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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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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
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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
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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
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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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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.
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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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: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
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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
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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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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
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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