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Heart to Heart Luncheon
Presenting
Dr. Ramin Beygui Director Cardiac, Thoracic, and Vascular Surgery
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Novel Technology in
Cardiovascular Surgery
Presented by
Dr. Ramin Beygui Director Cardiac, Thoracic, and Vascular Surgery
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Coronary Artery Bypass Graft
• 1946, Vineberg, Implanted bypass to myocardium
• 1953, Gibbon Jr., Developed Heart-Lung Machine
• 1954, Murray: Systemic Artery to Coronary anastomosis
• 1958, Longmire: Coronary endarterectomy IMA to RCA bypass
• 1962, Sones & Shirey: Cine Coronary Arteriography
• 1967, Kolessov: IMA coronary anastomosiss for angina, in 6 Patients, without CPB
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Off-Pump CABG
Shumacker (1983) credits Longmire with the first internal
mammary to coronary artery anastomosis. “It was almost
surely Longmire, long-time chairman at U.C.L.A. and his
associate, Jack Cannon, who first performed an
anastomosis between the internal mammary artery and a
coronary branch, probably in early 1958”
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Off-Pump CABG W. Dudley Johnson, one of the pioneers in the
development of coronary artery surgery, wrote, “From
1962 to 1967, several sporadic instances of coronary
grafting have subsequently been reported. All were
isolated cases and, for uncertain reasons, were not
reproduced. None had an impact on the development of
coronary surgery”
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Green GE, Stertzer SH, Reppert EH Coronary arterial bypass grafts. Ann Thorac Surg 1968; 5: 443
• Green et al. advocated using cardiopulmonary bypass (CPB), fibrillating the vented heart, cross clamping the aorta, and washing all blood from the coronary system while performing the anastomosis.
• 1970s: CABG on CPB with cold cardioplegia : “GOLD STANDARD”
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Coronary Artery Bypass Graft
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Coronary Artery Bypass Graft
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Coronary Artery Bypass Graft
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Cardiopulmonary Bypass
• Adsorbed Proteins from Heparinized Blood • Activation of Blood Elements
– Contact System: XII,XI, Prekallekrein, HMWK – Complement System: C3a, C5a – Intrinsic Coagulation pathway, Extrinsic
Coagulation Pathway – Fibrinolysis – Platelets
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Off-Pump CABG
• Minimally Invasive Direct Coronary Artery Bypass (MIDCAB) by Cardiothoracic Systems
• The Octopus System was devised by Medtronics
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Off-Pump CABG Coronary Shunting
• Reduces Coronary Occlusion Time
• May Avoid Ischemic Pre-conditioning
• Reduces the Risk of Dysrhythmias
• Allows More Time for Anastomosis
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Off-Pump CABG Shunt Insertion
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Off-Pump CABG Shunts
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Indications for Off-Pump CABG
• Feasibility of Optimal Revascularization* • Reason to Avoid CPB:
– Cerebrovascular disease – Diseased Ascending Aorta – Jehovah’s Witness ?
– *Circumflex Branches were initially deemed inaccessible for
OPCABG
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Conclusion: • OPCABG can be done safely with
significant morbidity <2% and mortality <1.5%
• With improved stabilization techniques and coronary shunting full re-vascularization, including circumflex Branches, is feasible
• It can be done safely in the elderly
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Conclusion:
• It can be done safely in urgent cases
• It can be done safely in patients with low EF
• Early graft patency is comparable to CABG on CPB
• It may reduce hospital charge
• Long-term durability of OPCABG is yet to be determined
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Application of Robotics • Small incisions
• Significantly reduced patient pain
• Shorter hospital stays
• Applicable for beating-heart and stopped-heart approaches
• Improved surgeon precision and dexterity
• Improved visualization in 2-D or 3-D
• Minimized surgeon fatigue with an ergonomic operating environment
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Atrial Fibrillation Surgery: Minimally Invasive
• If concomitant surgery is not needed, atrial fibrillation can be treated using minimally invasive techniques
• Ablation to eradicate atrial fibrillation
• Video Assisted Thoracoscopy, beating heart or hybrid procedures
– Dual Epicardial Endocardial Persistent Atrial Fibrillation (AFib) Study (DEEP Trial)
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Stent-Graft Repair of Aortic Aneurysms, A Review
• Single Piece Tapered Stent-Graft for AAA Repair
• Single Piece Stent-Graft for descending TAA Repair
• Bifurcated Modular Stent-Graft for AAA Repair
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Abdominal Aortic Aneurysm Incidence
• Autopsy 1.5-3.0%
• Unselected Ultrasound Screening 3.2%
• Selected Patients with CAD 5.0%
• Selected Patients with PVOD 10.0%
• Femoral/Popliteal Aneurysms 50.0%
• Men 80-85 6%
• Men/Women >70, Hypertensive 11-12%
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Aortic Aneurysm Etiology
• Degenerative/Atherosclerotic
• Cystic Medial Necrosis
• Dissection
• Ehlers-Danlos Syndrome
• Collagen Vascular Disease
• Mycotic
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Aortic Aneurysm
• Natural History of Thoracic and Abdominal Aortic Aneurysm: Increasing Diameter & Rupture
• 15000 deaths/year in USA due to AAA rupture (13th leading cause of death)
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Abdominal Aortic Aneurysm
Incidence of Ruptured Aneurysms at Autopsy
Aneurysm Size % Ruptured <4cm 10 4.1-5cm 23.4
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Operative Mortality and Late Survival of Elective AAA Repair
Patients Age Mortality 5-yr. Survival (n) (yrs) (%) (%) Whittemore 110 68 0 84 (1980)
Crawford 860 66 5 63 (1981)
Reigel 499 76 3 66 (1987)
Bernstein 123 71 1 72 (1988)
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Operative Morbidity of Elective AAA Repair
Patients *Major Morbidity (n) (%)
Johnston et al, 202 30% 1989 (multicenter)
Cambria et al, 666 15% 1992 (single institution)
*cumulative
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• In good-risk patients, aneurysms > 5 cm in diameter are best treated by replacement with a prosthetic graft. – Operative mortality should be < 5% 1-year survival
> 90%.
– Aortic endograft techniques must meet or exceed these standards if they are to supplant standard surgical repair”
• Aneurysms 4-5cm documented 0.5cm increase in diameter in 6 months
• Aneurysms 2 x the diameter of infrarenal neck or saccular J Endovasc Surg 1997 Aug;4(3):232-41 Operative repair for aortic aneurysms: the gold standard.
Zarins CK, Harris EJ Jr Department of Surgery, Stanford University Medical Center, California 94305-5450, USA.
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AAA Repair with
Single Piece Tapered Stent-Graft
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Stent-Graft Repair of
Thoracic Aortic
Aneuryms
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Bifurcated Modular
Stent-Graft Repair
of AAA
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New Developments
in the
Treatment of Heart Failure
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Heart Failure Demographics •Over 4.8 million Americans with heart failure
•Over 400,000 new cases per year
•Most common of all Medicare admission DRG’s
•Over 240,000 deaths per year
•Most common cause is Coronary Artery Disease *about 2 / 3
•Severe heart failure - Heart Transplants + 5,000 listed + 2,500 tx’d per year
•Candidates for mechanical devices as destination 40,000 to 80,000
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End Stage Heart Disease Therapeutic Options
•Medical Management
•Conventional Surgical Procedures
•Innovative Surgical Procedures
•Heart Transplantation
•LV Assist Devices
•Artificial Heart
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Relative Risk
2yr Mortality
None 35%
ACE Inhibitor ↓ 23% 27%
Aldosterone Antagonist ↓ 30% 19%
Beta Blocker ↓ 35% 12%
ICD (CAD, EF<30%) ↓ 31% 8.5%
Cummulative risk reduction if all four therapies are used: 75% Absolute risk reduction: 26.5% Moss et al. NEJM 2002
ACE b ?
Surv
ival
Time (years)
Drug Placebo
Al
Cumulative Impact of Heart Failure Therapies
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Ischemic Cardiomyopathy Treatment Alternatives
Medical Therapy Transplantation Revascularization
Angiogenesis Tissue Regeneration/Tissue Engineering
Stem Cell Therapy
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ETIOLOGY OF END-STAGE CARDIAC FAILURE
• ischemic heart disease
• idiopathic dilated cardiomyopathy.
• infectious (viral), inflammatory, toxic, metabolic, postpartum and familial
• valvular heart disease
• congenital heart disease
• Intractable angina, refractory malignant ventricular arrhythmias, allograft occlusive coronary artery disease
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Heart Failure
• Over 4000 patients awaiting heart transplant in USA
• Over 700 people die while on transplant list annualy
• Over 40,000 patients with heart failure die or never listed for transplantation
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Ventricular Assist Devices
• To prevent or reverse end –organ dysfunction due to heart failure
• Used as bridge to recovery (example myocarditis)
• Used as bridge to transplantation
• Used as target
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Thoratec Ventricular Assist Device
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Thoratec Ventricular Assist Device
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Abiocor Total Artificial Heart
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Abiocor Total Artificial Heart
This artificial heart system uses a hydraulic motor, powered by batteries.
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SynCardia Temporary Total Artificial Heart
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Jarvik Ventricular Assist Device
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HeartWare Left Ventricular Assist Device
HeartMate II Left Ventricular Assist Device
Left Ventricular Assist Devices for Heart Failure
• Bridge to Recovery • Bridge to Transplant • Bridge to Eligibility
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Cardiovascular Tissue Engineering and Tissue
Regeneration
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Delivery Options for Stem Cell Transfer Modalities to the Heart
BE Strauer and R Kornowski, Germany, Circulation 2003.
The red colored area represents apical lesion of the left ventricle by myocardial infarction. Blue and green arrows suggest the possible
route of cell infusion and migration into the infarct.
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ASCs Home to Heart After Injury MI induced
(LAD occl or cryo)
Stem cells injected into circulation
+
Stem cells injected
intraventricular
β-Gal positive myocytes identified
Assessment of LV Function
2.50
3.50
4.50
5.50
ESD
(mm
)
LVEF LVEDD 40
50
60
70
80
90
% E
F
4 weeks Post-MI
Control Saline ADCs
*
* ** **
β-Gal positive ADCs isolated
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Cell transplantation improves LV Function Post-MI
Autologous Atrial Appendage, Cryolesion, Tx 3W, 2 × 106 cells, n = 12 rats T. Sakai et. al. Ann Thorac Surg 68:1999, 2074 Contractility Relaxation
0
200
400
600
800
1000
1200
1400
1600
+dP/dt -dP/dt
No InfarctPost M.I.Post M.I. + Cell Tx
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How does cell transplantation work? Direct
• Many cell types which do not contract improve function
• Skeletal myocytes are not coupled electrically by gap junctions
• Regenerate contractile muscle
Indirect
• Cell transplantation leads to stabilization of the scar preventing infarct expansion and subsequent LV remodelingmatrix secretion
• Induction of angiogenesis
• Paracrine action of transplanted cellsAnti-apoptotic
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Cell Types Utilized for Cell Transplantation
• Skeletal Myoblasts
• Adult Stem/Progenitor Cells
• Bone Marrow Stem Cells
• Endothelial Progenitor Cells (EPCs)
• Adipose Tissue-derived Stem Cells (ASCs)
• (Embryonic Stem CellsEthical Issues)
• Induce Pluripotent Stem Cell
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CABG and Cell Transplantation • 24 subjects total • 10 million cells • 30 million cells • 100 million cells • 300 million cells
LVAD and Cell Transplantation • 6 subjects total • 300 million cells
3 to 30 sites are injected. Each 0.1 ml injection has 10 million cells per injection
Myoblast Transplantation
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Serious Adverse Events DSMB determined unrelated to Cell Injections*
CABG • Mortality- 1* • Arrhythmia- 4* • AICD ACTIVATION 1 • Pneumothorax 1* • Infection 1* • Infarction 1* • CVA 2*
LVAD • Mortality- 3* • Arrhythmia- 2* • AICD ACTIVATION N/A • Pneumothorax 0 • Infection 3* • Infarction 0 • CVA 1
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Non-sustained Ventricular Tachycardia • 3 patient (100 x 106 dose group) 1 week post
transplant.
• ICD implantation performed
• No further Arrhythmias detected during interrogation of ICD at 6-months follow-up.
Adverse Events Possibly related to Cell Injection
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Trichrome
Skeletal MHC
(MY-32)
FDG Uptake
Baseline
6 mo f/u
Inferior
Apex
Anterior
Myoblast Stably Engraft in Human Myocardium
3 months Post-Tx Myoblast + with LVAD listed for OHTXP
Pagani et al, JACC 41-2003
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CD31 Staining
# C
D-3
1 +
vess
els
Scar Transplant
72
226
* P<0.0001
Baseline
6 month follow-up
Apex
Septum Lateral
Wall
Perfusion
Engrafted Myoblast Induce Angiogenesis
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Associated with a decrease in NYHA Classification from an average of 2.1 Pre-CABG to 0.8 Post-CABG
Menasche P, J Am Coll Cardiol 2003 Apr 2;41(7):1078-83
10
20
30
40
50
60
Baseline Week 12
EF
(%)
10 million 30 million 100 million 300 million
Effect of CABG + Myoblast Transplantation on EF
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Control Group
# of pts
Delivery Method
Dose Revasc Outcomes
Dib et al. None 30 Transepicardial (during CABG)
0.1-3X108
Yes Global EF ↑ Perfusion/Viability in Infarct Area ↑
Menasche et al.
None 10 Transepicardial (during CABG)
9X108 Yes Global EF ↑ Regional Wall Motion Global EF ↑ Increased VT
Herros et al. None 11 Transepicardial (during CABG)
1.9X108 Yes Global EF ↑ Regional Wall Motion Global EF ↑ Viability in Infarct Area ↑
Chacques et al. None 20 Transepicardial (during CABG)
34X108 Yes Global EF ↑ Regional Wall Motion Global EF ↑ Viability in Infarct Area ↑
Smits et al. None 5 Transendocardial* (NOGA catheter)
3X108 No Global EF ↑ Regional Wall Motion Global EF ↑ 1 pt developed VT
Siminiak et al. None 10 Catheter Base (Coronary Sinus)
0.004-0.5X108
Yes Global EF ↑ Regional Wall Motion Global EF ↑ 4 pts developed sustained VT
Published Clinical Trials of Myoblast Transplantation
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Skeletal muscle
Smooth muscle
Bone Marrow Mesenchymal
stem cells
Cardiac muscle
Bittner et al., Anat Embryol 1999;199:391-6.
Adult Stem Cells are an Alternative Source of Cells
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18 pigs underwent permanent coronary artery occlusion Received ~8x107 BMC or vehicle IC 1 month post-MI
Time (months) -2 -1 0 1 2 3
Ejec
tion
frac
tion
(%)
36
40
44
48
52
56
60
64
Cell Tx Control
n=4 n=3
n=10
n=5
n=8
n=8
n=10
n=10
*
Cell Transplantation
*
Bone Marrow Cells Improve LV Function Post-MI
Rates of differentiation to cardiac myocytes range from 0% to 60-80% in the infarcted region
Shake et al, Ann Thorac Surg. 2002
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Fusion:
Stem Cell Myocyte
Differentiation:
Stem Cell Myocyte
Liver
Nerve
Differentiation vs. Fusion of Stem Cells
+ Rates of fusion of
delivered stem cells to endogenous
cardiac myocytes range from 0% to
~50% in the infarcted region
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Control Group
End point
Length of F/U (mon)
Time to cell
infusion
N LVEF Baseline
LVEF End point
% LVEF Increase
p
Schächinger et al.
None LVEF 4 4.3 dy CPC 30 51 59 15.7%
BMC 29 49 57 12.2% <0.001
Strauer et al. PCI alone LVEF 3 5.9 dy Control 10 60 64 4.0% NS
BMC 10 57 62 5.0% NS
Wollert et al. PCI alone LVEF 6 4.8 dy Control 30 51.3 52 0.7% NS
BMC 30 50 56.7 6.7% 0.003
Chen et al. PCI alone LVEF 6 18 dy Control 35 49 54 5%
BMC 34 48 67 19% 0.01*
Assmus et al (TOPCARE-
AMI)
PCI alone LVEF 48 4.5 dy Control BMC CPC
20 11 9
51 52
53 60
0.003
Human Trials of Stem/Progenitor Cells Post-MI
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Stefan Janssens et al The Lancet, Volume 367, Issue 9505, 14 January 2006-20 January 2006,
STEM CELL Tx Post-MI
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Stefan Janssens et al The Lancet, Volume 367, Issue 9505, 14 January 2006-20 January 2006,
STEM CELL Tx Post-MI
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Stefan Janssens et al The Lancet, Volume 367, Issue 9505, 14 January 2006-20 January 2006,
STEM CELL Tx Post-MI
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Stable Ischemic Heart Disease, Transcoronary Infusion, No cell (23 patients) CPC (24 patients)
BMC (28 patients) Assmus B, NEJM, 2006, Sept 21, 355(12)
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Unanswered Questions
• Issues of dose, timing, delivery route and optimal cell type remain unresolved?
• Optimal source of donor stem cells is unknown and clinical utility of Skeletal Myoblasts vs. BMCs vs. “off the shelf” MSCs?
• What is the risk of ventricular arrhythmias?
• Mechanism of action of transplanted cells?
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B. Clonal Analysis Adipogenic Osteogenic Chondrogenic
Tri: (A, O, C) 7 of 33
Dual: (A, C) 3 of 33
Dual: (O, C) 10 of 33
Dual: (A, O) 10 of 33
Single: A only 6 of 33
• Sca1+, cKit-, Stro-1lo
• Similar to BM-MSC – CD13+,CD29+,CD44+ – CD11c-, CD45-
• Distinct from BM-MSC – CD106-, CD54+, CD34lo
A. Stem Cell Markers
Adipose Tissue Contains a Stem Cell
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Human/ Animal
Preclinical ?
ADC
Human Lipoaspirate
Human In Vitro
Adipose Cardiac Sk Muscle Cartilage Bone Angiogenesis
Human Adipose Tissue Contains a Multipotent Stem Cell
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Conclusion • Heart Failure Treatment is Mainly Symptom
Management
• Heart Transplantation is the ONLY curative option
• Heart Txp is limited by organ shortage, immunologic rejection, and immunosuppression
• Evidence for Autologous Cell Therapy & Tissue Regeneration is Promising
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Tissue Engineering’s Most Popular
Approach is Based on the Premise that
Preparation of Cells, Extracellular Matrix,
and Growth Factors Leads to Tissue
Reconstruction, and that 3-dimensional
Biodegradable Scaffolds are Useful
Alternatives for Extracellular Matrix
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TGFβ FGF Hemo-dynamic
Polymers Gels Fibers Membranes
Cultivated Adult Stem Cells Embryonic stem cells Autogenous Mobilized Allogenic Engineered
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1. Vascular grafts 2. Heart valve prostheses 3. Cardiac muscle grafts
Three Areas of Cardiovascular Tissue Engineering
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Campbell JH et all, 1999
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Hoestrup SP, et al 2000
Pulse Duplicator Bioreactor
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Figure 3. TE heart valve after 14 days of conditioning in bioreactor.
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