Cardiopulmonary Transplantation
Charles Hoopes MD
Associate Prof Surgery
University of Kentucky
Jan 2011
Brief history of “the operation” … surgical education (1960 to 1968)
Barnard CN. The operation. A human cardiac transplant:
an interim report of a successful operation performed at
Groote Schuur Hospital, Cape Town. S Afr Med J 1 967;
41 (48): 1 271 –1 274.
Evolving role of mechanical cardiopulmonary support … clinical practice
Novel applications of solid thoracic organ transplant … basic science
extended donor/extended recipient and
allograft biology
Kantrowitz
Barnard
Lillehei
DeBakey
Lewis
Lower
Shumway
Cooley
Historical development of extracorporeal gas exchange and
circulatory support..
1812 Le Gallois “parts of the body may be preserved by external perfusion”
Brown-Sequard (from 1848 -1858) “loss of rigor mortis in guillotined prisoners by perfusion with
their own blood”
Guillotined head of a dog in perfusion
experiments of Brukhonenko and Tchetchuline.
This preparation relied on gas exchange from a
second donor dog's lungs. Diaphragm-like pumps
pumped blood into the recipient dog's carotid
arteries. Dog heads perfused in this manner
remained functional for a few hours. (Reprinted
from Brukhonenko S, Tchetchuline S. Experiences
avec la tete isolee du chien.1.Technique et
conditions des experiences. J Physiol Pathol Gen
1929;27:42)
..a “biological oxygenator”
3 October 1930
“..at 8AM respirations ceased and the blood pressure could not be
obtained. Within 6 min and 30 sec Dr. Churchill opened the chest,
incised the pulmonary artery, extracted a large pulmonary embolus, and
closed the incised wound..”
“the idea occurred to me if it were possible to remove continuously some
of the blue blood from the patient’s swollen veins, put oxygen into the
blood and allow carbon dioxide to escape from it, and then to inject
continuously the now red blood back into the patients arteries, we might
have saved her life. We would have bypassed the obstructing embolus
and performed part of the work of the patients heart and lungs outside
the body.”
Gibbon JH Jr. The maintenance of life
during experimental occlusion of the
pulmonary artery followed by survival. Surg
Gynecol Obstet 1939;69:604
Miller BJ, Gibbon JH Jr, Gibbon MH. Recent
advances in the development of a mechanical
heart and lung apparatus. Ann Surg
1951;134:699
1953 Cecelia Bavolek (closure of ASD)
Gibbon-IBM II “screen oxygenator”
JH Gibbon
Biological oxygenators..
28 operations on children between
1951 and 1956 using a “monkey
lung” oxygenator, 3 survivors..
WT Mustard
Monkey's Lung Used In Heart Operation
(TORONTO, 9 June 1952)
A 19-months-old Peterborough girl today
underwent a heart operation during which her
blood passed through a lung removed from a
monkey. The operation was performed on
Lucinda Rowe by Dr.W.T. Mustard, Toronto
heart surgeon. The monkey's lung was chosen as
the temporary artery for the patient's blood
because it most closely resembles a human lung.
The operation had never been successful in
Canada before, but has been performed at the
University of Minnesota where the blood of a
boy was pumped for 15 minutes through a lung
removed from a dog.
Biological oxygenators..
45 operations on children
between 1954 and 1955 using
controlled cross circulation…
28 survivors (ASD,VSD,TOF)
W Lillihei
..to mechanical oxygenators at the University of Minnesota
DeWall “bubble oxygenator”…
first used in May 1955
VSD repair 1955
BLTx 2005
DeWall oxygenator
“I awoke with a simple solution ..cool the whole body,
reduce the oxygen requirement, interrupt the
circulation, and open the heart.”
“Cold Hearts”
WG Bigelow
University of Minnesota
1950’s
Hypothermic circulatory arrest or
cardiopulmonary bypass ?
Lewis and Taufic (1952) Closure of atrial
septal defects with aid of hypothermia:
experimental accomplishments with the
report of one successful case. Surgery
33:52
SELECTIVE HYPOTHERMIA OF THE
HEART IN ANOXIC CARDIAC ARREST
NORMAN E. SHUMWAY, M. D., RICHARD R. LOWER,
M. D., and RAYMOND C. STOFER, D. V. M., San
Francisco, California
STUDIES ON ORTHOTOPIC HOMOTRANSPLANTATION
OF THE CANINE HEART *
RICHARD R. LOWER, M. D., AND NORMAN E. SHUMWAY, M.D.
“if the immunologic mechanisms of the host were
prevented from destroying the graft, in all
likelihood it would continue to function adequately
for the normal life span of the animal.”
No significant manuscripts ‘61
Anton Refregier 1961 UK
James D Hardy, MD
Lung homotransplantation in man.
Hardy, Webb, Dalton, Walker
JAMA (1963) 186:1065
11 June 1963
John Richard Russell, 58, was serving a life
sentence for murder in Mississippi State
Penitentiary at Parchman when he developed
squamous cell cancer in his left lung, pneumonia
in his right lung, and renal insufficiency.
* terminal illness
* recovery of functional quality of life
* antecedent laboratory survival
Survival for 18 days, death from kidney failure
with no rejection of the allograft at autopsy…
lung transplantation re-emerged 20 years later
with Joel Cooper and the Toronto Lung
Transplant Group (#45,Tom Hall, 7 Nov 1983)
In Jan of 1964 James Hardy consented
the sister of Boyd Rush – a 68 yo comatose
deaf mute with ischemic heart failure and
lower extremity gangrene – for “the insertion
of a suitable heart transplant if such should
be available..”
In the absence of a legal definition of
“brain death” potential donors of hearts had
to “die a cardiac death” – given the required
short ischemic time, cardiac transplantation
would require the simultaneous “death” of a
donor and “near death” of a recipient.
On 23 Jan Rush decompensated and
was placed on cardiopulmonary bypass.
In the absence of a viable donor Hardy transplanted the heart of
a 45 kg chimpanzee (“Bono”). The heart provided hemodynamic support
for 90 minutes but of insufficient size to maintain an adequate cardiac output.
The transplanted heart demonstrated no rejection at autopsy.
“The first known successful heart transplant..”
“The heart came from a dead man..”
“..surgeons at Baylor hailed the Jackson transplant..
The Baylor surgeons say there are two solutions for
support of the failing heart..transplants from humans
or animals and artificial hearts. The Baylor group is
concentrating its efforts on developing an artificial
heart. ”
May 1965
Associated Press, 25 Jan 1964
Early attempts at ex vivo liver perfusion
in hepatic failure - extracorporeal liver
assist
First use of Gore-Tex (portal vein)
“multi-system organ failure”
Ann Review Med 1966
“..the way is clear for a trial of human heart
transplantation.”
Shumway (20 Nov 1967)
JAMA
On 2 Dec 1967 25 yo Denise Darvall was struck
by a drunk driver while leaving a local bakery in
Cape Town, South Africa. She met the criteria set
by the Groote Schuur Hospital administration –
she was not “colored”, she was brain dead – a clinical concept that had no legal meaning
in the United States.
On 3 Dec 1967 Christian Bernard transplanted Darvall’s heart into
53 yo Louis Washkansky - the 1st cardiac transplant. He survived 18 days.
Homotransplantation of the Heart in
Puppies Under Profound Hypothermia:
Long Survival Without Immunosuppressive
Treatment
Kondo, Grädel, and Kantrowitz
Ann Surg. 1965
On 6 Dec 1967 Adrian Kantrowitz (Brooklyn, NY) began “cooling” Jamie Scudero – a two
week old infant with tricuspid atresia. At 4:25 AM the heart of David Bashaw, a 2 day
old infant with anencephaly transferred from Jefferson Medical College, stopped.
At 5:30 AM the heart of Bashaw was cardioverted to sinus tachycardia in the chest of
Scudero and the child transferred to the ICU.
The donor heart – after six and half hours of hemodynamic support – became asytolic and
could not be resuscitated.
“…we consider that this procedure was an unequivocal failure. We were trying to make
one whole individual out of two individuals who did not have a chance for survival when
they were born…but we failed.”
On 6 Jan 1968 Norman Shumway transplanted
the heart of 43 yo Virginia Mae White into a 54 yo
steel worker – Mike Kasperak – the 1st adult transplant
in the US and 4th cardiac transplant worldwide.
“…the logical culmination of approximately nine years
of laboratory work..”
The Shumway group developed endomyocardial biopsy,
the use of cyclosporine, and the first combined
heart-lung block in 1981.
1968
9 March 1981
Reitz et al (1982) Heart-lung transplantation:
Successful therapy for patients with
pulmonary vascular disease. NEJM 306:557
The “me too” era of heart
transplantation and the call for “moratorium”
(March 1968, San Francisco,
American College Cardiology)
Between Dec 1967 and
June 1968 twenty one
transplants were
performed…22% were
alive at one year.
In 1968 one hundred
and seven transplants
were performed by 64
transplant surgeons in 24
countries…the majority
survived less than 6
months
Tucker v. Lower
Richmond, Virginia
Law and Equity Court
23 May 1972
In May of 1968 Dr. Richard Lower transplanted the heart of 56 yo
Bruce Tucker, “a Negro man”, into Joseph Klett, a retired
white executive...
this was the first cardiac transplant at the Medical College of Virginia,
the sixteenth heart transplant in history, the 1st death from fulminant
rejection after cardiac transplant (7 days), the first interracial cardiac
transplant, and the first transplant to result in litigation against the
surgeon for “wrongful death” of the donor
Integrity of transplant medicine...
Equity of organ allocation
Efficacy of solid organ transplant
Societal expectation and public trust
William Sweet
William Curran
J Folch-pi
Ralph Potter
D Farnsworth
E Mendelsohn
RS Schwab
Raymond Adams
A definition of irreversible coma: Report of the
ad hoc committee of the Harvard medical school to
examine the definition of brain death. JAMA (1968)
Henry Beecher
Pain in men wounded in battle. Ann Surg 1946
Deaths associated with anesthesia
and surgery. Ann Surg 1954
Joseph Murray
Ethics and experimental therapy. JAMA 1963
Resolved: brain death is a construct used by consensus to designate
a patient as being dead and is without clinical reality (a debate)
Charles Hoopes, MD
Asst Prof Surgery
Director, Cardiopulmonary Transplantation
Wade S. Smith, MD,PhD
Director, UCSF Neurovascular Service
Daryl R. Gress Endowed Chair of Neurocritical Care
and Stroke
Bibliography:
Neuropathology of braindeath in the modern transplant era. Wijdicks and Pfeifer (2008)
Neurology 70:1234
Dissecting brindeath: time for a new look. Saposnik and Munoz (2008) Neurology 70:1230
Variability of brain death determination guidelines in leading US neurologic institutions. Greer
et al. (2008) Neurology 70:252
Brain death. Finucane (2002) NEJM 345:786
“Is there an objective reality to be unearthed..”
Neuropathology (H/E) of clinical “brain death” (N=41)
* primary anoxic ischemic injury most severe cortical
necrosis, moderate brainstem ischemia (2/41)
* sporadic ischemic neuronal loss 2/3 hemispheres, 1/3
thalami, 1/2 various brainstem regions, and 1/2 pituitary
* neuronal loss widespread, total brain necrosis absent
“the neuropathologic findings lack sufficient distinctive
characteristics .. the diagnosis of brain death should be
based on clinical assessment alone.”
% mod to severe ischemia
Neuronal ischemic changes
Neuropathology of brain death in the modern transplant era.
Wijdicks and Pfeifer (2008) Neurology 70:1234
Variability of brain death determination guidelines in leading
neurologic institutions. Greer et al. (2008) Neurology 70:252
Methodology: a copy of “institutional guidelines”, “top 50” neuro programs (US News )
1. guideline performance (Amer Academy Neurology 1995)
2. preclinical testing
3. clinical examination
4. apnea testing
5. ancillary testing
"Major differences exist in brain death
guidelines among the leading neurologic
hospitals in the Unites States. Adherence to
the American Academy of Neurology guidelines
is variable. If the guidelines reflect actual
practice at each institution, there are
substantial differences in practice which may
have consequences for the determination of
death and initiation of transplant procedures.“
“.. surprisingly low rate of involvement of neurologists and neurosurgeons…
the requirement that an attending physician be involved in the determination
was conspicuously uncommon.”
On 6 April 1969 Haskell Karp underwent a “myocardial
resection with ventriculoplasty” for ischemic cardiomyopathy –
he failed to come off bypass - Denton Cooley excised the
heart and implanted the “Liotta” total artificial heart. The prototype had a limited
experimental history, was developed with NIH money directed to DeBakey, and was
implanted without DeBakey’s knowledge.
The pump supported Karp for 65 hours before a cardiac transplant –
he died 36 hours after implantation from multiorgan system failure.
The questions of prior intent, medical appropriateness, and
institutional protocol violations created the “Texas Heart War”.
Haskell Karp ‘s case represents the 1st “bridge to transplant”.
DeBakey and Cooley reconciled in 2006.
Brief history of “the operation” … surgical education (1960 to 1968)
Barnard CN. The operation. A human cardiac transplant:
an interim report of a successful operation performed at
Groote Schuur Hospital, Cape Town. S Afr Med J 1 967;
41 (48): 1 271 –1 274.
Evolving role of cardiopulmonary support technologies … clinical practice
Novel applications of solid thoracic organ transplant … basic science
extended donor/extended recipient and
allograft biology
Thoracic transplantation and social expectation
Demographic trends and outcomes in clinical cardiac transplantation…
Stehlik et al (2010) The registry of the ISHLT: 27th official heart transplant report – 2010.
J Heart Lung Transpl 29(10)
Patient selection…
Late-stage cardiac disease with limited life expectancy and/or poor quality of life in whom all
conventional treatment options have either failed or are inappropriate:
Severe functional limitation NYHA class III or IV on optimal medical therapy irrespective of EF
Severe or recurrent myocardial ischemia not amenable to revascularization
Recurrent/refractory dysrhythmias at high risk of sudden death or unacceptable quality of life due
to frequent ICD discharges
Other conditions that place the patient at risk of sudden death or decompensation (infiltrative cardiomyopathies)
The decision to transplant should be
determined by the natural history of
underlying disease, the relative efficacy of
medical therapy, and the patients perception
of quality of life.
Evolving paradigms and competitive therapies in end stage
heart failure…
36 yo O+ female with ischemic cardiomyopathy … acute anterior MI with DES.
Subsequent re-stenosis (noncompliance ?), cardiogenic shock rescued with IABP
and pressors,…subsequent LIMA to LAD CABG
H/o methamphetamine abuse , cardiolipin antibody/clotting diathesis ?
Now presents with CHF…EF 20%, elevated filling pressures with normal PVR,
VO2 max 14, nonviability of LAD distribution with aneurysm dilatation.
Of note, SAB c/in 6 months of CHF dx.
CrCl 40 (Cr 1.6), inotrope dependent (milrinone).
Evolving paradigms and competitive therapies in end stage
heart failure…
…”revascularization” with Dor (Yale)
…”SAVER” procedure with LVAD back-up (Hopkins)
…LVAD to transplant (Duke)
…medical therapy to “moratorium of decision” LVAD (Michigan)
…resynchronization therapy QT > 150 msec (Cinncinati)
…heart transplant (UCLA)
…heart transplant vs. medical therapy ? (Stanford)
…LVAD, possibly destination (Columbia)
…combined heart – kidney transplant (UCSF)
CABG to inotrope bridge
to transplant
CABG to recovery
‘Ischemic cardiomyopathy” and myocardial recovery…?
medical therapy x 2
revascularization (PCI,surgery,hybrid) x 4
revascularization and mechanical support x 2
revascularization and stem cells 0
resynchronization therapy +/- revascularization x 3
VAD to transplant x 1
transplant x 2
50% of patients have come to transplant within 36 months..early EDV has
been an accurate predictor of surgical failure.
Should this patient be transplanted ?
Evaluation of criteria for patient selection (OHTx)
1.
2.
3.
4.
5.
6.
7.
cardiopulmonary stress testing (VO2 max, maximal cardiopulmonary exercise, CPX)
right heart catheterization (RAP,PVR,PCWP,CO)
heart failure prognosis scores (risk stratification)
co-morbidities (diabetes, renal dysfn, PVD, h/o malignancy, age, weight)
serology (CMV, hepatitis, HIV)
psychosocial/economic (compliance, social and financial support)
non-transplant alternatives (destination LVAD)…30% “bridge to transplant”
1. Cardiopulmonary stress testing..maximal CPX: RER >1.05 and achievement of anaerobic threshold
on maximal pharmacologic therapy
peak VO2<14 cc/kg/min (β blocker intolerant)
peak VO2<12 cc/kg/min (on β blocker)
peak VO2<10cc/kg/min at anaerobic threshold
(or peak VO2 max < 50% expected)
“transplant”: consider age, gender, and weight…
ventilation to carbon dioxide slope (Ve/VCO2 slope>35) for
submaximal effort (RER<1.05).
2. Right Heart Catheterization
Pulmonary artery hypertension and elevated PVR should be considered as a relative
contraindication to cardiac transplantation when the PVR is 5 Wood units or the
PVRI is 6 or the TPG exceeds 16 to 20 mm Hg
If the PAS exceeds 60 mm Hg in conjunction with any 1 of the preceding 3
variables, the risk of right heart failure and early death is increased
If the PVR can be reduced to 2.5 with a vasodilator but the systolic blood
pressure falls below 85 mm Hg, the patient remains at high risk of right heart
failure and mortality after cardiac transplantation
3. Risk stratification..timing and selection of recipient candidates
Heart Failure Survival Score (HFSS)
* HFSS
* Seattle Heart Failure Model
www.SeattleHeartFailueModel.orgr
* ADHERE (BUN>30, SBP<115, Cr>2.75)
* Neurohormonal biomarkers (BNP)
van Kimmenade (2006) JACC
48:1621
Clinical characteristic
Value(x)
Coefficient(β) Product
Ischemic cardiomyopathy
Resting heart rate
LVEF
Mean BP
IVCD
Peak VO2
Serum sodium
1
90
17
80
0
16.2
132
+0.6931
+0.0216
-0.0464
-0.0255
+0.6083
-0.0546
-0.0470
+0.6931
+1.9440
-0.7888
-2.0400
0
-0.8845
-6.2040
HFSS: low-risk strata, <8.10; medium-risk strata, 7.20 to 8.09; high-risk
strata, <7.20.
http://www.ccont.ca/CHFrisk
*Cardiorenal syndrome and
circulatory-renal limit (CRL)
Kittleson at al (2003) JACC 41:2029
Knowing the risk of dying and the
prognosis of patients receiving
optimal medical therapy is critical
to the determination of transplant
candidacy and timing.
4. Co-morbidities…all are relative
* age > 70 years, BMI > 30kg/m2 or
percent ideal body weight > 140%...
“cardiac cachexia” (BMI < 18 kg/m2)
* malignancy...case specific vs 5 yr exclusion
* diabetes
20% to 40% increase in 1 and 5 yr mortality (ISHLT)
HbA1c > 7.5 and secondary end organ injury
* peripheral/cerebrovascular disease
* renal insufficiency
CrCL>80 cc/min corrected for BSA and
urine protein<150 mg/24 hrs…no significant perioperative risk
estimated GFR (eGFR)…http:nephron.com/cgi-bin/mdrd.cgi
renal ultrasound
renal biopsy
combined heart-kidney transplant
15% at 5 yrs
5. Serology…and perioperative risk
1. cytomegalovirus (CMV) seropositive…no contraindication
CMV mismatch (CMV+ donor/CMV-recipient): CMV IgG 150 mg/kg iv x 7 days
valganciclovir x 1 yr
2. hepatitis B seropositive…relative contraindication
3. hepatitis C seropositive (HepC Ab+)…relative contraindication
viral titre and viral genotype ?
4. HIV seropositive…relative contraindication
viral titre (“undetectable”) and CD4 count > 200
…no increase in infection or cardiac rejection at two years (UCSF)
6. Psychosocial and economic (public health costs)
* compliance, psychosocial support, and neurocognitive testing
* costs 148K (50K to 287K)…787K total charges (34K pre tx admission, 94K procurement, 486K
hospital costs, 50K physiscian fees, 100K post tx admission, meds 22K)…
Milliman Research report 2008
* equity and access…23% of donors uninsured (King et al, 2005, Health insurance and cardiac
transplant, JACC 45:1388)
“It is our institutional bias that the decision to transplant is individualized and directed
towards patient – specific quality of life. We do not question that transplantation improves
cardiac function but always question whether "fixing the heart" will significantly improve
the patient…
While individual physicians advocate for patients the decision to transplant is collective
and represents the balance of interest between responsible utilization of a shared limited
resource and appropriate patient need. Heart transplantation as an operation should not
exist outside an integrated heart failure service and active mechanical circulatory assist
program. We do not consider decompensated heart failure an indication for
transplantation …
Every effort is made to establish a euvolemic state with adequate end organ perfusion
before proceeding to transplantation. Patients intolerant of maximal medical therapy are
referred for ventricular device placement and patients with acute cardiogenic shock
refractory to medical therapy are stabilized with extracorporeal life support (ECLS)
before placement of definitive ventricular assist devices and consideration for transplant.
The separation of mechanical ventricular assist technology and transplantation in this
discussion is editorial and does not reflect current thinking in the surgical management of
end stage heart disease”.
Hoopes (2009) Heart Transplantation
Critical Care (Civetta, Taylor, and Kirby)
The mechanics of heart transplantation…donor (allograft) selection
Every surgeon wants a good organ, no surgeon wants a bad organ …
every patient needs an appropriate organ
The appropriateness of an organ is determined by donor biology,
recipient biology, the logistics of transplant and nontransplant
alternatives, and the natural history of the process …
The substance of thoracic transplantation is to implant an appropriate
organ in the appropriate patient at the appropriate time … so, how is
the appropriate organ identified ?
Organs we never use (disease)
Organs we could have used (discernment)
Organs we should have used (data)
Organs we never use (disease) … hepatitis C, HIV, Chagas, cardiomyopathy
Organs we could and have used (discernment) … bicuspid aortic valve, WPW, extended down time
Organs we should have used (data, and the proportional hazards model)
100%
Recipient: 63 y.o. male, Dx=CAD, pulsatile LVAD, PRA < 10%,
weight=85 kg, PVR=2, volume=25/year, year of tx ‘99/’00, bili 0.9,
PAD 23, Cr 1.3
Donor: 30 y.o. male, COD = MVA, weight = 80 kg, height = 70 in.
Donor: 50 y.o. female, COD = CVA, weight = 70 kg, height = 65 in.
Predicted Survivall
90%
Cohort average
80%
70%
60%
50%
0
1
2
3
4
5
Positive associations with primary graft failure (odds ratio, p<0.05)
Heart failure etiology: congenital
Mechanical circulatory support:
extracorporeal VAD
ECMO at transplant
Donor age: 30–39 yr
Ischemic time (warm): 1 hr
Heart failure etiology: hypertrophic
Multiorgan donor: lung
Previous heart transplant (redo)
Female donor to male recipient
Ischemic time (cold): 6 hr
Positive crossmatch
5.32
5.93
10.29
2.02 In general…very short (<1 hr) and very long (>4 hr) ischemic time,
sick patients
(ECMO), complex operation (redo, congenital), positive
6.63
3.41 crossmatch, female to male (size mismatch ?)
1.58
4.97
1.62
3.79
Donor age
1.67
Russo et al (2010) Factors associated with primary graft failure
after heart transplantation Transplantation 90:444
Organ allocation…
UNOS (United Network Organ Sharing) oversees 11
regions with 58 OPTN (Organ Procurement Transplantation
Network)
Hearts are allocated based on medical urgency
and geographic zones – sickest “status” local
patients (1A,then 1B) followed by sickest patients to 500 miles
from OPO (zone A: 1A, then 1B), then local status 2.
Listing criteria…
Status 1A: one high dose inotrope, two inotropes with
continuous hemodynamics (PA catheter), mechanical ventilation,
mechanical support device (LVAD<30 days, ECMO, TAH, IABP)
Status 1B: inotrope dependent, LVAD>30 days
Status 2: compensated CHF at home, no IV
…”sensitized” patients and perioperative risk
Crosssmatch (CDC), panel reactive antibody, donor specific antibody, and “virtual crossmatch”
A complement–dependent cytotoxicity (CDC) assay…recipient serum with separated donor T cells. When donor
reactive antibodies are present, the addition of complement results in cell killing…a POSITIVE crossmatch
The percent PRA (panel reactive antibody) value
is a measure of a patient’s level of sensitization
to donor antigens. It is the percentage of cells
from a panel of blood donors against which a
potential recipient’s serum reacts. The PRA
reflects the percentage of the general population
that a potential recipient makes antibodies (is
sensitized) against. The higher the PRA, the
more sensitized a patient is to the general donor
pool, and thus the more difficult it is to find a
suitable donor. The liklihood of finding an
appropriate donor can be calculated from the
Hardy-Weinberg equilibrium.
* “Virtual crossmatch”…donor specific
antibody by single antigen beads
* “Desensitization protocols”…
plasmapharesis, IVIG, Rituximab
(anti-B cell/anti-plasma cell)
Donor specific antibody:
Recipient and Donor Data
The donor is HLA mismatched with the recipient for the antigens that are shown in red font in the table below.
The donor’s predicted HLA-DQ3 subtype is likely to be different from that of the recipient.
HLA Types
ID Relationship Transplant
Data
Race
Sex
A
B
Bw
Cw
DR
DRw
DQB
M
2,26
38,61
4,6
3,7
9,15
51,53
3,5
M
2,68
39,61
6
3,7
4
53
3
Testing for HLA Alloantibodie
No donor-specific HLA antibodies were detected in a 05/28/2009 sample.
The top table provides the fluorescence intensities (MFI)
for the single antigen beads containing HLA molecules that are mismatched in
the donor (alleles predicted based upon the donor’s HLA type and HLA frequencies) and the bottom table lists the PRA data.
The recipient has high levels of HLA Class I antibodies, but the donor antigens are negative in the PRA and single antigen assays.
There may be some extremely weak antibodies against HLA-DP (<500 MFI) in the 5/28/2009 serum.
A sample has been sent to UCLA for MICA antibody testing.
HLA-A, -B, -Cw, -DR, and –DQ Mismatches in the Donor
(MFI from Representative Molecules in the Single Antigen Panel*)
Sample Date POD
A68
B39
DR4
04/30/2009
1,025
NEG
NEG
NEG
05/28/2009
1,053
NEG
NEG
NEG
The current threshold for a positive result is 500 MFI.
PRA
Sample Date
07/09/2006
04/30/2009
05/28/2009
POD
-2
1,025
1,053
Class I
33%
67%
55%
DQ3
NEG-105
NEG
DP?
??
??
Class II
0%
0%
0%
Limitations
The MFI for HLA alleles used for the single antigen table are alleles that are predicted (or most closely related alleles) based
upon HLA allele and haplotype frequencies.
The predictions may be incorrect and the donor may express alleles that are not represented in the panel.
The recipient’s serum has additional HLA specificities which are detailed in the test reports.
The MFI are raw values that have not been normalized.
Technical variation may contribute to the observed differences between longitudinal samples.
Acute cellular rejection
T cell mediated…antigen presenting cells (APCs) present donor MHC antigen peptides to the CD3 receptor complex…
CD4 co-receptor for MHC class II (see figure), CD8 co-receptor for MHC class I presentation.
Allo-activation of the T cell requires co-stimulatory binding of the APC B7 receptor to the T cell CD28 receptor.
The binding mechanism results in transcriptional activation of the calcineurin, nuclear factor kappa B (NFKB),
and mitogen activated protein kinase pathways with production of IL2. Autocrine stimulation by IL2 results in cell
proliferation via a pathway involving target of rapamycin (TOR) and cyclin/cyclin dependent kinase.
Targets of immunosuppression:
daclizumab
basiliximab
calcineurin inhibitors (cyclosporine, tacrolimus)
TOR inhibitors (sirolimus, everolimus)
antiproliferatives (mycophenolate, azathioprine)
cyclosporine
tacrolimus
sirolimus
everolimus
IL2 receptor antagonists (daclizumab, basiliximab)
CTLA-4 Ig, antiCD40 ligand, and selective JAK3i
steroids
mycophenolate
azathioprine
Modified from Hunt and Haddad (2008) J Am Coll Cardiol 52:587–98
immune tolerance and “microchimerism”
Endomyocardial biopsy and histopathology of acute cellular rejection
Grade
0R
1R
2R
3R
Nomenclature
0
1A
1B
2
3A
3B
4
No rejection
Focal (perivascular or interstitial) infiltrate without necrosis
Diffuse but sparse infiltrate without necrosis
One focus with aggressive infiltration and/or focal myocyte damage
Multifocal aggressive infiltrates and/or myocyte damage
Diffuse inflammatory process with necrosis
Diffuse aggressive polymorphous infiltrate
+/-edema, +/- hemorrhage, +/- vasculitis with necrosis
3 specimens…5% false negative interpretation
5 specimens…3% false negative interpretation
Complications: mortality 0.05%, cardiac perforation 0.3 to 0.5%,
pneumothorax 1% (thromboembolism, arrhythmias)
Caves, Stinson, Billingham, and Shumway (1963) Percutaneous transvenous endomyocardial
biopsy in human heart recipients: experience with a new technique. Ann Thor Surg 16:325
Non-rejection biopsy findings
Perioperative ischemic injury (up to 6 weeks)…
myocytolysis and vacuolization, no inflammatory
cell infiltrate
Quilty effect…dense inflammatory infiltrate confined
to the endocardium
Peri-operative ischemic injury
Quilty effect
Acute antibody mediated rejection (AMR)
*allosensitized patients (redo, VAD, pregnancy, transfusion))
*myocardial capillary injury with endothelial cell swelling, intravascular macrophages,
intravascular thrombosis and myocyte necrosis without cellular infiltrate
*immunofluorescence C4d capillary staining, immunoglobulin (IgG, IgM)
*donor specific antibody (MHC allograft specific serum antibody)
*non-MHC antibodies (MICA and MICB)
Acute cellular rejection (ISHLT standardized biopsy grade)
0R…no rejection
1R (mild): interstitial and/or perivascular
infiltrate with < 1 focus myocyte damage
1R
1R
2R (moderate): two or more foci of
infiltrate with associated myocyte damage
3R (severe): diffuse infiltrate with
multiple foci of myocyte damage +/edema +/- hemorrhage +/- vasculitis
2R
3R
3R
Biomarker approaches to allograft rejection…
“The risk of cardiac rejection is time-dependent and may require
dynamic surveillance strategies:
Three distinct periods of immunologic adjustment (early),
allograft adaptation, and then the stable phase of allograft
maintenance require distinct vigilance strategies.
Early on, a very concerted and aggressive strategy is required
while adjustment of immunosuppression is underway. In months 2
to 6, as allograft adaptation ensues, risk stratification for
intense vs less intense strategies may be needed, perhaps guided
by the predictive ability of gene-expression testing. In the
maintenance phase, a clinical and functional evaluation structured
approach may be adequate. “
Mehra and Parameshwar (2010) J Heart Lung
Transpl 29:599
Deng et al (2006) for the CARGO investigators. Non invasive detection of rejection
in cardiac allograft recipients using gene expression profiling. Am J Transpl 6:150
Pham et al (2010) for the IMAGE study group. Gene expression profiling for
rejection surveillance after cardiac transplantation. NEJM 362:1890
Donor requirements are dictated
by recipient biology and natural
history of the disease
Each of these patients is 5'6“...
who goes first ?A
t least
early on
CHRONIC REJECTION AFTER LUNG TRANSPLANT
OBLITERATIVE BRONCHIOLITIS (ISHLT database,circa 1998)
Probable Risk Factors
• Acute rejection
• Lymphocytic bronchitis
• CMV pneumonitis
• Anti-HLA
pretransplantation
" progressive obliteration of
bronchioles, metaplasia of
the airway epithelium"
Potential risk factors
• CMV infection
• Community respiratory infection
• Donor antigen-specific reactivity
• Medical non-compliance
• GERD
• Older donor age + longer
ischemic time
CHRONIC REJECTION AFTER LUNG TRANSPLANT
OBLITERATIVE BRONCHIOLITIS (ISHLT database,circa 2008)
Probable Risk Factors
• Acute rejection
• Lymphocytic bronchitis
• Anti-HLA
pretransplantation
Potential risk factors
• Community respiratory infection
• Donor antigen-specific reactivity
• Medical non-compliance
• GERD
• Older donor age + longer
ischemic time
No progress !
" progressive obliteration of
bronchioles, metaplasia of
the airway epithelium"
The rationale for interest in GERD ..
1st
Quartiles, lymphocytic bronchitis (EBB)
4th
100
overall survival
% freedom BOS
p=0.0008
UCSF '01 to '03 (N=50)
0
2
years
4
6
(Hayes et al, submitted)
Lymphocytic bronchitis predicts bronchiolitis obliterans,
bronchiolitis obliterans predicts allograft failure.
If aspiration contribute to lymphocytic bronchiolitis, and GERD contributes
to aspiration .. then preventing gastroesophageal reflux might ..?
"…we suggest that GER should be considered as a
potentially reversible cause of BOS among lung transplant
recipients."
Do preoperative gastroesophageal studies predict post operative
gastroesophageal function ?
Mean (distal) Acid Contact Times* – pre and post transplant
total
supine
upright
pre-tx (Duke)
post tx (Duke)
pre-tx (UCSF)
post-tx (UCSF)
5.6%
5.1%
6.2%
9.3%
11.4%
7.8%
6.6%
3.4%
7.5%
7.2%
8.2%
6.4%
•Duke data: Chest 2003 (N=23,11 COPD)
•UCSF data: unpublished, N=35 (interstitial lung disease, including MCTD/scleroderma)
• mean study date 100 days post tx (Duke), 6 months to two years (UCSF)
Pre transplant
Post transplant
Are these patients "better",
"worse", the "same" ?
motility normal
abnormal motility
aperistaltic
20%
60%
13%
20%
66%
15%
% prox pH < 4
2.6%
4.7%
DeMeester score
89(30-250)
55(0.5-182)
gastric emptying
60%
92%
Who deserves fundoplication ?
Immunological link between primary graft dysfunction and
chronic allograft rejection.
Primary graft dysfunction induces proinflammatory cytokines
that can upregulate donor HLA-II antigens on the allograft.
Increased donor HLA-II expression along with PGD-induced
allograft inflammation promotes the development of donor
specific alloimmunity. This provides an important mechanistic
link between early posttransplant lung allograft injury and
reported association with broncholitis obliteran syndrome."
Bharat et al. (2008)
Ann Thor Surg 86:189
* any donor allograft characteristic which
influences the risk of primary graft dysfunction
directly influences patient survival and QOL
as measured by the incidence of BO ..
A composite marker of aspiration (biological and nonbiological)..
The natural history of the pulmonary allograft is a consequence of the
environmental ecology of the tracheo-bronchial tree .. including both biological and
nonbiological components
Observations:
*microaspiration and ventilator associated pneumonias (UCSF)
*association of IL8 and BAL bacteria/fungus with bile refluxate (Toronto)
*association between bile injury and innate immunity (Toronto)
"environmental ecology" (aspirates, chemical and biological)
innate immunity
alloimmune (MHC)
allo Ag independent
Injury
adaptive immunity
Inflammation
Fibrosis (BO)
Post transplant BAL:
genomic DNA PCR 16S rRNA primers
subcloned pCR4-TOPO vectors (Invitrogen)
sequenced (DOE Joint Genome Institute)
bioinformatics (species diversity, abundance, temporal change)
M33
8000
7000
6000
scleroderma, BOS
H. pylori
5000
4000
All transplanted patients (N=5,ILD)
to date wide array oral, nasal, gut
flora ..
Non-transplant patients w/o gut
flora
Antibiotics decreases species
diversity (n=1) ..
3000
2000
1000
0
unpublished data,Flanagan and Kronish
Transplantation for pulmonary metastases and BAC ?
Etienne et al. (1997) Successful double lung transplantation for bronchoalveolar carcinoma .
Chest 112:1423
Garver et al. (1999) Recurrence of bronchoalveolar carcinoma in transplanted lungs. NEJM
340:1071
Paloyan et al. (2000) Lung transplantation for advanced BAC confined to the lungs.
Transplantation 69:2446
Zorn et al. (2003) Pulmonary transplantation for advanced BAC. J Thorac Cardiovasc Surg
125:45
Shargall et al (2003) Bilateral lung transplantation for metastatic leiomyosarcoma .
J Heart Lung Transplant 23:912
de Perrot et al. (2004) Role of lung transplantation in the treatment of bronchogenic
carcinomas for patients with end stage pulmonary disease. J Clin Oncol 22:4351i
Lee et al (2007) Lung transplantation for pulmonary metastases
and radiation-induced pulmonary fibrosis after radioactive iodine ablation of extensive lung
metastases from papillary thyroid carcinoma . Thyroid 17(4):367
Paraskeva et al (2010) Lung transplant survival despite unexpected pulmonary metastatic thyroid
cancer in the explant. Transpl Int 23:e45
Lung primary
* bronchoalveolar carcinoma (BAC)
* squamous cell (early stage lung primary)
Pulmonary metastases
* leiomyosarcoma (uterine)
* papillary thyroid carcinoma
* osteosarcoma ?
Bilateral lung transplantation for metastatic
leiomyosarcoma
"…if the original tumor has been completely resected
and controlled, the metastatic process confined to
the lungs, the tumor biology favorable, and no other
treatment options (systemic or surgical) are
available, then lung transplantation can provide an
increased quality of life and an extended lifespan to
selected patients.”
*
*
*
*
control of primary
isolated pulmonary metastases
favorable tumor biology (genomics)
“salvage” for QOL and survival
Shargall et al (2003) Bilateral lung transplantation for metastatic
leiomyosarcoma. J Heart Lung Transplant 23:912
Lung transplantation for extensive lung
metastases from papillary thyroid carcinoma
Cinical history:
total throidectomy with central dissection May '02
miliary disease Sept '02 (thyroglobulin 15,000)
I-131 ablation (250 mCi) October '02
redo neck dissection, left laryngeal n. resected July '02
I-131 ablation (200 mCi) July '02 (thyroglobulin 1200)
needle biopsy positive disease left neck, redo neck dissection Sept
'04 (negative PET)
intubated x 2 Oct ‘04, vent dependent Jan ‘05
Bilateral lung transplant (CPB) Jan '05 … pathology
demonstrated diffuse metastatic papillary thyroid
carcinoma left lung (2/7 nodes +),
right lung (2/3 nodes +), subcarinal node positive.
Subsequent I-131 ablation (200 mCi)
March '05 (thyroglobulin 60), thyroglobulin undetectable
since April '05.
Lee et al (2007) Lung transplantation for extensive lung metastases
from papillary thyroid carcinoma. Thyroid 17(4):367
BAC and lung transplantation…
57 yo female with non-mucinous bronchoalveolar carcinoma
bilobectomy June '02, no adjuvant therapy
recurrent disease bilaterally Sept '03, 18 mo. Iressa rx
progressive disease, subsequent Tarceva c/b mucositis
no cytotoxic therapy, staging mediastinoscopy negative
no extrapulmonary disease by PET
progressive dyspnea (sats 81%)
"…complete resection with preservation of functional capacity"
Barlesi et al. (2003) Eur J Cardiothorac Surg
BAC: myths and realities in surgical management
Mechanical Circulatory Support (LVAD) and
cardiac transplantation …
* implications for management
NYHA IV (30 to 90 days)
elevated filling pressures (PCWP 20)
end organ (renal) dysfn
subindex (CI) pump failure (low EF)
* implications for organ allocation
“large male, blood type O”
“elevated PRA”
“moratorium of decision”
* implications for “recovery”… LVAD induced remodeling
1400
BNP
1200
1000
800
600
400
V
A
D
200
0
Explant day 1
inotropes
LVAD pod 1
preVAD
May ’08 (CHF)
Dec ’08 (LVAD)
Explant day 12
Feb ’09 (explanted, post LVAD)
Stehlik et al (2010) The registry of the ISHLT:
27th official heart transplant report – 2010.
J Heart Lung Transpl 29(10)
30%
Mechanical Cardiopulmonary Support … the “learning curve”
No device has ever saved or killed a patient …
good surgeons using good devices have done
both (clinical application)
No device program has everything … effective
device programs have everything they need ..
device technology accomplishes nothing but
facilitates everything (materials science)
Mechanical circulatory support is designed to
resuscitate the injured .. it cannot reanimate
the dead (device deployment)
Recipient selection for ambulatory ECMO…
1. Rationale
2. Device technology and deployment
…trans-thoracic total support (“oxyRVAD”) or
percutaneous near total support
dual lumen central VV ecmo (Avalon) or
pumpless extracorporeal lung assist (pECLA)
3. Deployment algorithms
4. Organ allocation policy and transplant logistics
Extracorporeal membrane oxygenation (ECMO/ECLS): institutional epidemiology
University of California San Francisco
2002 to 2010 (N=100)
35% of device deployments…
“bridge to pulmonary transplant”
1. Acute exacerbation of progressive disease (IPF)
2. Complications of progressive disease (CF)
3. End stage disease (pulmonary hypertension)
4. Avoid mechanical ventilation (COPD)
5. “salvage transplant” secondary to ECMO for
“moratorium of decision” (failure to recover)
Rationale for ambulatory ECMO bridge to transplant…
“50% of patients die in a relatively acute
manner with progressive symptoms of less
than one month's duration…the extent of
restrictive physiology is a poor predictor
of mortality”
King et al (2005) Chest 127:171
…"acute exacerbations" or an "accelerated phase of rapid clinical decline" –
without an identifiable cause – characterizes the clinical course of IPF and is
associated with a poor prognosis…a consensus definition should be developed
and the etiology, risk factors, pathogenesis, treatment, and predictors need to
be studied.”
Kim et al. (2006) Natural history of the idiopathic
interstitial pneumonias.
Proc Am Thorac Soc 3:285
Is there a role for ECMO in acute exacerbation
of progressive, lethal lung disease …?
Rationale for ambulatory ECMO bridge to transplant…
"… mechanical ventilation does not benefit
these patients…initiation of mechanical
ventilation is questionable and should be
restricted to patients in whom lung
transplantation can be performed."
"Management" of acute exacerbations in
idiopathic pulmonary fibrosis ?
Blivet et al (2001) Outcomes of patients with IPF admitted to the ICU with respiratory failure. Chest 120:209
"… not improved by mechanical ventilation."
Fumeaux et al (2001) Mechanical ventilation for respiratory failure in patients with IPF. Intensive Care Med 27:1868
"…mechanical ventilation for acute respiratory failure in IPF patients was associated with 100% mortality."
Saydain et al (2002) Outcome of patients with IPF admitted to the ICU. Am J Respir Crit Care Med 166:839
"…patients with IPF admitted to the ICU have poor short and long term prognosis."
Bag et al (2004) Respiratory failure in interstitial lung disease. Curr Opin Pulm Med 10:412
"… may not benefit from prolonged aggressive therapy including mechanical ventilation."
“Standard of care” is “no care” or “bad care”…
Pulmonary transplant from an ECMO bridge … UCSF/Kentucky
30
60
37
46
55
55
24
29
58
47
30
51
56
58
14
48
38
63
49
23
43
42
22
34
23
yo
yo
yo
yo
yo
yo
yo
yo
yo
yo
yo
yo
yo
yo
yo
yo
yo
yo
yo
yo
yo
yo
yo
yo
yo
male (CF, redo)
male (scleroderma)
male (IPF)
male (IPF)
male (IPF)
male (IPF)
male (Hamman Rich, AIP)
male (CF)
female (scleroderma)
female (sarcoid)
female (IPPH)
dermatomyositis
BOS (IPF)
male (IPF)
female (IPPH)
dermatomyositis
BOS (CF)
male (PHTN, COPD)
male (PHTN, COPD, AoS)
female (CF)
male (AIP)
male (IPF)
female (PVOD)
male (CF)
male (CF)
hypoxia/acidosis (mixed)
hypoxia/RV failure
cor pulmonale (PEA)
cor pulmonale (PEA)
cardiogenic shock (RV)
ardiogenic shock (RV)
hypoxia
hypoxia/acidosis (mixed)
cardiogenic shock (RV)
cor pulmonale (PEA)
cor pulmonale (PEA)
respiratory failure
hypoxia
hypoxia, RV failure
PEA (peripheral VA)
hypoxia (RA to PA)
hypoxia (DLC VV)
PEA (PA to LA)
PEA (RA to Ao)
respiratory failure (DLC VV)
hypoxia (RA to PA)
PEA (PA to LA)
PEA (peripheral VA)
respiratory failure (VV DLC)
hemoptysis (PA to LA)
dead (14 mo) s/p redo BLTx
withdrawl of support
alive s/p BLTx (68 mo)
alive s/p BLTx
alive s/p BLTx
alive s/p BLTx
alive s/p BLTx
alive s/p BLTx
alive s/p BLTx
withdrawl of support
alive s/p HLTx…redo single lung
withdrawl of support
alive s/p redo BLTx
alive s/p BLTx
alive s/p BLTx…subsequent redo BLTx
alive s/p BLTx
alive s/p redo BLTx
alive s/p BLTx
alive s/p HLTx
alive s/p BLTx
alive s/p BLTx
alive s/p BLTx
alive s/p BLTx
alive s/p BLTx ( 2 weeks)
withdrawl of care (hepatic failure)
"Pump failure" – not primary lung failure – was the indication for mechanical support early on…
“respiratory failure” is now the most common indication (disease demographics and
evolution of device technology)
“Ambulatory right heart bypass” ..for pulmonary hypertension and secondary RV failure, hypoxia
Goal: adequate LV preload and systemic cardiac
output, no end organ ischemia
Criteria: norepi<0.04 ucg/kg/min, PaO2<60mmHg
in an ambulatory patient
Pump driven..regulate LV preload and RV afterload
(flows 1.5 to 4.5 L/min)
PA
LA
Alternative cannulation: RA to PA (thromboemboli,
anticoagulation, and intrathoracic pressure)
versus
Pumpless extracorporeal lung assist (pECLA)..
native RV perfusion across low resistance
oxygenator and pulmonary vascular bed (in series)
flows between 1.6 and 2.3 L/min (PVR dependent)
This is ECMO ?
“walking ECMO”…dual lumen VV (hypoxia, CO2
secondary BOS.. to redo BLTx)
“walking bypass”…RA to Ao cannulation
(BiV failure, PHTN s/p PEA..to HLTx)
“ambulatory right heart bypass”…PA to LA cannulation
(RV failure, hypoxia, PHTN s/p PEA..to BLTx)
“pumpless extracorporeal lung assist” (pECLA)..PA to LA
cannulation (RV failure, hypoxia..to Tx)
Management algorithm
Peripheral femoral VA ECMO (“salvage, moratorium of decision, or transport”)
(retrograde flow, open deployment, < 72 hrs)
Norepi > 0.04 mcg/kg/min or
Epi > 0.04 mcg/kg/min
“pump failure/PHTN”
Norepi < 0.04 mcg/kg/min or
Epi < 0.04 mcg/kg/min
Peripheral femoral AV ECMO w/o pump (pECLA)
(antegrade flow, ~ 1.5 L/min)
Adequate gas exchange (PaO2 60,
PCO2 60, pH 7.36) and perfusion (RV
ECHO)
OxyRVAD
Venovenous (DLC) ECMO…ambulation
(central cannulation…ambulation)
RA to PA
RA to Ao
PA to LA…pECLA or Centrimag
Does the history of cardiac mechanical circulatory support inform the
application of pulmonary support technologies…absolutely !
1.
2.
3.
4.
5.
6.
7.
Critical cardiogenic shock … fulminant respiratory failure
Progressive decline … escalating mechanical support
Stable inotrope dependent … vent dependent
Recurrent advanced disease … absence of pulmonary reserve
Exercise intolerant … exercise intolerant (PHTN)
Exercise limited … exercise limited
Advanced NYHA class III … anatomical substrate (parenchyma)
Deployment of MCS technologies in the context of medical futility generally
results in futile deployment of technology…it is rarely “the device”
MCS technology generally restores physiology but may not
alter survival depending upon the specifics of deployment
Unnecessary surgery performed well has excellent outcomes..device technology
should be deployed based upon clinical trajectory and the natural history of
the disease process…
MCS can support patients awaiting good clinical decision making but generally is
ineffective in supporting bad clinical decisions
LVAD induced remodeling: Basic science and clinical implications for recovery
May ‘08
Inotrope dependent
Leftward shift of the EDPVR (structural “reverse
remodeling”)
Dec ‘08
‘08
LVAD
Feb ‘09
s/p LVAD
Time dependent reduction in heart size
(EDP of 30 mmHg, V30)
Regression of cellular hypertrophy
In response to electrical forces, cultured
cardiomyocytes rearrange their cytoskeletal
structure and modify their gene expression
profile (in vitro)
Cardiac conduction is required to
preserve cardiac chamber morphology
PNAS 2010 Aug
Neil Chi, Jeff Olgin, Robin Shaw
Cardiac electrical forces are required to preserve
cardiac chamber morphology and may act as a
key epigenetic factor in cardiac
remodeling…zebrafish dco mutation…murine cnx46
Disrupted cardiac conduction leading to
changes in the intracellular calcium
gradients results in redistribution of
integrins and mislocalization of these
adhesion molecules could lead to loss of
cell–cell contact between cardiomyocytes
and could affect cell shapes and overall
cardiac morphogenesis.
CRT and reverse remodeling ?
BIN1 localizes the L type calcium channel to
cardiac T tubules
L-type calcium channels must localize to “Ttubule” membrane invaginations of heart muscle
cells … data suggests the channels are delivered
by dynamic microtubule highways that tether
specifically to T-tubules via the membrane
curvature protein BIN1. Serum levels of BIN1
vary with cardiac performance (in vivo human)…
Cardiac myocyte cytoskeletal biology
predicts conduction pathway biology…
TT Hong and Robin Shaw PLOS 2010
Clinical transplantation of a tissue-engineered airway
“…surgical training does not
give surgeons the flexibility to
engage with top scientists—
that is why surgical research
has fallen into the doldrums.”
Decellularization and autologous cell
reconstitution…
exclusion of donor MHC !
Macchiarini et al, and Birchall
Lancet 372 (2008)
Tissue-Engineered Lungs for in Vivo
Implantation
…decellularization paradigm for respiratory tissue was
described in 2008, when Macchiarini and colleagues
implanted a reseeded tracheal matrix into a patient
with severe bronchomalacia
Petersen et al (2010)
Science 329