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The Robyn J Barst Keynote Lecture

“The Last 25 Years Of Treatment For Idiopathicand Heritable PAH in Children

Saji T , MD, PhD, FAHA,FACC,FSCAI

Emeritus Professor,Advanced and Integrated Cardiovascular Research Course ,Toho Univ. Faculty of Medicine, Tokyo. JAPAN

Est. in 1925

by PHA

L.JP.MA.09.2016.0359

1992.7~ Oral Prostacyclin (Beraprost) was approved for ASO,

and started in 27 y/o female iPAH patient.

1994.11 Present oral Beraprost data in AHA, first met Robyn J Barst

1996.4 Oversea transfer of 11y/o iPAH girl for living-donor LT to CHLA (Prof. Starnes)

1997.4 Oversea transfer of 8 y/o iPAH girl for DIV epoprostenol to CHLA

followed by another 3 iPAH children transferred

1999.4 Epoprostenol DIV apprved for adult PAH in Japan

2002.4 Sildenafil for ED approved, started off-label use in pediatric PAH , 1st Visit Tokyo

2005.6 Bosentan for adult PAH approved, started off-label use in pediatric PAH, 2nd Visit Tokyo

2007.12 Long-acting Beraprost for adult PAH, started to off-label use in pediatric PAH

2008.4 Oral sildenafil for adult PAH

2009.10 Tadarafil for adult PAH, started to off-label use in pediatric PAH

2010.9 Ambrisentan for adult PAH, started to off-label use in pediatric PAH

～2017.2 join Riociguat, Treprost. SC/IV、 Iloprost Inhal. Macitentan, Selexipag trial ,and

approved for adult PAH

Personal & Historical Progress in the management of PAH

Saji T, et al

“ Show me the tablet! ”

“Soba restaurant

right now ! ”

Served as Chair, Committee of CHD,CVDY,AHA1999-2000, and kindly recommended me to FAHA in 2006. July

“ Although our counsil is smallest, but productivity is greatest”

Fall,1999

Similarities

Robyn J Barst Ben T Saji

BD July 19,1950 Feb 25,1951

BP Los Angeles, CA Japan (stayed in Los Angeles 1987-1988,

worked @ CHLA. My grand father

lived in LA (1915.July -1941,Dec 9)

Marital Status married, 2 children married, 2 children

Favor: Soba noodles, Green tea, Sushi Same, and pumpkin pie

Education UNC 1976 passed ECFMG 1976,

1985~ Assistant Professor in 1985 visited NY for presentation

Columbia U. NY in 1st World Congress PC.

1999~2000 chair, committee of CHD, 2011~2014 Int’l. Liaison,

CVDY, AHA CVDY, AHA

Case: YM 14 y/o female HK 12 y/o female

Dx. iPAH, NYHA-II iPAH, NYHA-IV

Tx. started DIV epoprostenol Living-donor lung transplant

Date: 1996,April,26 1996, April,13

Location: Columbia PB Hosp. NY CHLA, USC, LA,

Physician: Robyn J Barst Vaughn Starnes (TL. surgeon)

Return Home: 1996 July 1996 August

with letter from Robyn J Barst transferred to/from CHLA by

F/U by Ben T Saji ~1999 by Ben T Saji ~now

on high-dose Epo. 20years passed after LDLT.

received LDLT in 2001,Jan 5 with BOS on F’s side

due to worsening HF/hemoptysis SpO2 99%, NYHA-I

Current status: full-time worker full-time worker

Similarities in 2 Japanese CasesFollow the Fate of PAH: coincidence in 1996, April, in NY and in LA

State of the Art:

Long-Term Treatment with Continuous Intravenous

Epoprostenol in Children with Idiopathic PAH

Professor Robyn J Barst, MDDirector, Division of Pediatric Cardiology,

Pulmonary Hypertension Center,

New York Presbyterian Hospital

Columbia Campus

Birth Los Angeles, CA, USA,

Education Univ. Rochester, BA 1972, UNC, MD 1976

Training Columbia U. Coll. of Phy. & Surg. 1976~,

Acad. Appointments

Fellow ~1981, Assist. Prof. 1983~,

Assoc,Prof 1992~, Prof. of Pediatrics 2000~

Distinguished Honors, Awards

Reviewers, Grants, Invited professors, Teaching

Publications & Presentations for PH

Gave 3 Lectures in Annual JSPCCS Meeting

July 7, 2005, Tokyo, Japan

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Her Future Strategies in 2005 by Robyn J Barst� Identifying the Cause(s) of PAH

・Prevention of PAH in Susceptible Individuals

� Studies in different forms of PAH (HIV, portal hypertension, CHD)

� Early therapy, Combination therapy, Transition therapy

� Novel therapy

・・・・“Cure” as Opposed to “Palliative” Therapy

・・・・Providing Evidence for Combination Therapy

� Studies in early stage ,and early therapy of the disease

・・・・ Proper evaluation of safety and efficacy of combination therapies

・・・・ Additional new compounds with different mechanisms, e.g. VIP,

adrenomedullin, elastase inhibitors, 5HT antagonists

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8

Period: 1992.4 ～～～～ 2016.12

Total Case #: 150 (boy/men 67: girl/lady83)

Age: 3m ～ 71 y/o

0～17y: 109, 18～71y: 41 cases

Classification : Idiopathic 78

Hereditary/Familial 22 subtotal = 100

Associated 50

(CHD;33, portal;6,CTD;3, PPHN3, PTE;1, others: 4)

Prognosis: Alive: 103 （LTx 13 cases (Living-donor:8, Cadaver:5 ）)

Died: 47 （ 〃 4 cases (LD:2, C :2) ）

Period: 1992.4 ～～～～ 2016.12

Total Case #: 150 (boy/men 67: girl/lady83)

Age: 3m ～ 71 y/o

0～17y: 109, 18～71y: 41 cases

Classification : Idiopathic 78

Hereditary/Familial 22 subtotal = 100

Associated 50

(CHD;33, portal;6,CTD;3, PPHN3, PTE;1, others: 4)

Prognosis: Alive: 103 （LTx 13 cases (Living-donor:8, Cadaver:5 ）)

Died: 47 （ 〃 4 cases (LD:2, C :2) ）

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Chida A, Saji T, et al: Am J Cardiol. 2012;110(4):586-93.

Shintani M, Saji T, et al

J Med Genet 2009;46:331-337

Smad8 nonsense mutation C202X in 8 y/o boy

Fujiwara M, Saji T, et al

Circ J 2008、72：127-133

Chida A, Saji T, et al Circ J 2012; 76:1501-8

Genetic Studies for Japanese Pediatric PAH -1

Saji T,et al

Speculate “Two –Hit Theory”

with modifier genes polymorphism

such as ACE,AT-II, and eNOS

L.JP.MA.09.2016.0359

Chida A, Saji T ; Mol. Genet Genomic Med. 20142, 229-239

Results of Genetic Study for Japanese Pediatric PAH -2

Saji T,et al

Notch1 receptor

Notch signaling is important in

・ Vascular stability・ Angiogenesis・ Normal hematopoiesis

L.JP.MA.09.2016.0359

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Event Name Human IPAH Human IPAH Human IPAH Human IPAH 1 S. Chartarum injected Model (Mouse) 2Hypoxia-induced

Model (Rat) 3Hypoxia-induced Model (Mouse) 4

MCT-induced Model (Rat) 5

Signaling by TGF beta DOWNDOWNDOWNDOWN ― UP UP UP

Signaling by BMP DOWN DOWN UP/DOWN ― ―

WntWntWntWnt/PCP pathway/PCP pathway/PCP pathway/PCP pathway UPUPUPUP ― ― ― ―

JAK/STAT signaling UP UP ― ― ―

Hemostasis UP UP DOWN UP/DOWN UP/DOWN

Estrogen receptor signaling UP UP UP ― DOWN

Serotonin receptor signaling UP UP UP/DOWN ― DOWN

Signaling by PDGF UP DOWN UP UP/DOWN DOWN

Signaling by VEGF UP DOWN ― ― DOWN

Response to hypoxiaResponse to hypoxiaResponse to hypoxiaResponse to hypoxia UPUPUPUP ― UP/DOWN UP DOWN

ROCK activation by RhoROCK activation by RhoROCK activation by RhoROCK activation by Rho UPUPUPUP ― UP ― DOWN

Regulation of apoptotic process UP/DOWN Down UP/DOWN ― UP/DOWN

― : Not IdenFfied

1 Laumanns IP et al. Am J Respir Cell Mol Biol 40: 683-691, 2009 2 Shimodaira K 、、、、Saji T. Respir Res 13:103, 2012. 3 Moreno-Vinasco L et al. Physiol Genomics 33:278–291, 2008. 4 Kwapiszewska G et al. Respir Res 6:109, 2005. 5 Vaszar LT et al. Physiol Genomics 17:150–156, 2004,

*

Abnormal Signaling: Discrepancy in human and in animal models

Saji T,et al

*

**

PAH; Onset triggering genes：：：：Summary

No direct

Relation with

TGF-β Signal

>75% of hPAH

20-30% IPAH

Both

PAH a/w HHT

Downstream

Of TGFβ

Disruption of

Caveoral Formation

Encode K-Channel

protein

Wnt/PCP 2012年 Shimodaira K (Japan)(Japan)(Japan)(Japan)

ELF2AK4 (GCN2) 2013年 Eyries M （France) Gene for PVOD(PCH)NOTCH 3 2014年 Chida A (Japan)TBX4: 2013年 Kerstjens-Frederikse WS,(The Netherland) Gene for small patella syndrome

Saji T, et al

Saji T, et al

Saji T, et al

Saji T, et al

2008 Fujiwara M, Saji T, et al

Saji T,et al

Saji T, Circ J 2013,77:2639-2650

L.JP.MA.09.2016.0359

Katano H , Saji, T et al. J Infect Dis. 2005:191:743-45

Plexiform Lesion (HE) of PAH patient

Positive control of HHV-8 Ag

in Kaposi’s Sarcoma

Re-Exam. Conclusion:No HHV-8 antigen positive samples in iPAH patients.

Negative Data of the Result in NEJM

Negative for HHV-8 in all PAH

Re-confirmation of Viral infection as one etiology of PAH

Saji T, et al

18

Hereditary hemorrhagic telangiectasia (HHT)

� Incidence： 1/8,000 （3,000～5,000・）

� Dx. Criteria ： Typical:≧３ Doubt: 2

1, Rec. Epistaxis

2, Telengiectasia （Lip,Mouth,Finger, Nose,

G-I tract, etc )

3, AVMs , AVF Lung,Liver, Brain,,

4, Family history

5, associated PAH

� Genes ： ALK1(HHT-1), ENG(HHT-2), Smad4(+polyposis)

� IPAH with ALK1 Mutation+, without signs of HHT (2005)

(Osler-Weber-Rendu syndrome)

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L.JP.MA.09.2016.0359

Patients # 1 2 3 4 5

Sex M M F F F

Onset age (y/o) 7 12 14 2 7

Mutation

Exon 9 8 7 10 10

ALK-1nucleotide change

1270C→A 1142T→C 936C→G 1451G→A 1436G→A

ALK-1amino acid change

P424T L381P H312Q R484Q R479Q

Family

Mutation N.E. N.E. + + +

PAH in Fx. brother brother sister father brother

HHT sign None None None None None

Outcomes Dead alive Dead alive alive

N.E. : not examined

Alk1 mutation-PAH in HHT: Poor Prognosis in patients and family membersSaji T,et al

Chida A, Saji T, et al: Am J Cardiol. 2012;110(4):586-93.

20

* Complications usually apparent after age >20~30

Age of Onset

■ Nosebleeds■ Telangiectasia

Age of Onset: Pulmonary AVF Severe Infections (incl. Brain Abscess)

Alk1 mutation-PAH in HHT: Age of Manifestations

PAV Fistula pre & post coil embol.

L.JP.MA.09.2016.0359

Chida A, Saji T

Am J Cardiol 2012；；；；110:586-593

76%@5y

72% @10yBMPR2

ALK1

Saji T,et al L.JP.MA.09.2016.0359

female male F:M

All patients 47 (48%) 50 1: 1.1

iPAH 23 (40%) 35 1: 1.5

hPAH 12 (63%) 7 1: 0.6

Conclusion:

Gender difference

does not give impact

on incidence or

survival of Pediatric i/h PAH

No Gender Difference of Pediatric i/hPAHSaji T, et al

L.JP.MA.09.2016.0359

Takatsuki S, Saji T et al : et al 49th Annual meeting of JSPCCS, Tokyo

0

5

10

15

20

25

30

35

0

5

10

15

20

25

30

35

Acute response of PVRI Chronic response of PVRI

Female Male Female Male

PV

RI(

un

itxm

2)

NS NS NS NS

-23% -14% -21% -23%

Acute response; on oxygenation

Chronic response; on newly initiation of vasodilator drug

No Gender Difference of Pediatric i/h PAH : Response to vasodilators

Saji T, et al

Am Heart J. 2011 Aug;162(2):201-13

Current therapeutics and practical management strategies for pulmonary arterial hypertension.

Agarwal R1, Gomberg-Maitland M.1Section of Cardiology, Department of Medicine, University of Chicago, IL, USA

Novel Prize

to

PGI2(1983) &

Nitric Oxide (1998)

Epoprostenol Treprostinil SC IV Ambrisentan

CCB Bosentan Iloprost Sildenafil

Trepro inh.

Tadarafil

2013~

• Riociguat

• Macitentan

• Selexipag

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L.JP.MA.09.2016.0359

:Anti platelet aggregation ：Whittle BJ,et al:Prostaglandins 16:373,1978, :Anti SMC proliferation, Lurumaya H,

Thrombus & Circulation, 7:185,1999, :Angiogenesis：Pola P, et al. J Mol Cell Cardiol 36:363-370,2004, Miyahara

Y,et al: BBRC 349:1242-1249,2006 :Treprostinil inhibits Remodeling of Fibroblast, Ali FY, Egan K, FitzGerald GA,

Desvergne B, et al :Role of prostacyclin versus PPAR B receptors in prostacyclin sensing by lung fibroblasts. Am J

Respir Cell Mol Biol 34:242-246,2006 :BPS activates K channel. Yamaki F, et al,Jap J Pharmacol. 122：37－39

Pleiotropic Biological Activity of ProstacyclinAnti-inflammatory, Anti-Proliferative, Anti-degenerative

Saji T, et al L.JP.MA.09.2016.0359

GⅠⅠⅠⅠ（（（（PAH) GⅡⅡⅡⅡ GⅢⅢⅢⅢ

24

16

8

2

0

TXB2 / 6-keto-PGF1α

Hashiguchi R, Saji T, et al I Jap J PCCS, 1991, 7:253-260Tamura K, Saji T, Thromboxane Synthase Inhibitor (OKY-046) Ozagrel :

Effect on TXB2/ PGI2 ratio in PAH. Kokyu to Junkan,2000,48:849-853

Elevated TXB2 / PGI2 Ratio in PAH

Classic Theory of Mechanism:

The Imbalance of Vaso-dilator and Vaso Constrictor

Saji T, et al

Saji T, et al Am J Cardiol, 78;244-247、1996Conclusion:

Oral Prostacyclin , Beraprost, is effective in short- and mid-term management of PAH

CI,mPCWP, ↑

mPAP, mRAP, PAR, Pp/Ps↓

First patient of iPAH treated with Oral PGI2,

Beraprost , Case ;30 y/o female in 1992.7current 54 y/o in 2017.2

L.JP.MA.09.2016.0359

3d. after lobar resection

Oversea Transfer from Tokyo to CHLA to receive living –donor lung transplantation

1996,March 12.

12 y/o female iPAH , NYHA-IV, 32 y/o , NYHA-I, in 2016

mid BOS

L.JP.MA.09.2016.0359

Oversea Transfer from Tokyo to CHLA to start DIV Epoprostenolin Case E.M, 7 y/o ,iPAH, NYHA-IV 1997.5

To ICU of CHLA with NYHA-IV

Saji T, et al

3wks later in Tokyo

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L.JP.MA.09.2016.0359

CI PAP SAP TRP/TSR TSR

1.0

2.0

3.0

4.0*P

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L.JP.MA.09.2016.0359

Before

After 1y

- Effect of Continuous Epoprostenol -Dramatic Improvement in Lung Blood-Perfusion Scintigraphy

Saji T, et al

My first case of epoprostenol started in CHLA, 1997

L.JP.MA.09.2016.0359

According to clinical improvements in

■ Pulmonary blood perfusion volume

■ Vaso reactivity to oxygen (-10% to -18%)

■ Capillary angiographic appearance

■ 6MWD, biomarkers, QOL, ADL, survival, etc

Circ J;71:1785-1790,2007

-10±8

-18±9

-30

-20

-10

0p

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43

Chida A, Saji T, et al: Circ J 2014;78:436-442

Soluble ST2 is a member of IL-1 receptor,

produced in endothelial cells,

seems to be a marker of cardiac stress.

L.JP.MA.09.2016.0359

Transit from *(n=4)Continuous on

**(n=11)p-value

Age of start EPO (y/o) 12.3±2.4 11.7±3 ns

Age of Exam. (y/o) 18.3±2.5 20.8±6.6 ns

Duration of Use Epo (yrs) 6.2±3.3 9.5±3.7 ns

Gender （（（（M/F) 3/1 4/7 ns

PAH, Familial (+/-）））） 0/4 4/7 ns

* 離脱進行中2例を含む** EPO維持量9例+増量中2例

n=15, Maintain WHO FC-II after Flolan

Mean Epo. conc. 15.6 ng/kg/min 23.6 ng/kg/min p=0.047

Mean PVR 8.3 UxM2 13.4 UxM2, p=0.001

Comparison with Cases with Transit from or on Epoprostenol

Saji T, et al

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45

Transit from Epoprostenol: Comparison of dosage, hemodynamics, 6MWD and BNP in Transit from with still on epoprostenol + combination

Tx.

Saji T, et al

Can be transit from if,

mPAP 4.0L/min

PVRI < 10 W/Unit

6MWD >550m

BNP < 20 pg/ml

L.JP.MA.09.2016.0359

12 weeks after starting Inhaled Iloprost

CO（mmHg） （L/min）mPAPPVRI

12 weeks

BL

（dyn･sec･cm-5･m2）

－10.0

5.0

0.0

－5.0

－2.0

2.0

1.0

－1.0

0.0

－200.0

100.0

0.0

－100.0

Pre 5 min 15min 30min

Ch

an

ge

from

Ba

se

line

(n=21)

mean

(n=21)

Mean

(n=21)

mean

The IBUKI Study Result-1: At week 12, PVRI, mPAP, CO improved from baseline

BL BL

12 weeks 12 weeks

Pre 5 min 15min 30min Pre 5 min 15min 30min

Efficacy and Safety of Inhaled Iloprost in Japanese Patients With Pulmonary Arterial Hypertension -

Insights From the IBUKI and AIR Studies. Saji T, et l al Circ J. 2016;80(4):835-42.

L.JP.MA.09.2016.0359

The IBUKI Study Selective Dilatation of Inhaled Iloprost for

Pulmonary Circulation

mPAP/mSAP ratioTPRPVR/SVR ratio

(n=21)

mean

(n=21)

mean

(n=21)

mean -0.10

-0.05

0.00

0.05

-200

-150

-100

-50

0

50

-0.10

-0.05

0.00

0.05(dyn･sec･cm-5)

Ch

an

ge

from

Ba

se

line

BL Pre 5min 15min 30min BL Pre 5min 15min 30min BL Pre 5min 15min 30min

12 weeks 12 weeks 12 weeks

.Saji T, et l al Circ J. 2016;80(4):835-42.

-118.98±132.13 -0.025±0.092-0.049±0.103

Blood

Flow

Good Oxygenation

No V/Q mismatch

- Systematic Review -Prostanoid therapies in the management of PAH

Continuous IV epoprostenol

Oral Beraprost

Inhalated Iloprost

IV・・・・ SQ Treprostinil

Overall

Therapeutics and Clinical Risk Management 2015:11 535-547.

RR

0.33

0.64

0.25

0.75

: 0.56

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PAH・・・・PGI2 & Thyroid Disease

• Age of Onset ：10.8（1.9-20.9） y/o m : f ： 22/23

• Tx. ： Combination with Epo. Triple ,Double 31 Cases

Oral Combination 14 Cases

• Thyroid Function: Normal in All Cases before Tx.

• F/U Period ： 10.1（3.2-15.4） year

• 12 / 45 （（（（27%）））） developed Thyroid Dysfunction

� Hyper Thyroid 12/ Hypo 0

� fT3 39.1(4.5-16.8), FT4 3.1(1.7-7.8), TSH < n.d in 8/11

• Male / Female：：：： 4/8（χ2 analysis, p=0.34）

• Epo. +/-：：：： 12 /0 （χ2 analysis, p=0.01）

• Final Diagnosis ：

� Basedow disease 6，，，， Hashimoto’ toxicosis 3. Painless Thyroiditis 3

• Worsening of Heart Failure

� Basedow disease 4, Painless Thyroiditis 1

Epo Conc.(ng/kg/min)Dysfunction

27.2±±±±13.0Normal function

26.7±±±±9.10.45

Satoh M1, Saji T.et al: Circ J. 2010 Feb;74(2):371-4. .

Metabolism. 1995 Oct;44(10):1239-42.Increased plasma levels of endothelin-1 in patients with hyperthyroidism.Letizia C1 et al University of Rome, La Sapienza, Italy.

Abstract

• In hyperthyroid patients, plasma concentrations of ET-1 were significantly higher than in the control group (P < .0001) and in hypothyroid patients (P < .0001).

• In contrast, no differences were found between hypothyroid patients and controls.

• Plasma levels of ET-1 were similarly elevated as in patients with Graves' disease and those with toxic adenoma.

• No correlations were found between plasma ET-1 levels, thyroid hormones, and thyrotropin (TSH) in hyperthyroid, hypothyroid, and euthyroid groups.

• The results of our study clearly indicate that in hyperthyroidism, circulating levels of ET-1 are strongly increased, although the pathogenesis of the increase is unclear.

ESC/ERS

PAH Classification 2015

L.JP.MA.09.2016.0359

Thyrotoxicosis

+ n=12 - n=47

p

Male/ Female 5 / 7 25 / 22 0.69

Time after Onset

y/o

8.3

（（（（3.1～～～～13.6））））7.5

（0.4～19.4）0.992

Tx. with Epo

with ERA

with PDE5-I

12

（（（（100 %））））5

（41.7 ％）10

（83.3 ％）

27

（57.4 ％）36

（（（（76.6 ％％％％）45

（95.7 ％）

0.015

0.046

0.377

� Conclusion:

The Risk of

thyro-toxicosis

is

more frequent

with Epo.

and

less frequent

with ERA Odd Ratio 95％％％％ conf. level p

with Epo 8.220 1.257～53.737 0.028

without ERA 5.331 1.288～22.059 0.021

Thyroid Dysfunction in Patients with i/h - PAH on Combination Tx.

Saji T, et al

Endocrine On line ;19、March, 2016

Hypertyiroidism Hypothyroidism

: Selective IP-receptor Agonist

Hyperthyroidism :n=8

in Selexipag Group

*

*

*

*

Selex-i-p-ag

Selective IP prostanoid agonist

（ Guideline of Drug- induced Lung Dysfunction by Japanese Society of Pulmonology）

:Epoprostenol, Nitric oxide

1．．．．Chemotherapy

2．．．．Immunosuppressive drugs

3．．．．Anti fungal drugs

4．．．．Respiratory Medicine

Drugs Causing Non-cardiac Lung

Edema

5．．．．Diuretics

6．．．．Anti-depressant

7．．．．NSAIDs

8．．．．Tocolytic agents

9．．．．Contrast agent

10．．．．Others

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Circulation August 9 2016

FIRST： Flolan is contraindicted in NYHA-IIIB,IVREACH & ENABLE:

ERA; Liver dysfunction & worsening of HF

Worsening heart failure：：：：B(11%）＋Epo(17.7%）＋Sil(30.3%) 59%！！！！

Bleeding Tendency：B(5.5)+PGI2(21.4%)+ Sil(14.6%) = 41.5%

L.JP.MA.09.2016.0359

Dec 26 Feb Mar NovAug

2007 2008 2009Jan

Case : 18 y/o IPAH 5th years of Epoprostenol

C.C.: Sudden onset of dyspnea and hemoptysis

2007/12

2009/2

after Tx. by iMP/PSL

Diffuse alveolar hemorrhage (DAH) & Interstitial pneumonia in

Patient treated with epoprostenol

Saji T, et al L.JP.MA.09.2016.0359

Red arrow ; dilatation of

small arteries & pulmonary

hemorrhage around obstructed

arteriole

Histopathology of PAH patients with hemoptysis: HE staining 40X

Saji T, et al

L.JP.MA.09.2016.0359

2015（23 y/o） 2009（17 y/o） 2004 (12y/o）

A Case with acute chest pain in patient with large main and branch PA aneurysm @2015.11

Q: What is a snap diagnosis ?

Rare Complication in patient with IPAH on epoprostenol

L.JP.MA.09.2016.0359

mPA compresses the Left main Coronary artery

Answer：：：： LMCA compression syndrome by dilated PA

IVUS

CAG

Demerouti E, et al : Cardiac Dual-source Computed Tomography for the Detection of Left Main Compression Syndrome in Patients with

Pulmonary Hyper-tension. Open Cardiovasc Med J. 2016 Jun 30;10:130-7.

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Yanagisawa M, 1988

Discovery of new Peptide, Endothelin in

Nature 332 31 March 1988

Yanagisawa M, 2014

Clozel M, 2014

L.JP.MA.09.2016.0359

0

1

2

3

4

5

NYHA IIINYHA II NYHA IV

Plasma level of ET-1

(pg/ml)

p=ns

r= -0.566

p=0.022

Plasma level of ET-1

0 100 200 300 400 500 600

6MWD (meters)NYHA-FC

Plasma ET-1 & NYHA functional class, 6MWD

Nakayama T, Saji T, et al : Effects of long-term treatment with epoprostenol on plasma adrenomedullin in patietns with

primary pulmonary hypertension. J Cardiol. 2001,38:263-271

Saji T, et al

L.JP.MA.09.2016.0359

1.5

2

2.5

3

3.5

4

4.5

5

5.5

1

2

3

4

5

6

0

100

200

300

400

500

600

700

800

0

200

400

600

800

1000

1200

1400

＊

hANP BNP

m-AdrenomedullinET-1

1.5

2

2.5

3

3.5

4

4.5

5

5.5

1

2

3

4

5

6

0

100

200

300

400

500

600

700

800

0

200

400

600

800

1000

1200

1400

＊

hANP BNP

m-AdrenomedullinET-1

Before 1m 3m 6-12mBefore 1m 3m 6-12m

Nakayama T, Saji T, et al : Effects of long-term treatment with epoprostenol on plasma adrenomedullin in patietns with

primary pulmonary hypertension. J Cardiol. 2001,38:263-271

Conclusion:Mature-type Adm. significantly correlated

with

� BNP (p=0.03),

� ET-1(p=0.006),&

� BNP/ANP Ratio.(p=0.0009)

Neuro humoral mediators after starting epoprostenol

Saji T, et al L.JP.MA.09.2016.0359

bfr declamp 0 3 6 12 24hrs

Kawasaki M, et al: Endothelin-1 Concentration in Extra-Corporeal Circulation,

J Toho Univ. 1997;44:53-59

Conclusion:

・ET-1 increased after Aortic Declamp・ET-1 in Pulmonry Vein

is more elevated than systemic Vein

Plasma ET-1 in Extracorporeal Circulation after ICR

Saji T, et al

病日1

PCPS

5

extubation

10

20

40

30

50

3 7 14 35

Discharge

On Respiratormean PAP

(mmHg)

PH crisis immed. after Crush (aspiration) Surgery

for Ocular Melanoma : A case 56 y/o male

ET-1: 9.6pg/ml (＜2.3pg/ml) Bosentan 62.5mg/day

start

Unexpected pulmonary hypertensive crisis after surgery for ocular malignant

melanoma.

Sato K, Saji T, et al

Life Sci. 2014 Nov 24;118(2):

420-3.

doi: 2014.03.004.

Epub 2014 Mar 13 Pressures [mmHg] @

ICU

RA(A/V/M) 18/16/15

RV(S/D/E) 68/32/32

PA(S/D/M) 66/40/53

PCW(A/V/M) 18/15/11

Pathology of Ocular Melanoma

H&E stain (ｘ400)

Malignant

melanoma

Anti ET-1 Ab stain (ｘ400)

Strong ET-1

expressionの存在

•Melanoma cells produce ET-1, and grow in a autocrine fashion．

(Reid K, et al. Development 1996; 122: 3911-19)

2017/3/3

12

L.JP.MA.09.2016.0359

Endothelin-1 & Tumor Growth

L.JP.MA.09.2016.0359

Phosphodiesterase 5 Inhibitor : sildenafil & tadarafil

Novel Prize in 1999

NYSU UCLA Texas

L.JP.MA.09.2016.0359

Sildenafil reduces PVR in single ventricular （（（（Fontan) physiology

Mori H, Saji T, Nakanishi T, et al et al Int J Cardiol. 2016;221:122-7.

70

Fontan Pre Post P value

NYHA -FC (n) p < 0.05

I 4 8

II 18 14

III 2 1

IV 0 0

6 MWD (m)415.8

± 74.2485.0

± 71.8p < 0.01

PVRI

mPAP

15.9 ±4.4↓

12.8±3.0mmHg

(p

2017/3/3

13

L.JP.MA.09.2016.0359

73

Mono Tx.,

[値]

Double Tx.

[値]

Triple Combo

Parenteral

PGI2 30

Triple Combo.

Oral PGI2 [値値値値]

Triple

Combo 45

Trend of the combination of major 3 agents

Current Administration Drugs (n=61)

Saji T, et al L.JP.MA.09.2016.0359

5 years survival rate＠Toho U.

Group D 96.4+/-3.5% (Combo.Tx.)

Group C 84.3+/-7.2%Group B 69.3+/-13.2%Group A 42.9+/-13.2%

A vs D p female2. Familial (hereditary) PAH with positive BMPR II mutation

3. h/PAH with Alk-1 positive HHT patients

4. Poor/no Responder in AVT (PVR, 300, NYHA-FC> III, IV

6. No clinical Improvement after 3 years on Tx

7. Resistant to Combination Tx. after 3 years

8. SSc-related PAH

9. WHO group- III. Respiratory Disease(COPD,IPF) –related PAH

10. Pts. without ABO compatible donors in family for

living-donor Lung TX (need to wait cadaver LT >3years)

Speculated Factors for Poor Prognosis in the PAH Clinics

Personal Opinion 2017.3

For Future StrategiesFor Future Strategies

L.JP.MA.09.2016.0359

My favorite paper

“A Comparison between Children and Adults”

78

In Conclusion、more similarities than differences in the characteristics of PAH in children and

adults, resulting in guidelines recommending similar diagnostic and therapeutic

algorithms in children (based on expert opinion), and adults ( evidence-based)

Eur Respir J, 2011, 37:665-677. Ref. 177

2017/3/3

14

Saji T, Circ. J,

2013; 77:239-2650In Memoriam

I would like to dedicate this work to the memory of Robyn J Barst, MD, FAHA, Professor Emeritus of Columbia University and a distinguished member of the Council on CVDY, who passed away in April 17, 2013,after a long illness.

She devoted her life to the health and happiness of children with PAH. Dr. Barst visited Japan, first in 2002, and presented informations that offered new hope for managing PAH, I would like to express my personal appreciation to Robyn, who was a great lover of the healthy food, nature, and culture of Japan, and a gracious colleague to all pediatric cardiologist in this country. I always remember her e-mail response to a question of mine in 2009

regarding the off-label use of a hopeful drug for PAH (Imatinib), which was found 3 years later to increase the risk of PAH and heart feilure.

With great foresight, she urged caution in light of the possible risks to me.

Saji T, Circ. J, 2013; 77:239-2650

May 28,2009,

Dear Ben,

How very nice to hear from you. I hope you and your family are well.

Regarding your questions below, yes 2 patients in the phase II Gleevec trial did die

from PAH aneursym rupture but one patient was on placebo and one was on active

drug.

The data provides adequate proof of concept for pursuing a phase III RCT trial in adult

patients that will be starting later this year. I am reluctant to treat patients with Gleevec

off label particularly children although I do have one young adult on Gleevec.

The sorafenib data is also interesting but again very preliminary and I would not use it

off label in any patients at this time. We did not see any adverse effects on cardiac

function in the Gleevec 6 months RCT trial but that does not preclude cardiac toxicity

long-term and very few patients continued on Gleevec past the 6 months due to our

concerns at the time.

Thus the long-term open label extension of the phase III Gleevec trial will be very

important. Will you be in Cairns in June?

Regards,

Robyn

May 28,2009,

Dear Ben,

How very nice to hear from you. I hope you and your family are well.

Regarding your questions below, yes 2 patients in the phase II Gleevec trial did die

from PAH aneursym rupture but one patient was on placebo and one was on active

drug.

The data provides adequate proof of concept for pursuing a phase III RCT trial in adult

patients that will be starting later this year. I am reluctant to treat patients with Gleevec

off label particularly children although I do have one young adult on Gleevec.

The sorafenib data is also interesting but again very preliminary and I would not use it

off label in any patients at this time. We did not see any adverse effects on cardiac

function in the Gleevec 6 months RCT trial but that does not preclude cardiac toxicity

long-term and very few patients continued on Gleevec past the 6 months due to our

concerns at the time.

Thus the long-term open label extension of the phase III Gleevec trial will be very

important. Will you be in Cairns in June?

Regards,

Robyn

2002,Tokyo

Lesson from my mentorTeam Pulmonary Hypertension ■■■■ Tokyo Women’s Medical College, Tokyo, for BMPR2, Alk1, Alk6, Smad8, Notch3 Research

� Toho University, Faculty of Medicine, Tokyo, for PAH Clinics, Surgery & Clinical Research

衛衛衛衛 医大医大医大医大 千田礼子千田礼子千田礼子千田礼子

研究・診療に御協力頂いた東邦大学循環器班・小児科学講座 の諸先生方･学兄に深謝致します。

Prof. Jeffrey Fineman

UCSFProf. Dunbar Ivy

University of Colorado

Prof. Ian Adatia

University of Alberta

Prof. Steve Abman

University of Colorado

Prof. Eric Austin

Vanderbilt University

Special thanks for giving exciting lectures & expertise in Tokyo and supports for research and clinics

Prof. Mike Takahashi

ex- Heart Institute,

CHLA,USC

Prof, Vaughn Starnes

H-L Transplant, CT Surgery

CHLA, USC

A Eulogy

Thank you Robyn for your kind attention, giving us hope, passion, warm heart , and leading to better patient’s

care. I would like to give this to husband Sam, daughter Nomi, and Lindsey.

Everlasting our mentor of PAH Sincerely 2017.Mar 10

AHA