apheresis in dilated cardiomyopathy · •26 to 46% patients (1 to 10% healthy controls and 10 to...

©2011 MFMER | slide-1

Apheresis in the Treatment of Idiopathic Dilated Cardiomyopathy

Jeffrey L Winters, M.D. Professor of Laboratory Medicine and Pathology Division of Transfusion Medicine

10th International Society for Apheresis Congress

May 13-16, 2015


DISCLOSURE

Relevant Financial Relationship(s)

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Off Label Usage

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Dilated Cardiomyopathy

• Chronic progressive biventricular enlargement and contractile dysfunction.

• Patient Population: 20 to 60 years of age

• Incidence and prevalence: stable incidence after 20 with increasing prevalence until age 60 to 70

• Presentation: CHF and/or symptoms related to arrhythmia, conduction disturbance, or thrombotic complications. May also present with sudden death.

Images courtesy of William Edwards M.D.,

Mayo Clinic, Rochester MN


Dilated Cardiomyopathy

• Causes:

• Idiopathic - 50%

• Myocarditis - 9%

• Ischemic heart disease – 7%

• Infiltrative disease – 4%

• Hypertension – 4%

• HIV – 4%

• Connective tissue disease – 3%

• Substance abuse – 3%

• Doxorubicin – 1%

• Other – 10%

• “Other” includes: Lyme disease, Chaga’s disease, nutritional deficiencies, sleep apnea, endocrine abnormalities, and inherited syndromes.

Felker GM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000;342:1077- 1084.


Idiopathic Dilated Cardiomyopathy

• Incidence: 36 per 100,000/yr in the United States

• 50% of cases of dilated cardiomyopathy • 15% of heart failure in the elderly • 50% of heart transplants in the United States

• Medical Treatment: • Angiotensin converting enzyme inhibitors • Angiotensin II receptor blockers • β-adrenergic receptor blockers • Aldosterone inhibitors • Diuretics • Digitalis



• Pathophysiology

• Susceptibility

• Autoimmunity

• Higher prevalence of autoimmunity than the general population.

• Family members have a higher prevalence of autoimmunity including:

• Psoriasis

• Thyroid disease

• Rheumatoid arthritis

• Warm autoimmune hemolytic anemia

• HLA association

• HLA-DR4 and HLA-DQ4

Lappe JM, et al. Recent insights into the role of autoimmunity in idiopathic dilated cardiomyopathy. J Card Fail 2008;14:512-530.



• Pathophysiology

• Viral Infection

• Up to 67% have viral genome on endomyocardial biopsy

• Parvovirus B19 – 36.6%

• Enterovirus – 32.6%

• Human herpes virus 6 – 10.5%

• Adenovirus – 8.1%

• Clearance associated with LVEF improvement.

• Presence of viral replication not associated with worse function.

• No difference in outcomes in those with and without detectable viral genome.

Kuhl U, et al. Viral persistence in myocardium is associated with progressive cardiac dysfunction. Circulation 2005;112:1965-1970. Kuethe F, et al. Detection of viral genome in the myocardium: lack of prognostic and functional relevance in patients with acute dilated cardiomyopathy. Am J Heart 2007;153:850-858.


Virus or toxin

Injury and Innate Immune Response

Initial myocyte injury from pathogen

or toxin

Antigen-presenting cells stimulate pathogen-specific

T-cell response

Antibodies to pathogens may cross-react with endogenous epitopes (e.g., cardiac myosin

and -adrenergic receptor)

Myocyte

Virus

APC

T-cell

-cell

Myocyte cell death from direct viral damage

cytolytic T-cells or apoptosis Exposure of

innate immune system to pathogens and intracellular

sequestered antigens

Decreased regulatory T-cells function, activation

of cytolytic T-cells, and increased Th1 and Th2

cytokines

Virus

Myocytes

Regulatory T-cell

APC

Recovery or Persistent Cardiomyopathy

Viral clearance and down-regulation of immune response

Ongoing injury with persistent viral infection or immune response


Evidence for the Role of Humoral Autoimmunity in Dilated Cardiomyopathy

• Animal Studies

• Immunization with M2 acetylcholine receptor or cardiac G-protein receptors induced DCM in rabbits

• Immunization with the second extracellular loop of the β1-adrenergic receptor induced antibodies and DCM in rats. Transfer of serum induced DCM.

• Immunization with Troponin-I induced antibodies and DCM in mice. Transfer of serum induced DCM.

Fu ML, et al. A synthetic peptide corresponding to the second extracellular loop of the human M2 acetylcholine receptor induces pharmacological and morphological changes in cardiomyocytes by active immunization after 6 months in rabbits. Clin Immunol Immunopathol 1996;78:203-207. Marsui S, et al. Peptides derived from cardiovascular G-protein coupled receptors induce morphological cardiomyopathic changes in immunized rabbits. J Mol Cell Cardiol 1997;29:641-655. Jahns R, et al. Direct evidence for a beta1-adrenergic receptor-directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy. J Clin Invest 2004;113:1419-1429. Goser S, et al. Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in the myocardium. Circulation 2006;114:1693-1702.



• Human Studies

• 63 to 80% have detectable cardiac autoantibodies

• Antibodies eluted from immunoadsorption columns or separated from serum:

• Lyse rat cardiomyocytes

• Decrease rat cardiomyocyte contractility

• Impair rat cardiomyocyte calcium transport

• Impair chick embryo cardiac function



• α-Myosin Antibodies

• 23 to 66% of patients (0 to 2.5% healthy controls and 4 to 21% with ischemic cardiomyopathy)

• Worsening left ventricular function and increased diastolic stiffness

• Cross react with β1-adrenoreceptor

• β1-Adrenoreceptor Antibodies

• 26 to 46% patients (1 to 10% healthy controls and 10 to 13% with ischemic cardiomyopathy)

• Depressed myocardial function, greater incidence of severe ventricular arrhythmia, and greater incidence of sudden cardiac death

• Presence predicts increased risk of all-cause and cardiovascular mortality

Lappe JM, et al. Recent insights into the role of autoimmunity in idiopathic dilated cardiomyopathy. J Card Fail 2008;14:512-530.



• Troponin-I Antibodies

• Increase L-type Ca2+ current

• Na-K-ATPase Antibodies

• Independent predictor of poor systolic function, ventricular tachycardia, and sudden cardiac death.

• M2-Muscarinic Acetylcholine Receptor Antibodies

• Greater incidence of atrial fibrillation

Lappe JM, et al. Recent insights into the role of autoimmunity in idiopathic dilated cardiomyopathy. J Card Fail 2008;14:512-530. Baba A. Autoantigen estimation and simple screening assay against cardiodepressant autoantibodies in patients with dilated cardiomyopathy. Ther Apher Dial 2008;12:109-116.


Mechanism of Autoantibodies

• How can autoantibodies toward diverse myocardial antigens produce a common physiologic effect (reducing calcium transients and cell shortening) and a common clinical syndrome?

• Cross linking of the target antigen and Fcγ receptor IIa present on cardiomyocytes is necessary!

Staudt A, et al. Fcγ Receptors IIa on cardiomyocytes and their potential functional relevance in dilated cardiomyopathy. J Am Coll Cardiol 2007;49:1684-1692.


Mechanism of Autoantibodies

F(ab’)2 fragments

blocked the effect of

intact antibody

Fc fragments

from normal

IgG blocked

the effect of

intact antibody

F(ab’)2 fragments and antihuman

F(ab’) IgG induced effect

Cardiac

Antigen

Sarcolemmal

Fcγ Receptor IIa

Modified from Figure 2 in Staudt A, et al. Fcγ Receptors IIa on cardiomyocytes and their potential functional relevance in dilated cardiomyopathy. J Am Coll Cardiol 2007;49:1684-1692.

Antibody binding

induces a negative

inotropic effect

F(ab’)2 fragments did not

induce effect


Apheresis Treatment

• Immunoadsorption • Antihuman Sheep Polyclonal

Immunoglobulin Column (Ig-Therasorb) • Antihuman Sheep Polyclonal

Immunoglobulin Column (Ig-Adsopak) • Staphylococcal Protein A Agarose Column

(Immunosorba) • β1-adrenergic Receptor Antibody Column

(Coraffin) • Tryptophan Polyvinyl Alcohol Column

(Myosorba/Immusorba) • PGAM146 Column (Globaffin)

• Plasma Exchange


Antihuman Sheep Polyclonal Immunoglobulin Column (Ig-Therasorb)

Centrifugal disk

separator

Anti-human

sheep Ig bound to

matrix

Waste Bag

Glycine HCL



• Dorffel 1997 – CS 9 patients

• Treatment on 5 consecutive days

• Improved cardiac output, index, and stroke volume at 3 months

• Decreased mean arterial pressure, LV filling pressure, and systemic vascular resistance

• At 3 years follow-up:

•5 alive with no increase in β1-adrenoreceptor antibody titers and continued improvement of LVEF

•4 dead, all had increase in β1-adrenoreceptor antibody titers with associated LVEF decline

RCT CT CS CR

2(43) 5(307) 4(45) 0



• Muller 2000 – CT 34 patients (17 treated and 17 control) • Treatment on 5 consecutive days • Improvement at 12 months in:

• LVEF • LV diastolic diameter • NYHA class

• Decrease at 12 months in: • Oxidative stress markers • β1-adrenoreceptor antibody titers

• Improved survival at 5 years (82% vs 41%, p=0.00071)

• Annual cost of treatment was less (€24,857 vs €28,875)



• Knebel 2004 – CT 34 patients (17 treated, 17 untreated) • Acute increase in LVEF (19.8 to 25.7%) • Decreased days of hospitalization (17.2 days versus

4.3 days). • Effect lasted beyond 2.5 years • Days of hospitalization gradually increased with time

after treatment.

• Lehmkuhl 2005 – CS 108 patients • At 2 years – 81% responders, 19% non-responders • Increase in LVEF, decrease in LVEDD in responders • Lower LVEF at start of therapy in non-responders • LVEF and LVEDD changes became more

pronounced over time • Sustained decline in β1-adrenoreceptor antibody in

responders



• Other studies have found • Improved cardiac index, stoke volume, LVEF,

and NYHA class at 3 months • Decreased systemic vascular resistance at 3

months • Decreased desmin gene expression, HLA class

II expression, and myocardial lymphocytes on EMB at 3 months

• Decreased β1-adrenoreceptor antibody titers

• Other key points: • Presence of β1-adrenoreceptor antibody did not

correlate with response (Mobini 2003) • Only patients with cardiodepressant antibodies

demonstrated a response (Staudt 2004)


Antihuman Sheep Polyclonal Immunoglobulin Column (Ig-Adsopak)

• Pokrovsky 2013 – RCT 16 patients (9 treated and 7 controls) • Not selected for antibody positivity • Treatment on 5 consecutive days • No IVIG replacement • Improvement immediately after treatment:

• LVEF (not statistically significant) • 6 minute walking distance • Brain natriuretic peptide (BNP) • NYHA class

• NYHA class improvement persisted at 6 month follow-up • LVEF improved at 3 month follow-up but declined at 6

months.

RCT CT CS CR

1(16) 0 0 0


Staphylococcal Protein A Agarose Column (Immunosorba)

Staphylococcal

protein A bound to

agarose

Buffer

Waste Bag

Na

citrate

pH 2.2

Apheresis

Device

Adasorb



Image courtesy of Fresenius KABI



• Phase III multicenter trial in Germany and Sweden (NCT00558584) • Estimated primary completion date: December 2015

• Staudt 2002 – CT 18 patients (9 SPAA vs 9 AHPI) • Treatments on 3 consecutive days then two days every 4

weeks for 3 months. • No change in LVEF or cardiac index with SPAA • Due to limited IgG3 removal by SPAA

• Staudt 2005 – CT 18 patients (9 modified SPAA vs 9 SPAA) • Enhanced IgG3 removal protocol • Improved LVEF at 3 months with modified protocol

RCT CT CS CR

1(22) 5(144) 9(349) 0



• Staudt 2006 – RCT 22 patients • Treatment on 5 consecutive days vs 5

consecutive days every month for 4 months • Equivalent LVEF and cardiac index improvement

at 6 months

• Other studies have found • Improved LVEF, VO2, exercise capacity and

NYHA class at 3 and 6 months • Continued improvement to 12 months • Decreased nt-proBNP, nt-BNP, and nt-ANP at 3

months • Decreased cardiodepressant antibodies at 6

months with return at 12 months



• Other key points • Shorter disease course and low affinity Fcγ

receptor IIa associated with greater LVEF improvement (Staudt 2009)

• Only those with cardiodepressant antibody improved (Trimpert 2010)

• Only those with antibody (β1-adrenoreceptor, Troponin-I) improved (Herda 2010)

• Shorter disease duration and greater IgG3 reduction associated with greater LVEF improvement (Doesch 2010)



• Other key points • Treatment associated with increased Treg and

decreased Tstim and Tcostim lymphocytes (Bulut 2010)

• Responders had fewer Treg and more Th17 lymphocytes than non-responders with increase in Tregs in responders (Bulut 2013)

• Response predicted by the presence of cardiodepressant antibodies and RANBP1, RGS10, UBE3B, and USP22 genes. (Ameling 2013) • Inhibitory antibodies correlated with UBE3B

and USP22 expression


β1-adrenergic Receptor Antibody Column (Coraffin)

Whole Blood

Pump

Plasma

Pump

Waste Bag

0.9% NaCl

PDCM075 peptide

column



Image and graphics courtesy of Fresenius KABI

Loop 1 Loop 2 PDCM349 (loop 1-peptide): 14mer peptide PDCM075 (loop 2-peptide): 18mer peptide



• Wallukat 2002 – CS 8 patients

• β1-adrenoreceptor antibody positive

• Treatment 5 consecutive days

• Increased LVEF

• Decreased LV diameter, β1-adrenoreceptor antibody titer, and oxidative stress at 12 months

RCT CT CS CR

0 1(105) 1(8) 0



• Dandel 2010 – CT 105 patients (54 SPAA vs 51 β1-receptor column)

• β1-adrenoreceptor antibody positive

• Improved LVEF and decreased LV diameter in both

• Similar response (78.4% SPAA vs 75% β1-adrenoreceptor column)

• No difference at 3 and 5 years

• 8.6% with β1-adrenoreceptor antibody recurrence and decreased function


Tryptophan Polyvinyl Alcohol Column (Myosorba/Immusorba)

Whole Blood

Pump

Plasma

Pump

Tryptophan

polyvinyl alcohol

column



Image courtesy of Asahi Kasei Image courtesy of Leslie Cooper, M.D.,

Mayo Clinic, Rochester MN



• Yazaki 2009 – CS 2 patients • Improved LVEF and decreased BNP in one patient at 3

months

• Baba 2010 – CS 18 patients • β1-adrenoreceptor or M2-muscarinic acetylcholine receptor

antibody positive • LVEF, 6 minute walk test, and BNP improved • LVEF improved greater at 3 months if cardiodepressant

antibody disappeared

• Nagatomo 2011 – CS 16 patients • Improved LVEF and 6 minute walk test at 3 and 6 months • Decreased BNP at 3 and 6 months

RCT CT CS CR

0 0 3(36) 0

GAM146 Column (Globaffin)

• Synthetic peptide binds immunoglobulin non-specifically

• Cannot be regenerated

• Limited published reports on use in DCM • Dandel 2012


Image and graphics courtesy of Fresenius KABI

Comparison of Immunoadsorption Devices

• Dandel 2012 – CT 182 patients


Column N Response

Rate LVEF Pre LVEF Post

5-yr HTx/VAD

free survival

Coraffin 23 78.3% 23.8+6.3% 32.3+7.8% 91.3+5.9%

Globaffin 24 79.2% 24.4+5.4% 33.6+6.2% 86.0+8.5%

Ig-Therasorb 25 80.0% 24.0+6.0% 30.7+12.4% 78.8+8.4%

Dandel M, Wallukat G, Engelert A, Lehmkuhl HB, Knosalla C, Hetzer R. Long-term benefits of immunoadsorption in β1-

adrenoreceptor autoantibody-positive transplant candidates with dilated cardiomyopathy. Eur J Heart Fail 2012;14:1374-1388.


Plasma Exchange

• Torre-Amione 2010 – CS 8 patients • 1 plasma volume • Albumin replacement • 5 treatments every other day • Improved LVEF and NYHA class • Decreased Ig deposition on EMB

• Remaining case reports treated patients with β1-adrenoreceptor antibody in whom SPAA was contraindicated or not available • Improved LVEF and NYHA class

RCT CT CS CR

0 0 1(8) 2


Other Points

• Studies have excluded patients with familial DCM, which represent 20% of iDCM and are due to inherited cytoskeletal abnormalities.

• Patients on optimum medical therapy with a minimum disease duration of 6 months.

• Most protocols treated NYHA class II to IV patients with some treating only NYHA class II or III.

• Role of cardiac autoantibody assays is unclear though bioassays indicating cardiodepressant antibodies have been associated with response.

• In most SPAA and AHPI column protocols, IVIG (0.5 g/kg) has been administered.

• SPAA: 471 vs 4 patients • AHPI: 142 vs 37 patients

• Published reports of plasma exchange have administered IVIG (0.5 g/kg).

• Tryptophan polyvinyl alcohol, β1-adrenoreceptor column, and AHPI (Ig-Adsopak) protocols have not administered IVIG.


2013 ASFA Guidelines

• Immunoadsorption

• ASFA Category: II (NYHA class II to IV)

Disorders for which apheresis is accepted as second-line therapy, either as a standalone treatment or in conjunction with other modes of treatment.

• Recommendation Grade: 1B Strong recommendation, can apply to most patients in most

circumstances without reservation.

• Plasma Exchange

• ASFA Category: III (NYHA class II to IV)

Optimum role of apheresis therapy is not established. Decision making should be individualized.

• Recommendation Grade: 2C

Very weak recommendation; other alternatives may be equally reasonable.

Schwartz J, Winters JL, Padmanabhan A, Balogun R, Delaney M, Linnenberger ML, Szczepiorkowski ZM, Williams M, Wu Y,

Shaz BH. Guidelines on the use of therapeutic apheresis in clinical practice—evidence-based approach from the Apheresis

Applications Committee of the American Society for Apheresis. The Sixth Special Issue J Clin Apheresis 2013;28:145-284.


References Antihuman Polyclonal Immunoglobulin Column (Ig-Therasorb)

1. Wallukat G, Reinke P, Dorffel WV, Luther HP, Bestvater K, Felix SB, Baumann G. Removal of autoantibodies in dilated cardiomyopathy by immunoadsorptionInt J Cardiol 1996;54:191-195.

2. Dorffel WV, Felix SB, Wallukat G, Brehme S, Bestvater K, Hofmann T, Kleber FX, Baumann G, Reinke P. Short-term hemodynamic effects of immunoadsorption in dilated cardiomyopathy. Circulation 1997;95:1994–1997.

3. Felix SB, Staudt A, Dorffel WV, Stangl V, Merkel K, Pohl M, Docke WD, Morgera S, Neumayer HH, Wernecke KD, Wallukat G, Stangl K, Baumann G. Hemodynamic effects of immunoadsorption and subsequent immunoglobulin substitution in dilated cardiomyopathy: three-month results from a randomized study. J Am Coll Cardiol 2000;35:1590–1598.

4. Dorffel WV, Wallukat G, Baumann G, Felix SB. Immunoadsorption in dilated cardiomyopathy. Ther Apher 2000;4:235-238.

5. Muller J, Wallukat G, Dandel M, Bieda H, Brandes K, Spiegelsberger S, Eberhard N, Kunze R, Hetzer R. Immunoglobulin adsorption in patients with idiopathic dilated cardiomyopathy. Circulation 2000;101:385-391.

6. Staudt A, Schaper F, Stangl V, Plagemann A, Bohm M, Merkel K, Wallukat G, Wernecke KD, Stangl K, Baumann G, Felix SB. Immunohistological changes in dilated cardiomyopathy induced by immunoadsorption therapy and subsequent immunoglobulin substitution. Circulation 2001;103:2681–2686.

7. Schimke I, Muller J, Priem F, Kruse I, Schon B, Stein J, Kunze R, Wallukat G, Hetzer R. Decreased oxidative stress in patients with idiopathic dilated cardiomyopathy one year after immunoglobulin adsorption. J Am Coll Cardiol 2001;38:178-183.

8. Christ T, Dobrev D, Wallukat G, Schuler S, Ravens U. Acute hemodynamic effects during immunoadsorption in patients with dilated cardiomyopathy positive for β1-adrenoreceptor autoantibodies. Methods Find Exp Clin Pharmacol 2001;23:141-144.

9. Felix SB, Staudt A, Landsberger M, Grosse Y, Stangl V, Spielhagen T, Wallukat G, Wernecke KD, Baumann G, Stangl K. Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption. J Am Coll Cardiol 2002;39:646-652.

10. Mobini R, Staudt A, Felix SB, Baumann G, Wallukat G, Deinum J, Svensson H, Hjalmarson A, Fu M. Hemodynamic improvement and removal of autoantibodies against β1-adrenergic receptor by immunoadsorption therapy in dilated cardiomyopathy. J Autoimmun 2003;20:345-350.

11. Dorffel WV, Wallukat G, Dorffel Y, Felix SB, Baumann G. Immunoadsorption in idiopathic dilated cardiomyopathy, a 3-year follow-up. Int J Cardiol 2004;97:529-534.

12. Staudt A, Staudt Y, Dorr M, Bohm M, Knebel F, Hummel A, Wunderle L, tiburcy M, Wernecke KD, Baumann G, Felix SB. Potential role of humoral immunity in cardiac dysfunction of patients suffering from dilated cardiomyopathy. J Am Coll Cardiol 2004;44:829-836.

13. Hessel FP, Wegner C, Muller J, Glaveris C, Wasem J. Economic evaluation and survival analysis of immunoglobulin adsorption in patients with idiopathic dilated cardiomyopathy. Eur J Health Econ 2004;5:58-63.

14. Staudt Y, Trimpert C, Birkenmeier K, Krieg T, Bemmann T, Beug D, Felix SB, Staudt A. Effects of antibodies obtained from patients with dilated cardiomyopathy on the function of isolated rat hearts. Eur j Clin Invest 2006;36:85-90.

15. Kallwellis-opara A, Staudt A, Trimpert C, Moutsias M, Kuhl U, Pauschinger M, Schultheiss HP, Grube M, Bohm M, Baumann G, Volker U, Kroemer HK, Felix SB. Immunoadsorptio and subsequent immunoglobulin substitution decreases myocardial gene expression of desmin in dilated cardiomyopathy. J Mol Med 2007;85:1429-1435.

16. Dandel M, Wallukat G, Engelert A, Lehmkuhl HB, Knosalla C, Hetzer R. Long-term benefits of immunoadsorption in β1-adrenoreceptor autoantibody-positive transplant candidates with dilated cardiomyopathy. Eur J Heart Fail 2012;14:1374-1388.

17. Knebel F, Bohm M, Staudt A, Birges AC, Tepper M, Jochmann N, Wernicke KD, Felix S, Baumann G. Reduction of morbidity by immunoadsorption therapy in patients with dilated cardiomyopathy. Int J Cardiol 2004;97:517-20.

18. Lehmkuhl H, Englert A, Dandel M, Siniawski H, Mueller J, Hetzer R. Immunoadsorption in idiopathic dilated cardiomyopathy - 2 year follow up. Eur Heart J 2005;26(Suppl1):758-759.


References Staphylococcal Protein A Agarose Column (Immunosorba) 1. Staudt A, Bohm M, Knebel F, Grosse Y, Bischoff C, Hummel A, Dahm JB, Borges A, Jochmann N, Wernecke KD, Wallukat G, Baumann G, Felix SB. Potential role of

autoantibodies belonging to the immunoglobulin G-3 subclass in cardiac dysfunction among patients with dilated cardiomyopathy. Circulation 2002;106:2448–2453.

2. Staudt A, Staudt Y, Dorr M, Bohm M, Knebel F, Hummel A, Wunderle L, Tiburcy M, Wernecke KD, Baumann G, Felix SB. Potential role of humoral immunity in cardiac dysfunction of patients suffering from dilated cardiomyopathy. J Am Coll Cardiol 2004;44:829-836.

3. Staudt A, Dorr M, Staudt Y, Bohm M, Probst M, Empen K, Plotz S, Maschke HE, Hummel A, Baumann G, Felix SB. Role of immunoglobulin G3 subclass in dilated cardiomyopathy: results from protein A immunoadsorption. Am Heart J 2005;150:729–736.

4. Staudt A, Staudt Y, Hummel A, Empen K, Dorr M, Trimpert C, Birkenmeier K, Kuhl U, Noutsias M, Russ D, Felix SB. Effects of immunoadsorption on nt-BNP and nt-ANP plasma levels of patients suffering from dilated cardiomyopathy. Ther Apher Dial 2006;10:42-48.

5. Staudt A, Hummel A, Ruppert J, Dorr M, Trimpert C, Birkenmeier K, Krieg T, Staudt Y, Felix SB. Immunoadsorption in dilated cardiomyopathy: 6-month results from a randomized study. Am Heart J 2006;152:712.e1-712.e6.

6. Chen J, Larsson L, Haugen E, Fedorkova O, Angwald E, Waaggstein F, Fu M. Effects of autoantibodies removed by immunoadsorption from patients with dilated cardiomyopathy on neonatal rat cardiomyocytes. Eur J Heart Fail 2006;8:460-467.

7. Burgstaler EA, Cooper LT, Winters JL. Treatment of chronic dilated cardiomyopathy with immunoadsorption using the Staphylococcal A-agarose column: A comparison of immunoglobulin reduction using two different techniques. J Clin Apheresis 2007;22:224-232.

8. Cooper LT, Belohlavek M, Korinek J, Yoshifuku S, Sengupta PP, Burgstaler EA, Winters JL. A pilot study to assess the safety of protein A immunoadsorption for chronic dilated cardiomyopathy. J Clin Apheresis 2007;22:210-214.

9. Doesch AO, Konstandin M, Celik S, Kristen A, Frankenstein L, Hardy S, Goeser S, Kaya Z, Katus HA, Dengler TJ. Effects of protein A immunoadsorption in patients with advanced dilated cardiomyopathy. J Clin Apheresis 2009;24:141-149.

10. Doesch AO, Mueller S, Konstandin M, Celik S, Kristen A, Frankenstein L, Goeser S, Kaya Z, Zugck C, Dengler T, Katus HA. Effects of protein A immunoadsorption in patients with chronic dilated cardiomyopathy. J Clin Apheresis 2010;25:315-322.

11. Voigt A, Trimpert C, Bartel K, Egerer K, Kuckelkorn U, Feist E, Gericke C, Klingel K, Kandolf R, Felix SB, Baumann G, Kloetzel PM, Stangl K, Staudt A. Lack of evidence for a pathogenic role of proteasome-directed autoimmunity in dialted cardiomyopathy. Basic Res Cardiol 2010;105:557-567.

12. Staudt A, Herda LR, Trimpert C, Lubenow L, Landsberger M, Dorr M, Hummel A, Eckerle LG, Beug D, Muller C, Hoffmann W, Weitmann K, Klingel K, Kandolf R, Kromer HK, Greinacher A, Felix SB. Fcγ-receptor IIa polymorphism and the role of immunoadsorption in cardiac dysfunction in patients with dilated cardiomyopathy. Clin Pharacol Ther 2010;87:452-458.

13. Trimpert C, Herda LR, Eckerle LG, Pohle S, Muller C, Landsberger M, Felix SB, Staudt A. Immunoadsorption in dilated cardiomyopathy: long-term reduction of cardiodepressnt antibodies. Eur J Clin Invest 2010;40:685-691.

14. Herda LR, Trimpert C, Naike U, Landsberger M, hummel A, Beug D, Kiebeck A, Dorr M, Empen K, Knebel F, Ewert R, Angelow A, Hoffmann W, Felix SB, Staudt A. Effects of immunoadsorption and subsequent immunoglobulin G substitution on cardiopulmonary exercise in patients with dilated cardiomyopathy. Am Heart J 2010;159:809-816.

15. Bulut D, Scheeler M, Wichmann T, Borgel J, Miebach T, Mugge A. Effect of protein A immunoadsorption on T cell activation in patients with inflammatory dilated cardiomyopathy. Clin Res Cardiol 2010;99:633-638.

16. Bulut D, Scheeler M, Niedballa LM, Miebach T, Mugge A. Effects of immunoadsorption on endothelial function, circulating endothelial progenitors, and circulating microparticles in patients with inflammatory dilated cardiomyopathy. Clin Res Cardiol 2011;100:603-610.

17. Bulut D, Creutzenberg G, Mugge A. The number of regulatory T cells correlates with hemodynamic improvement in patients with inflammatory dilated cardiomyopathy after immunoadsorption therapy. Scand J Immunol 2013;77:54-61.

18. Ameling S, Herda LR, Hammer E, Steil L, Teumer A, Trimpert C, Dorr M, Kroemer HK, Klingel K, Kandolf R, Volker U, Felix SB. Myocardial gene expression profiles and cardiodepressant autoantibodies predict response of patients with dilated cardiomyopathy to immunoadsorption therapy. Eur Heart J 2013;34:666-675.



References Tryptophan Polyvinyl Alcohol Column (Myosorba/Immusorba)

1. Nagatomo Y, Baba A, Ito H, Naito K, Yoshizawa A, Kurita Y, Nakamura I, Monkawa T, Matsubara T, Wakabayashi Y, Ogawa S, Akaishi M, Yoshikawa T. Specific immunoadsorption therapy using tryptophan column in patients with refractory heart failure due to dilated cardiomyopathy. J Clin Apheresis 2011;26:1-8.

2. Yoshikawa T, Baba A, Nagatomo Y. Autoimmune mechanisms underlying dilated cardiomyopathy. Circ J 2009;73:602-607.

3. Nagatomo Y, Baba A, Kurita Y, Nakamura I, Monkawa T, Matsubara T, Wakabayshi Y, Ogawa S, Akaishi M, Yoshikawa T. Short-term experience of immunoadsorption therapy for refractory heart failure due to dilated cardiomyopathy. J Card Fail 2008;14(suppl):S148.

4. Yazaki Y, Takahashi A, Horigome M, Kasai H, Izawa A, Ikeda U. effect of immunoadsorptio on hemodynamic, echocardiographic, and scintigraphic findings in a patient with dilated cardiomyopathy. J Card Fail 2008;14(suppl):S157

5. Yazaki Y, Horigome M, Kasai H, Ikeda U. Follow-up of two cases with dilated cardiomyopathy treated with immunomodulation. J Card Fail 2009;15(suppl):S174

6. Baba A, Akaishi M, Shimada M, Monkawa T, Wakabayashi Y, Takahashi M, Nagatomo Y, Yoshikawa T. Complete elimination of cardiodepressant IgG3 autoantibodies by immunoadsorption in patients with severe heart failure. Circ J 2010;74:1372-1378.


References β1-adrenoreceptor Antibody Column (Coraffin)

1. Wallukat G, Muller J, Roland H. Specific removal of (beta)(1))-adrenergic autoantibodies from patients with idiopathic dilated cardiomyopathy. NEJM 2002;347:1806.

2. Schimke I, Muller J, Dandel M, Gremmels HD, Bayer W, Wallukat B, Wallukat G, Hetzer R. Reduced oxidative stress in parallel to improved cardiac performance one year after selective removal of anti-beta 1-adrenoreceptor autoantibodies in patients with idiopathic dilated cardiomyopathy: Data of a preliminary study. J Clin Apheresis 2005;20:137-142.

3. Dandel M, Wallukat G, Englert A, Lehmkuhl HB, Hetzer R. Efficacy of immunoadsorption as bridge-to-transplant therapy in patients with idiopathic dilated cardiomyopathy and evidence of beta-1 adrenoreceptor autoantibodies. J Heart Lung Transplant 2010;20(suppl 2S):S1630S164.



References

Globaffin


Ig-Adsopak

1. Pokrovsky SN, Ezhov MV, Safarova MA, Saidova MA, Shitov VN, Afanasieva MI, Khaustov AI, Adamova IY, Afanasieva OI, Konovalov GA. Ig apheresis for the treatment of severe DCM patients. Atheroscler Suppl 2013;14:213-8.


References

Plasma Exchange 1. Sugiyama H, Hoshiai M, Sugita K, Matsuda K. Plasma

exchange for removal of antibeta1-adrenergic receptor antibody in a small child with dilated cardiomyopathy. Pediatr Cardiol 2009;30:374-376.

2. Gesinde MO, Tan LB, Gooi HC. Plasma exchange treatment to reduce anti-beta1-adrenergic receptor antibody in a patient with dilated cardiomyopathy. J Clin Apheresis 2007;22:241-242.

3. Torre-Amione G, Orrego CM, Khalil N, Kotther-Assad C, Leveque C, Celis R, Youker KA, Estep JD. Therapeutic plasma exchange a potential strategy for patients with advanced heart failure. J Clin Apheresis 2010;25:323-330.


References

Background 1. Baba A. Autoantigen estimation and simple screening assay

against cardiodepressant autoantibodies in patients with dilated cardiomyopathy. Ther Apher Dial 2008;12:109-116.

2. Felix SB, Staudt A. Non-specific immunoadsorption in patients with dilated cardiomyopathy: Mechanisms and clinical effects. Int J Cardiol 2006;112:30-33.

3. Jahns R, Boivin V, Schwarzbach V, Ertl G, Lohse MJ. Pathological autoantibodies in cardiomyopathy. Autoimmun 2008;41:454-461.

4. Lappe JM, Pelfrey CM, Tang WHW. Recent insights into the role of autoimmunity in idiopathic dilated cardiomyopathy. J Card Fail 2008;14:521-530.

5. Staudt A, Eichler P, Trimpert C, Felix SB, Greinacher A. Fcγ receptors IIa on cardiomyocytes and their potential functional relevance in dilated cardiomyopathy. J Am Coll Cardiol 2007;49:1684-1692.


References

Review Articles 1. Winters JL. Apheresis in the treatment of idiopathic dilated

cardiomyopathy. J Clin Apheresis 2012;27:312-319.

2. Dandel M, Wallukat G, Englert A, Hetzer R. Immunoadsorption therapy for dilated cardiomyopathy and pulmonary arterial hypertension. Atherosclerosis Suppl 2013;14:203-211.

apheresis in dilated cardiomyopathy · •26 to 46% patients (1 to 10% healthy controls and 10 to...

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