Autologous S tem Cell Therapy In Patients with Non- Reconstructable Critical Limb Ischemia Karl R S tark MD F ACS North Kansas City Hospital
DIS CLOS URES • Karl R. Stark, M.D. has disclosed that he is an investigator for Harvest and LifeCells Therapy with no personal relevant financial relationship.
DIS CLOS URES The following listed CME Advisory Committee members have disclosed that they do not have any relevant financial or other pertinent relationships with proprietary entities producing healthcare goods or services related to the content of this activity. Michael W. Farrar, M.D., Chair Gary L. Carter, M.D. Iris A. Comes, M.D. S arah J. Hon, D.O. Jay W. Kimball, M.D. James L. S tewart, M.D. Todd P . Hill, D.O. has disclosed that he is listed on the S peaker’s Bureau for Teva, Forrest Pharmaceuticals, and Otsuka Pharmaceuticals. William W. Pingleton, M.D. has disclosed that he is a Consultant for Oncimmune.
OVERVIEW • Define Critical Limb Ischemia; (CLI) • Natural history of CLI • Treatment option for patients with CLI • Patients with no reconstruction options • Types of stem cell therapy, and what type is used clinically • Evolution of stem cell therapy in patients with CLI • Two current autologus stem cell therapies being used at NKC Hospital
CRITICAL LIMB IS CHEMIA • Define as limb threatening ischemia of the lower extremity that has been present for several weeks if not months. It is the most severe form of peripheral arterial disease. • S eparate it from acute limb ischemia; in the duration of the process; and the underlying etiology is different. Acute limb ischemia is usually embolic or thrombotic occlusion of the arteries of the leg.
TREATMENT OF ACUTE LIMB IS CHEMIA • Intervention • Use combination of endovascular and open techniques to restore flow. • Unless flow can be immediately successfully restored the limb will be lost. • Common presentations are embolic sources from the heart such as in atrial fibulation, or thrombosis of underlying arterial disease.
CHRONIC PERIPHERAL ARTERIAL DIS EAS E • In Europe and North America 27 million people affected; worldwide 202 million. • 23.5% increase in incidence in the last 10 yrs. • Most patient have mild if any symptoms; 1 in 4 are symptomatic. • The severity of patient’s P AD directly correlates with the risk of cardiovascular events and death.
P ATIENT PRES ENTED WITH S EVERE FOOT P AIN Patient has palpable DP pulse around the ankle area
TYPICAL APPEARANCE OF LOWER EXTREMITIES IN A P ATIENT WITH CHRONIC S ERVERE ARTERIAL INS UFFICENCY -Thin, pale appearing skin -Patchy, irregular areas of marginally viable tissue distinguish embolization from a more generalized severe arterial flow pattern
TYPICAL APPEARANCE OF IS CHEMIA FROM EMBOLIZATION Appearance shows splotchy areas of ischemia, rather than diffuse distal tissue involvement seen in purely arterial-ischemic patients
RANGE OF S EVERITY OF PERIPHERAL ARTERIAL DIS EAS E • S everal classification scales range from no symptoms to non-salvageable limbs. • Appropriate treatment is based on the severity of the disease • All patients receive medical therapy • Intervention is reserved for more severely affected patients
MEDICAL THERAPY FOR P ATIENTS WITH PERIPHERAL ARTERIAL DIS EAS E • S moking Cessation • S upervised Walking Programs • S tatin Therapy • Antiplatelet Therapy • Weight Loss Therapy • Diabetes Management • These Therapies and Others to Lower the Overall Cardiovascular mortality Risk
DO THES E THERAPIES CHANGE OUTCOMES ? • S moking cessation alone doubles the life-span compared to a patient with peripheral arterial disease that smokes. • For patients undergoing interventions for peripheral arterial disease, the risk of failure is three times greater for those who continue to smoke. • Quick found in 244 patients with claudication, 8% progression to CLI in patients who quit smoking and a 79% progression in those who did not. * S tatins have a much more profound affect then simply helping lipid profiles. S tatin therapy reduces the risk of progression of disease, as well as increases walking distance in patients with claudication
CRITICAL LIMB IS CHEMIA: CLI MOS T S EVERL Y AFFECTED P ATIENT • 25% of patients with CLI die in one year Greater then 40% by five years. • One year amputation rate is 25% • Mortality risk for BKA 5% to 10% ; AKA 10% to 15% • Quality of life generally falls with amputation • Chances of independent living fall with an amputation.
APPROPRIATE THERAPY FOR CLI • Medical therapy • Revascularization if possible. • Non-viable extremities undergo early amputation. • Overall mortality is less if the extremity can be saved. * For revascularization; use a combination of endovascular and open techniques to improve arterial flow.
Patient with CLI and renal insufficiency CO2 arteriogram identifies chronic superficial femoral artery occlusion
Results of intervention S uccessful restoration of flow for treatment of patient’s CLI
FEMORAL-POPLITEAL BYP AS S FOR LIMB S AL VAGE Bovine carotid artery conduit used when autologous vein is not available for bypass
NON-DIRECT REVAS CULARIZATION TREATMENT OPTIONS FOR P ATIENTS WITH CLI Patients with CLI and no revascularization options
Pattern of Arterial Disease in Treated Patients Typical arterial disease pattern in patients with non-reconstructable arterial disease with critical limb ischemia and threatened limb loss. CT arteriogram showing non flow limiting proximal disease and severe tibial and plantar disease with no named arteries in distal leg and foot.
Patient with CLI and no reconstructable arteries; treated with HBO
HYPERBARIC OXYGEN THERAPY FOR CRITICAL LIMB IS CHEMIA • Group of patients with CLI and threatened limbs that could not undergo revascularization • The group that received HBO had a higher limb salvage rate and were twice as likely to heal their ischemic wounds • Mortality was also lower in the group that received HBO
S URVIVAL OF P ATIENT WITH CLI AND NON- RECONS TRUCTABLE ARTERIAL DIS EAS E Long Term Patient Survival 100% 80% 52% 60% 30% 40% 20% 0% Hyperbaric Oxygen Treatment Non-Treatment Group Group
EVOLUTION OF CELL THERAPY FOR ARTERIAL DIS EAS E: Inadequate results from other treatment modalities • Treatment of a specific group of patients in whom arterial reconstruction is not possible • Other modalities used include compression devices with limited success • Infusion of prostaglandins (beraprost) • S ympathectomy • S pinal cord stimulation • Vasodilators
GOAL: INDUCE ANGIOGENES IS • Change the balance between angiogenesis and angiostasis • Introduce new factors to stimulate angiogenesis • Induce arterial collateral formation • Introduce new cells to develop arteries
ARTERIAL AND ANGIOGENES IS GROWTH F ACTORS • Gene transfer by viral transfer, plasmid attachment, or bare DNA • Most used as intramuscular inj ections • Factors used include fibroblast growth factor 1, vascular endothelial growth factor, hypoxia-inducable factor 1, hepatocyte growth factor, and naked DNA forms of hepatocyte growth factor • Meta– analysis shows benefit from these factors
S TEM CELLS • Primary stem cells are embryonic • Embryonic cells are totipotent and may differentiate into the three germ layers: ectoderm, endoderm and mesoderm • Differentiation path is to multipotent stem cells • Multipotent stem cells are dedicated to specific tissues and organs, and farther differentiate to progenitor adult stem cells
ADULT S TEM CELLS LOCATION • Found in the postnatal bone marrow, blood, skeletal muscle, fatty tissue, and heart • Adult bone marrow contains differentiated cells, such as monocytes, lymphocytes, fibroblast, adipocyte, chondroblasts, osteoblast, and osteoclasts, as well as a group of undifferentiated cells. The extracellular matrix contains cytokines and growth factors. • Differentiated centrifugation can separate cells into subgroups • Now can separate even these stem cells into their tissue specific types.
PROBLEMS WITH EMBR YONIC S TEM CELLS US E IN THERAPY • Moral issues surrounding fetal source of cells • Potential for uncontrolled differentiation can lead to neoplasms • Use can lead to graft vs. host reaction; immunosuppression is required • Currently, use not supported by FDA
EVOLUTION TO CELL THERAPY • Early trials show greater potential then factor use • Religious and moral beliefs direct research toward autologous source of stem cells • Cell culturing risk: decreasing the activity of the desired beneficial effect, and risk development of the undesired side-effects • FDA has directed research toward autologous, non-cultured cells
CULTURED ADULT S TEM CELLS • FDA ’s general position is that with culturing cells, their effect may change • Can lead to ineffectivity for original therapy goal • Can lead to undesirable changes in cell function
CURRENT S TEM CELLS FOR TREATMENT OF CLI • Autologous bone marrow source • S pecifically the patient receives their own stem cells • Avoid moral, and neoplastic issues with embryonic cells • S tudies have shown this line of cells to be safe for patient treatment
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