Immunoadsorptio in dilated cardiomyopathy a real alternative to the cardiac transplant pr u schulz

Klinik für Thorax- und Kardiovas-

kularchirurgie

Immunoadsorption in DCM: A real alternative to the cardiac transplant (?/!)

Uwe Schulz Transplantationsstation und –ambulanz

Klinik für Thorax- und Kardiovaskularchirurgie Herz- und Diabeteszentrum NRW

Bad Oeynhausen

Klinik für Thorax- und Kardiovaskular- chirurgie


β1- Receptor peptides induce morphological changes

control survived died after 9 month

saline + adjuvants ß1-Peptide + adjuvants ß1-Peptide + adjuvants

Matsui, S et al: J Mol Cell Cardiol 29 (1997) : 641


after month 6-9:

left ventricular dilation and dysfunction diagnosed by echocardiography & catheterization

Sources: 1) Jahns, R et al: 68th Annual Meeting, German Soc. Cardiol. 2002: V235 2) Jahns, R et al:JCI, 2004

transfer of serum into rats

Immunisation of rats with β1-adrenergic receptor

15 months :

induction of anti-ß1-receptor antibodies

after month 9-15: progressive left ventricular dilation and dysfunction

serum DCM DCM


Spontaneously beating neonatal rat- cardiomyocytes


Actin HSP 60

ACh-receptor HSP 70

Aconitate hydratase Vimentin

Pyruvate kinase Laminin

Dihydrolipoamide DH Myosin

Creatin kinase NADD

Adenine nucleotide translocator UCR

ß1-adrenergic receptor SSA

Ca 2+ channel SSB

Carnitin ENA

Desmin ANCA

Myolemma ASA

Maisch, B et al: Herz 25 (2000): 200


Development of autoimmune-cardiomyopathy

?!Infections

viral/ bacterial

?!

?!Ischemia

myocardial infarction

Heart tissues are damaged

by …

… resulting in generation of

cardiac antibodies

Myocyte-antigens are presented to the immune-

system …

?!Toxins

(alcohol, chemotherapy)

Jahns et al., Progr. Inflamm. Res. 2008


Cardial targets for autoimmune reactions

Cytoskelettal Proteins !Tubulin (Latif 1993)!

Laminin (Maisch 1983)! cardial Troponin I (Okazaki, 2003) !cardial Aktin !

(Neumann 1990)!

cardial α-Myosin (Eriksson 2003)!

Sarkomer-Proteins!

G-Protein receptors!β1-AR (Magnusson 1994, Jahns 1999,2004) !

β2-AR (Sterin-Borda 1988)!α1-AR (Fu 1993, 2004)!

muscar. M2-R (Fu 1993; Borda 1996)!AT1-AR (Wallukat 1999, Fu 2000)

mitochondrial ADP/ATP-carrier !

(Klein 1984; Schultheiss 1986)!

GADPH; GPBB; Aconitathydrase!

(Buse 2008)!

Ion channels (?)!

L-Ca2+-channel!T-Ca2+-channel!K+-channels/-

ChlPs!K+-ChIP2!

(Felix 2002, 2008)!







Müller, J; Wallukat, G et al: Circulation 101 (2000): 385


Müller, J; Wallukat, G et al: Circulation 101 (2000): 385







Hessel F et al.: Eur J Health Economics. 2004

p=0.0071


Hessel F et al.: Eur J Health Economics. 2004

p=0.0071

Costs during 5 years: -  128 600 € IA -  75 500 control

With regard to survival benefit: -  24900 €/year IA -  28900 €/year control

„costs per life year gained“

>> 34 400 €


Poster ESC; Stockholm (2.-6. September 2005)











Heart transplantation HDZ NRW, Ruhr-University of Bochum

Bad Oeynhausen, 3/1989 – 11/2010

2 days - 77 years, mean: 49.9 yrs.

1468 male (81%) / 345 female(19%)

Recipients:

Donors:

1 day - 72 yrs., mean: 34.7 yrs.

927 male (51,1%) / 886 female (48.9%)

n = 1813

Non-VAD: 1431 (78,9%) / VAD: 382 (21,1%)














Clinical course:

EF (%) TI MI per. Ödeme NYHA

Prior to IA: 41 II° I°-II° + III

after Rtx: 43 II° I°-II° +/- III

after 1 month: 50 I° 0°-I° -- I-II

after 2 months: 64 I° 0°-I° -- I

after 3 months: 61 I° 0°-I° -- I

Successful management of antibody-mediated cardiac allograft rejection with combined immunoadsorption and anti-CD20 monoclonal antibody

treatment: case report and literature review. I Kaczmarek, MA Deutsch, S Sadoni, P Brenner, D Schmauss, SH Daebritz, M

Weiss, BM Meiser, and B Reichart J Heart Lung Transplant, May 1, 2007; 26(5): 511-5.

37-year old man; CAD; status after myoc. infarction implantation of Novacor-LVAD 12/02; HTX 04/2004

PRA 30%; no induction therapy 01/05 IST switched to SIR/MMF

>> 3 months later clinical signs of heart insufficiency


Successful management of antibody-mediated cardiac allograft rejection with combined immunoadsorption and anti-CD20

monoclonal antibody treatment: case report and literature review. I Kaczmarek, MA Deutsch, S Sadoni, P Brenner, D Schmauss, SH Daebritz, M



Successful management of antibody-mediated cardiac allograft rejection with combined immunoadsorption and anti-CD20 monoclonal antibody

treatment: case report and literature review. I Kaczmarek, MA Deutsch, S Sadoni, P Brenner, D Schmauss, SH Daebritz, M


„Nevertheless, effective standardized schemes for the treatment of antibody-mediated graft rejection have to be defined. We present a heart transplant recipient with sustained antibody-mediated graft rejection who was successfully managed with a combination treatment consisting of 3 cycles of immunoadsorption and a single-dose administration of the anti-CD20 monoclonal antibody rituximab.“


49 year old man; status after aortic valve replacement; 6 transfusions

HTx 2 years later with PRA 80%

11x IA in 35 days

Serum IgG 14,2 >> 0.7 g/l // Serum IgM 1,7 >> 0,2 g/l

IST: OKT3; CyA; Aza

expired pod 28: sepsis (pseudomonas aeruginosa)


Case 1:

Retransplantation

- 39 year old female patient with DCM

- First Tx 2003 after 4 weeks of LVAD support (Thoratec)

-  GVP detected 4/2008

-  HU listing 01/2009 due to progression of GVP in combination with increasing number and complexity of rhythm disorders and beginning deterioration of cardiac function (CI 1.9)

-  PRA 100%

(MHC Class I and II positive in ELISA and lymphocyte test)

- Prospective cross-match prepared


Case 1:

Retransplantation

-  2 organ offers rejected (positive donor X-match)

-  further deterioration of clinical situation

- Prospective X-match only possible in Germany not in all ET countries (waiting time longer!!)

-  2 Immunoadsorptions pre-Tx: 21.02. and 01.03.

-  intraoperative induction therapy (Thymoglobulin 2,5 mg/kg); Tac/MMF/Cortison as maintenance IST

-  2 Immunoadsorptions post-Tx: on pod 1 and 24

-  discharge on pod 28; follow-up 4 weeks after last IA

-  present PRA ?%

(MHC Class I and II weak positive in ELISA and lymphocyte test)

- 3rd postop IA next week planned electively


Case 2:

VAD-use: Total artificial heart (CardioWest)

-  36 year old female patient

-  HNOCM

-  CardioWest implant in cardiogenic shock 08/2007

-  24.02.2009 HTx

-  humoral rejection“: antibody treatment (r-ATG); plasmapheresis; catecholamine dependent, renal failure

-  >>> only marginal improvement

-  MHC class I and II positive in perioperative X-match:

-  1 course of immunoadsorption

-  slow but progressive improvement

-  discharge with recovered renal function and myocardial Bx ISHLT grade 0 4 weeks later

-  follow up 4 weeks after discharge uneventful


„immunological“ risk factors

-  VAD use

-  excessive use of blood and blood components

-  post-partum women

-  homograft use

-  retransplantation or second transplantation


Summary

-  apheresis can stabilize clinical course of patients with heart insufficiency and dilated cardiomyopathy

-  removal of autoantibodies is possible

-  HLA-antibody removal in sensitized patients makes Tx possible

-  further evaluation needed for both indications

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Der Antikörper-Staubsauger

Wer sagt eigentlich, dass bei Herzinsuffizienz nur Pillen und Transplantationschirurgen helfen können? Per Dialyse geht das

Wasser jedenfalls auch raus. Jetzt wollen extrakorporal veranlagte Kardiologen auch noch Antikörper absaugen, um

dem Wasser den Garaus zu machen.




Technology

Immunoadsorptio in dilated cardiomyopathy a real alternative to the cardiac transplant pr u schulz