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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 .

… Primary Pulmonary Hypertension (Idiopatic Pulmonary Arterial Hypertension) .When we can’t find the possible-rational cause.

EIF2AK4 (familial & non familial) Austin ED. The genetics of pulmonary arterial hypertension. Circ Res. Mutation in BMPR2 (bone morphogenic protein receptor type 2) Other mutations were also found: ALK1. CAV1. 2014. KCNK3. Primary Pulmonary Hypertension Familial PPH had been recognized.115:189-200 . Loyd JE.

SMAD9 genes .… Mutations in ALK1. (1950s) 1st description of Primary PH: isolated familial Studies in 1900-2000 discovered BMPR2 Its mutation is a major heritable risk for PH 2000 .Dresdale et al. ENG.

Loyd JE. Circ Res. The genetics of pulmonary arterial hypertension. 2014.115:189-200 .Rare varians (mutation) reported to associate with PH : Austin ED.

Bone Morphogenetic Protein Receptor type 2 Receptor that binds Bone Morphogenetic Proteins Member of TGF-ß superfamily ligands BMP involves in many cellular function. It causes transcription of mRNA involved in osteogenesis. cell differentiation) . neurogenesis.

phosphorylate type I receptors Type I receptors phosphorylate receptor-regulated SMAD transcription factors Target gene expression . TGF ß Signaling Pathway TGF ß superfamily ligands bind to type II receptors.

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 .

Loyd JE. Genetic basis of pulmonary arterial hypertension. Trembath RC. Morse JA.43:33S–39S . et al. Current understanding and future directions. J Am Coll Cardiol 2004.Mutation in BMPR2 : found in >50% familial PAH Activin-like Kinase type 1 (ALK-1) : minority pts w/ telangiectasia and coexistent PH Newman JH. Grunig E. Adnot S.

Grunig E. 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.43:33S–39S . Loyd JE. Genetic basis of pulmonary arterial hypertension. et al. Morse JA. Current understanding and future directions. Trembath RC. J Am Coll Cardiol 2004. Genetic basis of all PH is broader than “familial pulmonary arterial hypertension”. Adnot S.

10% of “sporadic” PPH have BMPR2 mutation. HIV : (-) . inherited or not PAH e. appetite-suppressant drug : (+) PAH e.c.c. scleroderma-spectrum disease : (-) —> ALK1 PAH e.c.

The carrier for BMPR2 mutation in population : 0.0.01% Symptoms in PPH : not exist unti advanced obstruction of vascular bed + extreme PH + R heart dysfunction .001 .

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.80 mmHg) Subject of PPH carrier who shows abnormal response to exercise manifested PPH within 3 yr. . (range 41 .

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 .

Although suspected to be autosomal dominant. penetrance of disease is low. BMPR2 mutation is a major risk for PAH Not strong enough to develop PAH. overall 27% female 42% male 14% .

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Many therapies had been suggested/ recommended No evidence of successful therapy. Needs more understanding on deep & specific pathophysiology .

Genetic engineering ??? .

TERIMA KASIH… .