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)
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
Cell therapy in cardiovascular diseases Acute Myocardial Infarction Refractory Angina Peripheral arterial occlussive disease Chronic post-infarction heart failure
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 + 3.7 percentage points increase in LV-EF ( p < 0.001 ) Abdel-Latif, Arch Intern Med 2007; 167:989
Absolute change in global LVEF ( %) Enhanced contractile recovery by BMC is confined to patients with failed initial recovery 10 p for interaction = 0.020 p = 0.002 p = 0.81 8 6 4 2 Baseline LVEF by QLVA 0 2.5 1.1 7.5 1.1 3.7 0.7 EF below median ( 48.9 %) 4.0 0.6 Placebo BMC Placebo BMC n = 52 41 40 54 EF above median (> 48.9 %) Schächinger et al., N Engl J Med 2006
Enhanced contractile recovery by BMC in patients with failed initial recovery results of recent controlled trials Change in EF (%) REGENT trial REGENT FINNCELL trial 80 70 60 50 Controls N=20 p=0.73 80 60 70 BMC < median N=46 39 39 50 37 40 60 40 50 p=0.01 p=0.007 31 36 30 25 20 15 < median > median p = 0.04 BMC Placebo 40 30 20 10 40 30 30 20 20 10 0 6 months 0 6 months Courtesy of M Tendera, European Heart Journal, 2009 10 5 0-5 Courtesy of H. Huikuri, European Heart Journal, 2008
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 = 0.01 120 p = 0.06 100 p = 0.7 80 60 40 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: 39 + 1.9 % Baseline EF: 56 + 2.3 % Dill et al., AHJ 2009
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.
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 - 100 90 BMC 80 Placebo 70 p = 0.009 (log rank) 60 0 0 100 200 300 400 500 600 700 days # exposed to risk Placebo 103 93 90 86 86 BMC 101 99 98 97 95 CirculationHeartFail 2009
BMC Therapy in Acute Myocardial Infarction Insights into potential mechanisms of action?
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
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)
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 = 0.005 0,8 p = 0.021 2,0 1,5 0,6 1,0 0,4 0,5 0,2 0,0 0.88 0.18 1.8 0.25 0,0 0.11 0.06 0.49 0.11 Placebo BMC Placebo BMC n = 26 n = 28 Erbs et al., Circulation 2007 n = 26 n = 27
Cell therapy in cardiovascular diseases Acute Myocardial Infarction Refractory Angina Peripheral arterial occlussive disease Chronic post-infarction heart failure
Cell Therapy for Refractory Angina JAMA, May 2009
Cell Therapy for Refractory Angina JAMA, May 2009
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 5 21-80 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
Seconds ACT-34 CMI: Increase in Exercise Time 160 140 120 100 80 60 40 20 0 Total ETT Time Change from baseline at 6 months p=0.013 Placebo Low High Series1 69 138 108 Courtesy of Doug Losordo
50 0-50 ACT-34 CMI: SPECT Total Severity Score - Stress Change from baseline at 6 months -100-150 p=0.002-200 Placebo Low High Series1 8.5-113.2 11.6 Courtesy of Doug Losordo
Cell therapy in cardiovascular diseases Acute Myocardial Infarction Refractory Angina Peripheral arterial occlussive disease Chronic post-infarction heart failure
Vorarbeiten zur TAO-Studie Intraarterial BMC therapy for PAOD: a randomized-start, placebo-controlled trial PROVASA-Study
Cell therapy in cardiovascular diseases Acute Myocardial Infarction Refractory Angina Peripheral arterial occlussive disease Chronic post-infarction heart failure
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
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
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 = 0.001 3 2 p = 0.38 2.500 2.250 p = 0.033 1 2.000 0-1 p = 0.03 1.750 1.500-2 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
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)
Predicting Prognosis in Chronic Heart Failure
Mortality (%) Consistently lower observed mortality than model-predicted mortality throughout 3 years Fup 25 20 15 10 5 observed model-predicted Val-HeFT 0 1 2 3 Years of Follow Up n = 295 244 202
Mortality (%) Estimated cumulative survival [%] Mortality (%) Only repeated intracoronary BMC treatment is associated with lower mortality than SHFM-model predicted mortality 25 20 15 10 5 Single BMC Administration mean SHFM Score 0.45 ± 0.9 1.00 Single BMC administration Repeated BMC administration 0 1 2 3 Years of Follow Up n = 189 158 132 0.95 0.90 30 20 10 0 n = Repeated BMC Administration mean SHFM Score 0.48 ± 0.9 1 2 3 Years of Follow Up 106 86 70 0.85 P=0.048 0 0 1 2 3 Years of Follow Up observed Model-predicted
Mortality (%) Mortality (%) Cumulative survival [%] Mortality (%) 30 25 20 15 10 5 0 25 20 Tertile I (CFU 17.5) (n=95) 1 2 3 Tertile II (17.5 CFU 29.5) (n=96) Application of functionally competent BMCs is essential for lower mortality than predicted 1.00 15 10 5 0.90 I Tertile 0 20 16 1 2 3 Tertile III (CFU > 29.5) (n=94) 0.80 II Tertile 12 8 4 0 1 2 3 Years of Follow Up 0.70 0 P (log rank)=0.02 0 1 2 3 4 Years follow-up III Tertile
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
Stefanie Dimmeler Birgit Assmus Volker Schächinger www.repair-ami.org
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