INTRODUCTION

: KOREAN REGISTRY OF PAH

정 해 억

가톨릭의대 심장내과

2008.03.07 혈관연구회 4회 학술 심포지움

Pulmonary Arterial Hypertension (PAH)

A syndrome characterised by a progressive

increase in pulmonary vascular resistance

(PVR)

leads to right ventricular overload

eventually leads to right ventricular failure

and premature death

PAH: how common is it ?

PAH is rare. an estimated prevalence of 3050 cases per million1

The prevalence in certain at-risk groups is higher HIV-infected patients (0.5%)2

sickle cell disease (2040%)3

systemic sclerosis (15-38%)4

Idiopathic PAH accounts for at least 40% of cases5,6

twice as common in women as in men7

most common in young women mean age of diagnosis 36 years8

1. Peacock AJ. BMJ 2003; 2. Speich R et al. Chest 1991;3. Lin EE, Rodgers GP, Gladwin MT. Curr Hematol Rep 2005; 4. McGoon M et al. Chest 2004;5. Humbert M, Simmoneau G. Orphanet encyclopaedia, Nov 2004; 6. Humbert M et al. Am J Respir Crit Care Med 2006; 7. Gaine SP, Rubin LJ. Lancet 1998; 8. Lane KB et al. Nat Genet 2000.

PAH: why does it develop?

Exact cause of PAH remains unknown

Endothelial dysfunction occurs early on the disease process

Endothelial dysfunction results in

reduced production of vasodilators

over production of vasoconstrictors

endothelial and smooth muscle cell proliferation

remodelling of the pulmonary vascular bed and increased vascular resistance

Prognosis of PAH is worse than some cancers

6 months

2.6 years

4.9 years

0 1 2 3 4 5 6

WHO Class I - II PAH

WHO Class III PAH

Advanced prostate cancer

Advanced breast cancer

Advanced colorectal cancer

WHO Class IV PAH

Advanced lung cancer

D’Alonzo et al. Ann Internal Med 1991; Kato et al. Cancer 2001

Survival times (years)

Diagnosis is made late in disease

Mean duration from symptom onset to

diagnosis of PAH is 2.5 years

Late diagnosis due to

• Under-recognition

• Non-specific symptoms

• Confusion with other conditions

• iPAH is a diagnosis of exclusion

Hoeper ERS 2003

PAH is an orphan disease for which the

trend is for management in designated

centers with multi-disciplinary team.

Rare, unknown, worse, and late

Definition of Pulmonary Hypertension

Definition of Pulmonary Hypertension

Mean PAP > 25 mmHg at rest or

> 30 mmHg with exercise

심장초음파를 이용할 경우 systolic PAP > 40 mmHg // TR Vmax > 3 – 3.5 m/s

Definition of Pulmonary Arterial Hypertension

Definition of Pulmonary Hypertension +

PCWP < 15 mmHg

PVR > 2 wood units

Danapoint Decision,2008

WHO World Symposium, Venice 2003Pulmonary hypertension classification

1. Pulmonary arterial hypertension (PAH)

2. Pulmonary venous hypertension

3. Pulmonary hypertension associated with disorders

of the respiratory system and/or hypoxemia

4. Pulmonary hypertension due to chronic thrombotic

and/or embolic disease

5. Pulmonary hypertension due to disorders directly

affecting the pulmonary vasculature

Simonneau G et al. JACC 2004;43(Suppl):S5

Idiopathic (iPAH)FamilialRelated to:

•Collagen vascular disease

•Congenital heart disease

•Portal hypertension

•HIV infection

•Drugs / toxinsPAH with significant venous and/or capillaryinvolvement

Persistent PH in the newborn (PHN)

National PAH Registry Program

In early 1980s: USA

Informed the natural history and the characteristics of PPH

In 2000: France

Provided novel information on PAH

• In 2007: China

-- One Hospital Registry

Primary Pulmonary Hypertension ; A National Prospective Study in USA

Rich S. Annals of internal Medicine 1987;107:216-223D’Alonzo GE. Annals of internal Medicine 1991;115:343-349

NIH multicentre PPH prospective registry study in US (1981-1987)

Objective: to characterize mortality in persons diagnosed with PPH and to investigate factors associated with survival.

Data from 32 centers on patients diagnosed by uniform criteria as having primary pulmonary hypertension

194 patients, between 1 July 1981 and 31 December 1985 followed through August 1988 for survival at 6-month intervals.

Estimated percentage of patients surviving

• Median survival ; 2.8 years

• 26%: Sudden death, 47%: right ventricular failure

• Mortality was most closely associated with RV

hemodynamic function

48

12

1

4643

17

PAH Registry of France

French Reference Center for Pulmonary Arterial Hypertension (Hôpital Antonie Béclère, Clamart, France) set up a French Network on Pulmonary Arterial Hypertension.

Humbert M. Am J Respir Crit Care Med 2006; 173: 1023-1030

Objectives- Clinical and hemodynamic parameters - Prevalence of PAH

Methods

- 17 university hospitals following at least five newly

diagnosed pts per yr

- All consecutive adult (> or = 18 yr), 674 patients

- between October 2002 and October 2003

Definition of PAH- The presence of a mean pulmonary arterial pressure greater than 25 mmHg at rest.- Pulmonary artery wedge pressure less than 15 mmHg at right heart catheterization.

Patients distribution in French PAH Registry

39.2%

3.9%9.5%

15.3%

11.3%

10.4%

6.2%4.2%

idiopathic PAH

Familial PAH

PAH associated with anorexin

PAH associated with CTD

PAH associated with CHD

PAH associated with portalhypertension

PAH associated with HIV

Others

• Prevalence of PAH : 15.0 cases/million of adult inhabitants • Incidence of PAH : 2.4 cases/million of adult inhabitants/yr. • One-year survival : 88% in the incident cohort

REGISTRY AND SURVIVAL STUDY IN CHINESE PATIENTS WITH IDIOPATHIC AND FAMILIAL PULMONARY ARTERIAL HYPERTENSION

Jing ZC et al. Chest 2007

Methods

- Fu wai Hospital between Jan 1999 and October 2004

- 72 patients of idiopathic & familial PAH followed up to 2006

- Compare variables, survival of 2 group “WHO class I/II vs

III/IV”

Definition of PAH

- The presence of a mean pulmonary arterial pressure

greater than 25 mmHg at rest by RHC or

- Systolic pulmonary artery pressure > 40mmHg in pt

without RHC by echo

Purposesthe clinical features and survival data of idiopathic PAH and familial PAH in Chinese patients

Demographic Data and Comparison with NIH & French Registry

Variables of RHC in different WHO class

*

Survival comparison among 3 national registry

Survival rate comparison: WHO cl I/II vs III/IV

I II

III IV

PAH in Korea

iPAH was designated as an orphan disease from Jan.1st, 2006

Limited information is available regarding Korean PAH patients

Korean PAH Registry

목적: 한국 PAH 환자의 특성조사 유병율 및 발생율

성별, 나이, 원인별 환자 분포

치료양상와 임상경과

예후, ….

조사방법:

- 웹사이트를 통핚 환자정보 입력

- 각 센터별 PAH 환자 발생시 인터넷에 연결하여 환자정보

입력

Center 1

Center 2 Center 3

Center 4

Server

환자발생

환자발생 or Follow Up Step

1. 인터넷연결

2. CRF에환자정보입력

3. Follow up시 추가 data 입력

Korean PAH registry program

Common Diagnostic Criteria !!

혈관연구회

폐 고혈압의 진단과정

1. 임상적 의심 증상 및 징후, 이학적 검사, 가족력, 과거력…

2. 확인 심전도, 흉부 X선 검사, Echo, and Right Heart Cath. (확진)

3. 원인검사 혈액검사, 폐기능검사, ABGA, V/Q scan, high resolution CT, ..

4. 상태 및 중등도 평가 6 minute walking test, CPX, RH cath중 vasoreactivity test, BNP, NYHA class, ...

Cardiologist !!

TFT : 정해억, 김용진, 정욱진, 최의영, 신혜선

Common Diagnostic

Criteria & CRF

for Korean PAH

1. 모든 환자는 반드시 Right Heart Cath.을 시행하여

mean PAP > 25mmHg &

PCWP < 15mmHg을 만족핚다.

Provisional Diagnostic Criteria by Korean PAH Registry TFT

• Catheterization이 불가능하거나, 환자가 거부할경우는 ?

2. Doppler Echo를 이용하여 진단핚다.

- systolic PAP > 40mmHg (peak TR velocity ≥ 3m/sec)

- mean PAP > 25mmHg

두가지를 모두 만족해야 핚다.

진단의 specificity를 높이고, follow up 검사와의 통일성을 위하여 RA pressure를 항상5 mmHg로 estimation하여 sPAP를 측정한다.

Mean PAP는 두가지 방법으로 측정하는데, 두 방법중 하나이상에서 계산핚 값이 >25mmHg를 만족해야 핚다.

1) RVOT에서 Acceleration time을 측정하여

구하는 방법 (Mahan’s equation)

MPAP = 79 – 0.45 X AcT

2) peak PR velocity를 측정하여 구하는

방법(Masuyama’s method)

MPAP = 4 X peak PR velocity2

3. Exclusion of LV origin PH

1. Pulmonary arterial hypertension (PAH)

2. Pulmonary venous hypertension

3. Pulmonary hypertension associated with disorders

of the respiratory system and/or hypoxemia

4. Pulmonary hypertension due to chronic thrombotic

and/or embolic disease

5. Pulmonary hypertension due to disorders directly

affecting the pulmonary vasculature

4. Essential Diagnostic Testings

1. Classification

□ Idiopathic PAH

□ Familial PAH

□ PAH related to Collagen vascular disease (specify )

□ PAH related to Congenital heart disease (specify )

□ PAH related to Portal hypertension

□ PAH related to HIV infection

□ PAH related to Drugs / toxins (specify )

□ PAH with significant venous and/or capillary involvement

□ Persistent PH in the newborn (PHN)

□ Pulmonary hypertension ass. with dis. of respiratory system or hypoxemia

(specify )

□ Pulmonary hypertension due to chronic thrombotic and/or embolic disease

□ Pulmonary hypertension due to dis. directly affecting the pulmonary vasculature

5. Case Report Form

2. Concomitant conditions

□ DM , □ HTN, □ IHD (specify ______________________________ ) □ Hx of smoking (current _______ ex ________)□ Hx of drug ingestion (specify _____________________________ )□ Family history (specify ______________________________ )□ Surgical operation Hx (specify_________________________)□ Tuberculosis □ other lung diseases □ Liver disease

3. Baseline clinical characteristics

SBP______, DBP_______, HR _____ Hb ______, Cr _______ECG □ NSR □ AF

4. Medications (for PH) ___________________________________________________________ ____________________________________

5. Functional assessment□ Six Min walk test : ____________ m□ WHO classification : ________

6. Core Echo Parameters Echo parameters (in every part)□ measured peak PAP, mean PAP□ TR grade (using vena contracta)□ Fractional area change of RV□ IVC diameter with respiratory variation□ TAPSE□ PVR (peak TR velocity / TVI RVOT x 10 + 0.16)□ CO measured in LVOT

7. Right Heart Cath. data

SBP ________ DBP ______ MAP __________ CI ________systPAP _______ diastPAP________ meanPAP ________PCWP __________ RVSP ___________ RVDP________RAP ________PVR (mean PAP – PCWP / cardiac output ) ________Pulmonary arterial capacitance (PP/SV)____________

8. Follow-up evaluation (Every year)

1. Primary end-point : death ( Y / N )

2. Secondary end-point : re-hospitalization ( Y / N )

3. Surrogate marker

- WHO classification ________

- 6 minute walk test ________ m

- Repeat echo evaluation

- CBC / LFT

- ABG without O2 supply / PFT

Special Echo measurements (in cardiology)

LV parameters - LVEDD __________ LVESD_____________- LAVI ___________ LVEF ____________ LVMI __________- E____________ A___________ DT __________- E’____________ A’ ________________ E/E’ ___________

RV parameters- RA size in 4ch (post processing) end-diastole _____, End-systole _____- Tei index- Pericardial effusion (diameter )- peak TRV ________- RVOT VTI __________, RVOT diameter______, Qp______, TVR ______ - TV E velocity _______, A velocity ________- Tricuspid TDI, Sa__________ Ea________ Aa______- Tricuspid IVA (isovolumic acceleration time) ____________- RVDA ____________ RVSA _________ RVFS ___________- Tissue velocity imaging for 4ch and modified 4 ch views- 2D global strain __________, RV free wall longitudinal strain ______- RV eccentricity index (4Ch view and mid LV short axis view)

a ________, b ________, c__________, d_________- LV eccentricity index (short axis view, end-diastolic phase)

e ________, f _________- PR CW Doppler (if possible) PREDV _______, PR Peak V ________

PAH registry program status

현재 PAH 관련 각 학회 별 registry program 진행

학회 갂 collaboration을 통핚 Korean PAH 자료 통합이 요구됨

혈관연구회산하 program으로진행중임상연구위원회산하 program으로진행중

학회내학술산하 program으로진행중소아폐동맥고혈압연구회발족연구회 program으로진행

Conclusions

The need for Korean PAH patient registry program has been shared among Medical societies.

However, nothing has settled down.

If you have any interests or idea for this program, please contact to the academic society which you are involved.

4. PVR 을 진단기준에넣을것인가 ?

; Very important diagnostic and prognostic index

RHC :

mean PAP – PCWP / cardiac output

Echo :

peak TR velocity / TVI RVOT x 10 + 0.16

Abbas AE, Lester SJ. 2003 JACC

Rt heart catheterization- mean right atrial pressure : 9.7 6 mm Hg

- mean pulmonary artery pressure : 60 18 mm Hg

- cardiac index : 2.3 0.9 L/min X m2

- pulmonary vascular resistance index : 26 14 mmHg/L/min X m2