An overview of Pulmonary Hypertension

Sarfraz Saleemi
MRCP FCCP FACP

Section of pulmonary medicine Department of medicine King Faisal Specialist Hospital & Research Center Riyadh, Saudi Arabia

Discovery of pulmonary circulation 13th Century

IBN AL-NAFIS

History of Pulmonary Hypertension

1891 E. Romberg, Germany, The first reported case , Autopsy thickening of the pulmonary artery but no heart or lung disease 1951
D.T. Dresdale. USA,39 cases Term pulmonary hypertension

used for the first time 1967 1973

10-fold increase in unexplained pulmonary hypertension in central Europe - Aminorex Fumarate, an appetite suppressant drug

Cardiac Hemodynamics

Pulmonary vascular resistance

High capacitance Low resistance

Mean PA - PAOP Cardiac output

(12-7)/5 = 1 Wood Unit (80 resist)

Systemic vascular resistance

Relatively fixed capacitance High resistance

Mean Ao - mean RA Cardiac output

(95 - 5)/5 = 18 Wood Units (1440 resist)

Hemodynamic definition of pulmonary hypertension

Pulmonary Hypertension
Post-Capillary PH
(PCWP>15 mmHg)
PAH Respiratory Diseases PE

Atrial Myxoma Cor Triatriatum

MV Disease

VC

RA

RV

PA PC

PV

LA

LV
LVEDP

Ao Systemic HTN AoV Disease

PV compression PVOD

Pre-capillary Mixed PH PH PCWP<15 mmHg PVR > 3 Wu

Myocardial Disease Dilated CMP-ischemic/non-isc. Hypertrophic CMP Restrictive/infiltrative CMP Obesity and others

Hemodynamic Grading of Pulmonary Hypertension

www.saph.med.sa

Classification of PH

WHO Symposia

1973 - First World Symposium on Pulmonary Hypertension, Geneva, Switzerland 1998 - Second World Symposium on Pulmonary Hypertension, Evian, France

2003 - Third World Symposium on Pulmonary Hypertension, Venice, Italy

2008 - Fourth World Symposium on Pulmonary Hypertension, Dana Point, USA

Clinical Classification of Pulmonary Hypertension

(Dana Point 2008)
1. Pulmonary arterial hypertension (PAH) 2. Pulmonary hypertension owing to left heart disease 3. Pulmonary hypertension owing to lung diseases and/or hypoxia 4. Chronic thromboembolic pulmonary hypertension (CTEPH) 5. Pulmonary hypertension with unclear multifactorial mechanisms
Simonneau G, Robbins IM, Beghetti M, et al. J Am Coll Cardiol. 2009 S43-S54.

Updated clinical classification of pulmonary hypertension (Dana Point, 2008)

Epidemiology of PH

Epidemiology of PHT PAH: how common is it?

PAH is rare Estimated prevalence of 3050 cases per million Mean age of diagnosis 36 years Females twice as common as males

The prevalence in certain at-risk groups is higher HIV-infected patients (0.50%) sickle cell disease (2040%) systemic sclerosis (30%)
True prevalence may be higher
Peacock AJ. BMJ 2003 Gaine SP et al. Lancet 1998 Sitbon O et al. Am J Resp Crit Care Med 2008 Lin EE et al. Curr Hematol Rep 2005 McGoon M et al. Chest 2004

Epidemiology of PHT

Retrospective 91-99 Prospective 99-04

SWISS MED WKLY 20 08;138(2526):379384

At-Risk Populations for PAH

Populations
IPAH CTD Systemic Sclerosis CREST syndrome CHD

Prevalence/Incidence
1-2/million

30% 50% Up to 50% of patients with large VSDs develop Eisenmenger syndrome, often associated with PAH

HIV
SCD Drugs/Toxins

0.5/%
20-40%

Direct relationship with anorexigens (amphetamines, cocaine); L-tryptophan may also be associated with PAH
Rich et al. CHEST 1989; Braunwald et al. Heart Disease, 6t ed.; Wigley et al. Arth Rheum 2005 Simmoneau et al. JACC 2004; 5Speich et al. CHEST 1991; Lin et al. Curr Hematol Rep 2005. Rich et al. CHEST 2000.

Updated risk level of drugs and toxins known to induce PAH

Survival in IPAH

Felker et al. N Engl J Med 2000

WHO classification of functional status of patients with pulmonary hypertension

I II
III IV

No limitation of usual physical activity; ordinary physical

activity does not cause dyspnea, fatigue, chest pain, or presyncope

Mild limitation of physical activity; no discomfort at rest; but

normal activity causes increased dyspnea, fatigue, chest pain, or pre-syncope

Marked limitation of activity; no discomfort at rest but less

than normal physical activity causes increased dyspnea, fatigue, chest pain, or pre-syncope

Unable to perform physical activity at rest; may have signs of

RV failure; symptoms increased by almost any physical activity

Survival in PAH

McLaughlin VV et al. CHEST 2004

Survival

SWISS MED WKLY 20 08;138(2526):379384

Pathophysiology of PH

Pathophysiology of PAH
Genetic Predisposition Other Risk Factors Altered Pathways and Mediators Proliferation

Thrombosis

Vascular Remodeling

Vasoconstriction

Targets Pathophysiology for Current or Emerging Therapies of PAH

Endothelin Pathway
Big Endothelin Endothelinconverting Enzyme

Prostacyclin Pathway
Arachidonic Acid

Nitric Oxide Pathway

Arginine

Prostacyclin Synthase

Nitric Oxide Synthase

Endothelin-1
cAMP
Endothelin Receptor Antagonists

Prostacyclin
cGMP Prostacyclin Prostacyclin Derivatives Derivatives

Nitric Oxide Exogenous Nitric Oxide

Phosphodiesterase Type-5

Endothelin Receptor A

Endothelin Receptor B

Phosphodiesterase Type-5 Inhibitors

Vasoconstriction and Proliferation

Vasodilatation and Antiproliferation

Vasodilatation and Antiproliferation

Humbert M et al. N Engl J Med. 2004;351:1425-1436.

Balance between vasoconstriction and vasodilator pathway

Mediators and Pathways in PAH

Increased Activity Endothelin-1 Serotonin Thromboxane A2 Clotting Factors Angiopoietin-1 PAI-1 Reduced Activity Prostacyclin Prostacyclin synthase Nitric oxide Nitric oxide synthase VIP K channel

Growth factors
Oxidant stress Inflammation

Fibrinolysis

Schematic Progression of PAH

Pre-symptomatic/ Compensated

Symptomatic/ Decompensating

Declining/ Decompensated

CO
Symptom Threshold

PAP PVR
PVR= PAP-PCW
Time

Right Heart Dysfunction

CO

Diagnosis

Symptoms

Physical Findings

clear lungs central and peripheral cyanosis stigmata of secondary causes of PAH:
scleroderma, cirrhosis, HIV, OSA/OHS

Accentuated P2 Right ventricular S4 RV heave Large A waves from stiff RV Large V waves from TR Elevated JVP Graham-Steele murmur of PR Right ventricular S3

Diagnostic algorithm Diagnostic algorithm

European Heart Journal (2009) 30, 24932537

Diagnostic algorithm. algorithm Diagnostic

European Heart Journal (2009) 30, 24932537

Diagnostic Tests

Management
General measures O2. Diuretics, Digoxin, anticoagulation Specific treatment Prostanoids, PDE5 inhibitors, Endothelin Receptor Antagonists Non-pharmacological treatment Atrial Septostomy Lung or Lung/heart transplant

Conclusion

Pulmonary Arterial Hypertension is a serious illness with poor prognosis if left untreated. It is under-diagnosed and under-estimated Every effort should be made to make an early diagnosis Comprehensive history and physical is foundation for diagnosis Referral to a specialist center is mandatory in view of specialized investigations and unique management of this illness

THANKS