysomnography (if done) Right Heart Cardiac Catheterization (if done) Final Remarks: Signature of Patient Signature of Investigator

GOLD 1

(MINIMAL)

(FEV1>70%)

GOLD 2 (MILD)

(FEV1=50-69%)

GOLD 3

(MODERATE)

(FEV1=30%-

49%)

GOLD 4

(SEVERE)

(FEV1<30%

)

1 REJIN VARGHESE 28 M 90 (BY

RHC)

26.3 HEREDITORY HEMORRHAGIC

TELENGIECTASIA WITH

PULMONARY AV

MALFORMATION

2 SANTOSH KUMARI 64 F 41 38% 60.8 COPD

3 ANURADHA C 63 F 76 42.2 INTERSTITIAL LUNG DISEASE

4 SARKARAJ 71 M 56 40% 38.4 SEVERE COPD

5 ARJUNARSAPPA 46 M 68 58 PRIMARY PULMONARY

HYPERTENSION

6 RAMASAMY 76 M 39 53.4 INTERSTITIAL LUNG DISEASE

7 SHANKAR NARAYAN 71 M 61 43% 59.7 COPD

8 VENKUBA RAO 75 F 36 68% 92.5 MILD COPD

9 SHANKAR RAJ 71 M 69 38% 48.2 SEVERE COPD

10 AROKIASWAMY 90 M 49 67.4 INTERSTITIAL LUNG DISEASE

11 INDIRA MOHAN DAS 52 F 63 86.2 PRIMARY PULMONARY

HYPERTENSION

12 SONTYANA BABU RAO 57 M 100 34% 36.4 SEVERE COPD

13 HARINATHA REDDY 50 M 40 36.6 PRIMARY PULMONARY

HYPERTENSION

14 ARJUN CHAVAN 48 M 68 59.1 PRIMARY PULMONARY

HYPERTENSION

15 SUDAMA BHANDARI 52 F 38 33.9 CONNECTIVE TISSUE

DISORDER WITH ILD

16 SHRIPAL RATHAUR 59 M 43 45% 57.4 MODERATE COPD

17 GOPAKUMARAN S 42 M 49 82.5 PRIMARY PULMONARY

HYPERTENSION

18 ANANTH KUMAR V 31 M 37 80.4 PRIMARY PULMONARY

HYPERTENSION

19 KRISHNAMURTHY 64 M 79 28% 32.2 SEVERE COPD

20 PACKIATHAI K 58 M 46 40 INTERSTITIAL LUNG DISEASE

21 LAXMAIAH 54 M 42 40% 70 COPD

22 KULKARNI 84 F 69 32% 28.2 ASTHMA COPD OVERLAP

SYNDROME (ACOS)

23 BIJI A 48 M 67 26% 39 ALLERGIC BRONCHO-

PULMONARY ASPERGILLOSIS

24 MUNISWAMY 65 M 45 45% 32 SEVERE COPD

25 MANJULA 43 F 40 75.4 OBSTRUCTIVE SLEEP APNEA

26 KANAKAMMA 54 F 41 68.4 OBSTRUCTIVE SLEEP APNEA

27 RAMESH 74 M 70 28% 36.2 SEVERE COPD

28 VC BABU 56 M 43 42% 46.5 COPD

29 CHANDRA 61 F 73 32% 50 COPD

30 K VASU 74 M 55 62% 63.7 COPD

31 VANITHA 63 F 55 60.3 PRIMARY PULMONARY

HYPERTENSION

32 JYOTHI 66 F 73 26% 32.2 SEVERE COPD

33 HARINATH REDDY 69 M 66 35% 35.5 SEVERE COPD

34 DEBASHISH MOHANTY 54 M 60 70.4 DRUG INDUCED INTERSTITIAL

LUNG DISEASE

35 V GOVINDASAMY 51 M 45 56.2 PRIMARY PULMONARY

HYPERTENSION

MASTER CHART

ANNEXURE III

OBSTRUCTIVE (FEV1/FVC<70%)MILD

(36-50)

MODERATE

(51-65)

SEVERE

(>65)

RVSP (in mm of Hg) WHO FUNCTIONAL CLASS DIAGNOSIS/ CAUSE

ON

LTOT

BIPAP CPAP DRUGS

(SILDENAFIL/

BOSENTAN OR

BOTH

THERAPEUTICSSL. NO.

NORMAL

NAME SEX

(M/F)

AGE

(YEARS)

SPIROMETRY (% of predicted) ABG ANALYSIS

NORMAL

(PaO2 > 80

mm of Hg)

SEVERE

HYPOXEMIA

(PaO2 < 40 mm

of Hg)

I II III IV MILD

HYPOXEMIA

(PaO2 = 60-79

mm of Hg)

MODERATE

HYPOXEMIA

(PaO2 = 40-59

mm of Hg)

RESTRITIVE