Genetic Aspects

of Pulmonary
Hypertension
Ratna F. Soenarto
Dept. Anesthesiology & Intensive Care
Faculty of Medicine, Universitas Indonesia
resting pulm BP 25 mmHg
exercise pulm BP 30 mmHg

 Histologic
Gradual Change
Gene abnormality
When we cant find the possible-rational cause,

Primary Pulmonary Hypertension

(Idiopatic Pulmonary Arterial Hypertension)
 Primary Pulmonary Hypertension

Familial PPH had been recognized.

Mutation in BMPR2 (bone morphogenic protein receptor type 2)

Other mutations were also found: ALK1, CAV1, KCNK3, EIF2AK4

(familial & non familial)

Austin ED, Loyd JE. The genetics of pulmonary arterial hypertension. Circ Res. 2014;115:189-200
Dresdale et al. (1950s) 1st description of Primary PH:
isolated
familial

Studies in 1900-2000 discovered BMPR2

Its mutation is a major heritable risk for PH

2000 -
Mutations in ALK1, ENG, SMAD9 genes
Rare varians (mutation) reported to associate with PH :

Austin ED, Loyd JE. The genetics of pulmonary arterial hypertension. Circ Res. 2014;115:189-200
Bone Morphogenetic Protein
Receptor type 2

Receptor that binds Bone Morphogenetic Proteins

Member of TGF- superfamily ligands

BMP involves in many cellular function. It causes transcription of

mRNA involved in osteogenesis, neurogenesis, cell differentiation)
 TGF Signaling Pathway

TGF superfamily ligands bind to

type II receptors, phosphorylate type I
receptors

Type I receptors phosphorylate

receptor-regulated SMAD

transcription factors

Target gene expression

 BMPR 2 Function :
inhibits proliferation of smooth muscle tissues
promoting the survival of PA endothelial cells
preventing arterial damage & adverse inflammatory response
inhibits pulmonary arterial proliferation in response to
growth factor
 Mutation of BMPR2:

X inhibits proliferation of smooth muscle tissues

X promoting the survival of PA endothelial cells
X preventing arterial damage & adverse inflammatory response
X inhibits pulmonary arterial proliferation in response to
growth factor
development of PULMONARY
HYPERTENSION
REVIEW : possible causes of PH

Left to Right shunt

Valvular heart disease Collagen vascular disease

Portal hypertension

HIV

Pregnancy

Drugs & toxins

Heritable Pulmonary Arterial Hypertension
(HPAH)

PH without known possible causes

2 or more family members have PH

known have mutations in genes strongly suspected in PH

Mutation in BMPR2 : found in >50% familial PAH

Activin-like Kinase type 1 (ALK-1) : minority pts w/ telangiectasia

and coexistent PH

Newman JH, Trembath RC, Morse JA, Grunig E, Loyd JE, Adnot S, et al. Genetic basis of pulmonary
arterial hypertension. Current understanding and future directions. J Am Coll Cardiol 2004;43:33S39S
 Genetic basis of all PH is broader than familial pulmonary
arterial hypertension.

The pattern of inheritance :

autosomal dominant
female predominant
clinical signs & symptoms : similar w/ other PAH

Marker for familial PAH: on chromosome 2q31-21

Gene approach: mutations in BMPR2

Newman JH, Trembath RC, Morse JA, Grunig E, Loyd JE, Adnot S, et al. Genetic basis of pulmonary
arterial hypertension. Current understanding and future directions. J Am Coll Cardiol 2004;43:33S39S
10% of sporadic PPH have BMPR2 mutation,
inherited or not

PAH e.c. appetite-suppressant drug : (+)

PAH e.c. scleroderma-spectrum disease : (-) > ALK1
PAH e.c. HIV : (-)
 The carrier for BMPR2 mutation in population :
0.001 - 0.01%

Symptoms in PPH :
not exist unti advanced obstruction of vascular bed
+ extreme PH
+ R heart dysfunction
Screening
Study on suspectected families with heritable PPH

t i c
a
om
p t
y m
Echocardiographic as
PAP measurements
 PAP measurements
at rest
exercise

95% family members (who have BMPR2 mutation) :

have abnormality of PAP (systolic) response to exercise.
(range 41 - 80 mmHg)

Subject of PPH carrier who shows abnormal response to exercise

manifested PPH within 3 yr.
 False (+)
PAP rises to over systemic in normal individuals
LV filling dysfunction > reactive PH

european union
project

Doppler echocardiography
during exercise
hypoxic challenge
controlled, prospective study
 BMPR2 mutation is a major risk for PAH
Not strong enough to develop PAH.

Although suspected to be autosomal dominant,

penetrance of disease is low.
overall 27%
female 42%
male 14%
 Many therapies had been suggested/
recommended

No evidence of successful therapy.

Needs more understanding on deep & specific pathophysiology

Genetic engineering ???
TERIMA
KASIH