Update on stem cells in cardiovascular disease

Transcription

1 Andreas M. Zeiher, MD Dept. of Internal Medicine III University of Frankfurt Germany Update on stem cells in cardiovascular disease Cardiology Forum 2010, Rome, 05 / 2010 Disclosure information: Guidant (research support) t2cure (co-founder, advisor)

2 Cells for functional cardiac repair Embyronic-like stem cells (ips) 4 genes: Oct4, Klf4, Sox2, myc somatic cells (skin fibroblasts) Cardiac stem cells Modified from Dimmeler et al, JCI 2005

3 Cell therapy in cardiovascular diseases Acute Myocardial Infarction Refractory Angina Peripheral arterial occlussive disease Chronic post-infarction heart failure

4 Cell Therapy in Acute Myocardial Infarction: therapeutic targets Acute Myocardial Infarction Adverse LV Remodeling Chronic Heart Failure infarct expansion chronic LV- dilatation Vascularization Apoptosis Paracrine factors Cardiac Regeneration Metaanalysis of randomized and cohort studies of progenitor cell therapy in ischemic heart disease N = 976; overall treatment effect percentage points increase in LV-EF ( p < ) Abdel-Latif, Arch Intern Med 2007; 167:989

5 Absolute change in global LVEF ( %) Enhanced contractile recovery by BMC is confined to patients with failed initial recovery 10 p for interaction = p = p = Baseline LVEF by QLVA EF below median ( 48.9 %) Placebo BMC Placebo BMC n = EF above median (> 48.9 %) Schächinger et al., N Engl J Med 2006

6 Enhanced contractile recovery by BMC in patients with failed initial recovery results of recent controlled trials Change in EF (%) REGENT trial REGENT FINNCELL trial Controls N=20 p= BMC < median N= p=0.01 p= < median > median p = 0.04 BMC Placebo months 0 6 months Courtesy of M Tendera, European Heart Journal, Courtesy of H. Huikuri, European Heart Journal, 2008

7 Endsystolic volume (ml) Adverse remodeling is confined to patients with failed initial recovery of EF and abrogated by BMC therapy EF < median EF > median Change of endsystolic volumes over time (MRI) 140 p = p = p = p = 0.9 p = 0.7 p = 0.5 BMC Placebo 20 0 Baseline 4 months 12 months Baseline 4 months 12 months Baseline EF: % Baseline EF: % Dill et al., AHJ 2009

8 Do beneficial effects of BMC therapy on adverse remodeling translate into clinical benefit?? Therapies preventing adverse remodelling reduce adverse cardiovascular events ACEI, ARB, ß-Blocker, Aldosteron-Ant.

9 Event-free survival (%) (death, myocardial infarction, rehospitalization f. heart failure) BMC therapy is associated with improved clinical outcome at 2 years - Death, MI, Rehospitalization for heart failure BMC 80 Placebo 70 p = (log rank) days # exposed to risk Placebo BMC CirculationHeartFail 2009

10 BMC Therapy in Acute Myocardial Infarction Insights into potential mechanisms of action?

11 Putative mechanisms for cardiac regeneration Cell homing and tissue integration EC Differentiation SMC Differentiation Paracrine Effects Cardiac Differentiation Fusion Angiogenesis Attraction/ Activation of CSC Arteriogenesis Cardiomyocyte Proliferation Vasculogenesis Cardiomyogenesis Cardiomyocyte Apoptosis Modulation of Inflammation Scar Remodelling FUNCTIONAL CARDIAC REGENERATION

12 Mechanistic Insights from Coronary Flow Assessment Assessment of maximum coronary vascular conductance Adenosine (140 µg/kg i.v.) NTG (epicardial vessel dilation) Doppler wire (Flowire ) APV Infarct artery and Reference vessel Coronary flow reserve Relative flow reserve CFR = APV adenosine / APV basal rcfr = CFR target vessel / CFR reference vessel Core Lab: Sandra Erbs / Rainer Hambrecht (Herzzentrum Leipzig) 3 Centers (54 patients) Herzzentrum Leipzig (32), J. W. Goethe University Frankfurt (20), Herz- u. Diabeteszentrum Bad Oeynhausen (2)

13 abs. infarct vessel CFR Intracoronary BMC Administration Normalizes Coronary Flow Reserve abs. Relative CFR Infarct vessel CFR Relative CFR (infarct vessel normalized to reference vessel) p = ,8 p = ,0 1,5 0,6 1,0 0,4 0,5 0,2 0, , Placebo BMC Placebo BMC n = 26 n = 28 Erbs et al., Circulation 2007 n = 26 n = 27

14 Cell therapy in cardiovascular diseases Acute Myocardial Infarction Refractory Angina Peripheral arterial occlussive disease Chronic post-infarction heart failure

15 Cell Therapy for Refractory Angina JAMA, May 2009

16 Cell Therapy for Refractory Angina JAMA, May 2009

17 Phase II ACT34 CMI Study Design Screening and Baseline Visits Subject population (n=167) Cell Mobilization (GCSF 5mcg/kg/d x 5d) Apheresis on Day yrs CCS class III or IV Angina Attempted best medical therapy Non-candidate for Surgical/Perc. revasc. Ischemia on SPECT 3-10 min. mod. Bruce protocol with angina or anginal equivalent at baseline 1 x 10^5 CD34+ cells/kg (n = 55) Randomization Placebo (n = 56) 5 x 10^5 CD34+ cells/kg (n = 56) Endomyocardial Mapping and Injection with NOGA Isolex selected CD34+ cells / Placebo Rx Follow-up Safety and Efficacy Assessments: 1-7 days, and 1, 3, 6, and 12 months; ETT at 3, 6, 12 months MRI at 6 months, SPECT at 6 & 12 months Courtesy of Doug Losordo

18 Seconds ACT-34 CMI: Increase in Exercise Time Total ETT Time Change from baseline at 6 months p=0.013 Placebo Low High Series Courtesy of Doug Losordo

19 ACT-34 CMI: SPECT Total Severity Score - Stress Change from baseline at 6 months p= Placebo Low High Series Courtesy of Doug Losordo

20 Cell therapy in cardiovascular diseases Acute Myocardial Infarction Refractory Angina Peripheral arterial occlussive disease Chronic post-infarction heart failure

21 Vorarbeiten zur TAO-Studie Intraarterial BMC therapy for PAOD: a randomized-start, placebo-controlled trial PROVASA-Study

22 Cell therapy in cardiovascular diseases Acute Myocardial Infarction Refractory Angina Peripheral arterial occlussive disease Chronic post-infarction heart failure

23 Aims of cell therapy Acute Infarction Adverse LV Remodeling Chronic Heart Failure Reverse LV Remodeling? Vascularization Apoptosis Paracrine factors Cardiac Regeneration 1. Prevent post-infarction heart failure LV- Dilatation 2. Reverse established heart failure

24 Aims of cell therapy Acute Infarction Adverse LV Remodeling Chronic Heart Failure Reverse LV Remodeling? Vascularization Apoptosis Paracrine factors Cardiac Regeneration 1. Prevent post-infarction heart failure LV- Dilatation 2. Reverse established heart failure Chronic Post-Infarction Heart Failure - Very modest effects on improvement of LV function - Lack of larger randomized controlled trials - Lack of data on clinical outcome with hard endpoints

25 Change in LV ejection fraction absolute (mean ± SEM, %) Moderate improvement in EF is associated with decreased NT-proBNP serum levels after BMC therapy in patients with chronic post-infarction heart failure NT-proBNP serum levels Mean ± SEM [pg/ml] LV-EF NT-proBNP p = p = p = p = BMC N=28 CPC N=26 Control N=18 0 Baseline Follow-up (3 months) BMC therapy; N=61 Assmus et al., N Engl J Med 2006 Assmus et al., Circ Res 2007

26 BMC therapy in CHF effects on mortality? Limited data on efficacy is available that suggest rather small beneficial effects on cardiac function, but there exists no data on mortality. Comparison of observed and model-predicted * mortality in 297 consecutive patients treated with intracoronary BMC infusion. Seattle Heart Failure Model (SHFM): multivariable risk model that predicts all-cause and cause-specific mortality in patients with chronic heart failure, including contemporary pharmacological and device therapies: (validated in 9942 patients from large clinical trials: ELITE2, Val-HeFT, UW, RENAISSANCE, IN-CHF)

27 Predicting Prognosis in Chronic Heart Failure

28

29 Mortality (%) Consistently lower observed mortality than model-predicted mortality throughout 3 years Fup observed model-predicted Val-HeFT Years of Follow Up n =

30 Mortality (%) Estimated cumulative survival [%] Mortality (%) Only repeated intracoronary BMC treatment is associated with lower mortality than SHFM-model predicted mortality Single BMC Administration mean SHFM Score 0.45 ± Single BMC administration Repeated BMC administration Years of Follow Up n = n = Repeated BMC Administration mean SHFM Score 0.48 ± Years of Follow Up P= Years of Follow Up observed Model-predicted

31 Mortality (%) Mortality (%) Cumulative survival [%] Mortality (%) Tertile I (CFU 17.5) (n=95) Tertile II (17.5 CFU 29.5) (n=96) Application of functionally competent BMCs is essential for lower mortality than predicted I Tertile Tertile III (CFU > 29.5) (n=94) 0.80 II Tertile Years of Follow Up P (log rank)= Years follow-up III Tertile

32 Enhancement strategies for cell therapy in chronic heart failure Pretreatment of progenitor cells Recruitment in target tissue Bone marrow Blood Skeletal muscle Adipose tissue Other sources Cell therapy *** * * * ** * * * * * * * * * * * genes small molecules enos enhancer p38 inhibitors PPARg agonist Pretreatment of the target region shock wave pretreatment nanofiber-based delivery Seeger et al, Nat Clin Pract Cardiovasc Med, 2007

33 Stefanie Dimmeler Birgit Assmus Volker Schächinger

34 Klinikum der Johann Wolfgang Goethe Universität Frankfurt am Main Clinician Scientists: J. Honold, R. Lehmann U. Fischer-Rasokat S. Fichtlscherer F. Seeger, C.Kissel S. DeRosa N. Bellera Gotarda Experimental Studies C. Urbich, A. Kühbacher M. Potente A. Aicher E. Chavakis, G. Carmona L. Rössig, D. Scharner M. Koyanagi, M. Iwasaki Th. Ziebart, C. Yoon & technical help (Andrea, Nicole, Ariane, Marion, Tino) T. Brühl, M. Vasa, K. Sasaki, C. Badorff, C. Heeschen Dept. of Hematology H. Martin / W. Hofmann D. Hoelzer Kerckhoff Clinic C. Hamm / T. Dill Dept. of Radiology N. Abolmaali / J. Schmitt T. Vogl Red Cross Frankfurt T. Tonn / Seifried