HEART TRANSPLANTATION.pptx

Surgical treatment
of
heart failure
Dr. Vivek Vilas Manade
Cardiology Resident

LVAD
http://www.j-circ.or.jp/english/sessions/reports/64th-ss/figures/margulies2.jpg
http://www.todayincardiology.com/199811/S8j00931.GIF
http://nypheart.org/img/rematch.jpg

LVAD
http://www.texasheartinstitute.org/ve_pump.jpg
http://www.texasheartinstitute.org/velvad2.jpg

Axial Flow Pumps
 Small
 Continuous, non-pulsatile flow
http://www.pbs.org/wgbh/nova/eheart/images/axialpump.jpeg
http://www.texasheartinstitute.org/j2f462s.jpg
http://www.texasheartinstitute.org/J2Syss.jpg

History of Artificial Heart
 June 2001
 http://discover.npr.org/featur
es/feature.jhtml?wfId=11238
33
 August 2001
58
 November 2001
60
http://images.usatoday.com/news/_photos/2001-11-30-heartguy.jpg

• 1958:
• Designed by Drs. Willem Kolff
and Tetsuzo Akutsu
• Polyvinyl chloride device
• Sustained a dog for 90 minutes
• 1965:
• Dr. Willem Kolff
• Silicone rubber heart
• Tested in a calf
http://www.accessexcellence.org/WN/graphics/jarvik.
jpg
http://www.abiomed
.com/images/prodtec
h/kolff65.jpg

• 1969:
• Dr. Domingo Liotta
• First to be implanted in human as
bridge to transplant
• Patient survived for 3 days with
artificial heart and 36 hours more
with transplanted heart
• 1982:
• Drs. Willem Kolff, Donald Olsen,
and Robert Jarvik,
• Jarvik-7
• First to be implanted in a human as
destination therapy
http://www.abi
omed.com/ima
ges/prodtech/li
otta.jpg

http://static.howstuffworks.com/gif/artificial-heart-abiocor-diagram.gif
http://www.ps-lk3.de/images/ABIOCOR.JPG

AbioCor Artificial Heart
http://www.heartpione
ers.com/newsimages.
html#
Cost: $70-100k
http://www.cardiocaribe.com/newsite/images/articulos/feb02/abiocor_hand.jpg

Orthotopic procedures (from Greek
orthos, straight + topos, place) are those
occurring at the normal place. Examples
include: Orthotopic liver transplantation, in
which the previous liver is removed and the
transplant is placed at that location in the
body. Orthotopic heart transplantation.
After the recipient's heart is removed, the
donor heart is prepared to fit and
implantation
begins. Heterotopic approach. Heterotopi
c transplantation, also called
“piggyback” transplantation, is
accomplished by leaving the recipient's
heart in place and connecting the donor
heart to the right side of the chest.

History of cardiac transplantation
The first heterotopic canine heart transplant was performed
by French surgeon Alexis Carrel & Charles Guthrie in 1905
at the University of Chicago.
Fig. 1 On the left, the elegant Alexis Carrel. On the right, the probable anastomotic arrangement: a=
distal carotid artery; a'= proximal carotid; b= distal jugular vein and b'= proximal jugular vein.

In 1933, Frank Mann at the Mayo Clinic further explored
the idea of heterotopic heart transplantation. [in dogs]
The heart was transplanted in the neck.
Pulmonary artery anastomosed to proximal jugular vein and
aorta to distal carotid artery with a more adequate coronary
perfusion.
They obtained a longest survival of eight days and mean
survival of four days.
They made observations of recipient donor heart different
response of rate and furthermore studied the histology of
rejection.

In 1953, Marcus at Chicago: Modified Mann technique
the donor left ventricle would act as a pump. The proximal end of
the divided recipient common carotid artery was anastomosed to
the donor left atrium and the recipient distal common carotid to
the donor innominate artery, so that the donor left ventricle
supplied blood to its own coronary arteries and to the recipient
cerebral circulation. Maximum survival with this technique was 48
hours. Longer survival were obtained later on with heterotopic,
non-functioning heart transplant.
In 1946, after unsuccessful attempts in the inguinal region,
Vladimir Demikhov of the Soviet Union successfully
implanted the first intrathoracic heterotopic heart
allograft.
Fig. 2 On the left, Vladimir Demikhov and a
dog with two heads. On the right, an
intrathoracic heart-lung transplant.

Vladimir Demikhov
In 1940, heterotopic heart transplantation in the inguinal
region.
In 1946, heterotopic first intrathoracic heart transplants.
Twenty-four variants were described and he mentions a 32
days survival of the graft.

Vladimir Demikhov
Transplantation of an additional head in a dog and the intrathoracic heart - lung
transplantation before the availability of cardiopulmonary bypass (Figure 2).
He performed 22 canine intrathoracic auxiliary heart transplants between 1951
and 1955.
This experiment was the first one to demonstrate that transplanted heart could
assume total circulation and the death of the dog was attributed to superior vena
cava thrombosis.

In 1959, Goldberg et al. at the University of Maryland
performed the first orthotopic heart transplantation in dog.
The first human cardiac transplant was a chimpanzee
xenograft performed at the University of Mississippi by
James Hardy in 1964.

In 1967 – on December 3, Christiaan Barnard performed the
first human-to-human heart transplant at the Groote Schuur
Hospital in Cape Town, South Africa.
Denise Darvall - Donor Louis Washkansky - Recipient

Adrian Kantrowitz performed the first pediatric heart
transplant in the world on December 6, 1967 at Maimonides
Hospital in Brooklyn, New York barely 3 days after
Christiaan Barnard.

In 1960, Shumway and his colleagues at Stanford
He is widely regarded as the father of heart transplantation
although the world's first adult human heart transplant
was performed by Christiaan Barnard in South Africa
utilizing the techniques developed and perfected
by Norman Shumway & Lower.
The introduction of transvenous endomyocardial biopsy by
Philip Caves in 1973 finally provided a reliable means for
monitoring allograft rejection.
The advent of the immuno-suppressive agent cyclosporine
dramatically increased patient survival and marked the
beginning of the modern era of successful cardiac
transplantation in 1981.

Organ transplantation act in India came in 1994
Dr. Venugopal led a team of doctors to perform the first
successful heart transplant in India on 3 August 1994.
This was the first of the 26 heart transplant procedures
performed by Dr. VenugopalAt KEM Hospital, Mumbai, Dr
PK Sen and his team performed the first heart transplant in
India in February 1968, months after the first attempt at
heart transplant was made by Christiaan N. Barnard in
December 1967 at South-Africa. Barnards's patient lived
for 18 days while Sen's patient died within 24 hours, this
was before immuno-supressing drugs were made

Surgical treatment of hf
Optimally treated HF patients
[Medical/ ICD/ CRT]
Still symptomatic
CABG
AVR/ MVR
SVR
Still symptomatic
Cardiac transplantation
Or
LVAD as destination therapy

Coronary artery bypass surgery[cabg]
STICH TRIAL: Surgical Treatment of Ischemic Heart Failure
Evaluation of outcome of revascularization in patients with
Ischemic Cardiomyopathy.
Ischemic Cardiomyopathy
Pathophysiology: Interrelated & overlap
Myocardial Hibernation
Myocardial Stunning
Irreversible myocyte death

CABG
Myocardial Hibernation:
Persistent contractile dysfunction at rest due to reduced
coronary blood flow.
It is partially or completely restored to normal by
revascularization.
Myocardial Stunning:
Prolonged but reversible post-ischemic contractile
dysfunction due to….
1. O2 free radicals
2. Loss of sensitivity of contractile filaments to calcium.
Irreversible myocyte death:
Ventricular remodelling & contractile dysfunction.

CABG
Selection of patients with HF for CABG:
 Extent of jeopardized but still viable myocardium: At least 25% of
myocardium should be viable.
 Presence of angina
 Severity of HF symptoms
 Degree of hemodynamic compromise
 LV dimensions
 Comorbid conditions
 Adequacy of target vessel & conduit strategy

CABG
Risk factors for CABG: [Risk is 2-10%]
Myocardial viability
LV dysfunction: LVEF < 35%
RV dysfunction
Advanced HF: NYHA III/ IV
LVEDP > 25 mm of Hg
Comorbidities:
Age > 70 years/ PAD/ MR/ COPD/ Renal dysfunction.
STS: Society of Thoracic Surgeons
Mortality increases with LVEF < 20% or with severe HF [NYHA IV].

[10 year follow up]
Randomized, Prospective, intention to treat study.
2800 patients from 100 centers.
Patients with LV dysfunction [LVEF < 35%] & CAD amenable to CABG were
randomly assigned to 3 different treatment strategy….
CABG
CABG + SVR
MED alone
Hypothesis:
1. CABG + MED Rx improves long term survival over MED Rx alone.
2. SVR provides additional long term survival when combined with CABG +
MED Rx .
Primary outcome: Death from any cause.
Secondary outcome: Death from CV cause + any cause.

[10 year follow up]

CABG
Recent guidelines for CABG:
Chronic HF with angina & LVEF < 35% with CAD:
LM
LM-equivalent
LAD
Multi-vessel
DM with complex multi-vessel CAD:
3 vessel
2 vessel, involving the proximal LAD.

cardiac transplantation: Recipient
Indications:
Contraindications:
Recipient Selection:
Recipient Evaluation:
Recipient Management:

Indications

indications of cardiac transplantation
1. Systolic heart failure (defined by LVEF <35%) with severe functional
limitations and/or refractory symptoms despite maximal medical therapy.
New York Heart Association Functional Class III–IV.
Maximal oxygen uptake (O2 max) of 12–14 mL/kg/min exercise testing.
2. Cardiogenic shock not expected to recover.
3. Ischemic heart disease with intractable angina not amenable to surgical or
percutaneous revascularization and refractory to maximal medical therapy.
4. Intractable ventricular arrhythmias, uncontrolled with standard
antiarrhythmic therapy, device therapy, and/or ablative therapy.
5. Congenital heart disease in which severe fixed pulmonary hypertension is not a
complication.

indications of cardiac transplantation
6. Cardiac tumors with low likelihood of metastasis.
7. Severe symptomatic hypertrophic or restrictive cardiomyopathy.
8. Refractory heart failure after previous cardiac surgery.
9. Significant cardiac allograft vasculopathy or chronic graft dysfunction of a
previous heart transplant.
10. Anatomically uncorrectable congenital heart disease.
11. Potentially correctable congenital heart disease associated with greatly
increased operative risk.

Contraindications

contraindications of cardiac transplantation
1. Age: >/= 70 years.
2. Obesity: BMI > 35 kg/m2 or Weight > 140% predicted for height & sex.
3. Malnutrition: BMI < 20 kg/m2.
4. Smoking: Current or recent tobacco use. [6 months abstinence]
5. Alcohol: Addiction or dependency. [6 months abstinence]
6. Illicit drugs: Addiction or dependency. [6 months abstinence]
7. Uncontrolled infection or sepsis
8. Active infection
9. Chronic viral infections: Hepatitis B, C & HIV & Chagas disease.

10. Malignancy:
Active or with high chances of recurrence
Exception, non-melanoma skin Ca, primary cardiac tumors restricted to
heart, & low grade prostatic ca.
11. Non-cardiac Vascular disease:
Cerebrovascular disease
Peripheral vascular disease: revascularization is not possible & associated
with ischemic ulcers.
Pulmonary infarcts
12. Diabetes:
Uncontrolled DM [HbA1c > 7.5%] or with end organ damage.
13. Renal dysfunction:
DM associated renal dysfunction is absolute contraindication. [unless
combined heart-kidney transplantation for irreversible renal dysfunction ]

14. Liver cirrhosis:
Secondary to cardiac disease(cardiac cirrhosis) is absolute
contraindication. [unless combined heart-liver transplantation for irreversible
hepatic dysfunction]
15. Pulmonary diseases:
Pulmonary fibrosis
Severe emphysema
FEV1 < 1 L or FEV1/FVC < 40% of the predicted
Recent [< 4 weeks] pulmonary infarct.
16. Pulmonary hypertension: Irreversible severe pulmonary arterial hypertension
Pulmonary vascular resistance (PVR) >5 Wood units
Pulmonary vascular resistance index (PVRI) >6
Transpulmonary gradient >16–20 mmHg
PASP >50–60 mmHg or >50% of systemic pressures

17. Systemic diseases with high recurrence:
Amyloidosis
Sarcoidosis
Hemochromatosis
18. GIT disease:
Uncontrolled GI bleeding
Diseases affecting the absorption of medications
19. Poor psychosocial factors:
Behavior pattern
Psychiatric illness
Mental retardation
Dementia
Inadequate social support

Recipient Selection

cardiac transplantation: recipient
Recipient Selection
Donor Allocation System
In US, the allocation of donor organs is done under the
supervision of the United Network of Organ Sharing [UNOS].
For a candidate who is > or = 18 years at the time of listing,
medical urgency is assigned according to UNOS policies.

Recipient Selection
Donor Allocation System
UNOS Allocation System:
Status 1 A
Status 1 B
Status 2

Status 1 A:
Candidates currently hospitalized in transplant hospital
1. Patient on mechanical circulatory support device: Total artificial heart/ IABP/
ECMO. [Status is valid for 14 days]
2. Patient requires continuous mechanical ventilation: [Status is valid for 14 days]
3. Patient requires continuous infusion of a single high dose iv inotrope or
multiple iv inotropes & continuous hemodynamic monitoring of LV pressures:
[Status is valid for 7 days]
Candidates current hospitalization is not required
4. Patient has a mechanical circulatory support device: LVAD/ RVAD/ BiVAD
[Status is valid for 30 days]
5. Patient has a mechanical circulatory support device & there is medical e/o
significant device related complications: [Status is valid for 14 days]

Status 1 B:[Status is valid for unlimited time]
LVAD
RVAD
BiVAD
Continuous infusion of iv inotrope
Status 2:[Status is valid for unlimited time]
Registered for listing, not 1 A or 1 B
Status 7: It is considered temporarily unsuitable to receive a thoracic organ
transplant.

Recipient Evaluation

Goal of heart transplant evaluation:
Patient should be sick enough: Cardiac status is limited
enough on optimal medical treatment.
Patient should be well enough: Absence of comorbidities that
would preclude the transplantation.
Patient should adapt to new transplant life style: Compliance
& social support.

Role of Exercise testing:
In patients undergoing transplant evaluation, measurement of peak
oxygen consumption (VO2) during cardiopulmonary exercise testing provides an
objective assessment of functional capacity and is more useful than NYHA
classification, ejection fraction, or other markers of heart failure severity, for
assessing prognosis and determining the optimal timing of listing for
transplantation.
VO2 is proportional to CO.

Role of Exercise testing:
Peak VO2 Survival Treatment
> 14 ml/kg/min
1- and 2-year survival rates that are
comparable or better than those
achieved with transplantation
Medically managed and undergo serial
exercise testing
10-14 ml/kg/min
Intermediate risk
Survival benefit similar to heart
transplantation among selected
patients that are able to tolerate beta
blockers, and have the protection of an
internal defibrillator
Continued medical therapy
< 12 ml/kg/min
In patients tolerating beta blockers,
appropriate threshold for
transplantation
Likely to derive a survival
benefit from transplantation.
< 10 ml/kg/min
Regardless of beta blocker use,
significantly reduced survival rates
with medical therapy compared to
cardiac transplantation
These patients should be listed for
transplantation.

Recipient Management

Standard of care for patients with HFrEF includes:
Optimal Medical treatment:
ACEI
ARBs
B-Blockers
Mineralocorticoid receptor antagonists
ARNI
Digoxin
Diuretics
Revascularization: PCI or CABG
Treatment for severe PAH:

Standard of care for patients with HFrEF includes:
Device treatment:
ICD
CRT
Mechanical circulatory support: For End stage HF
LVAD
RVAD
BiVAD
Total Artificial Heart
These are used as…..
Bridge to recovery
Bridge to transplant in patients awaiting to transplant.
Destination therapy in patients having contraindications to transplant.

cardiac transplantation: donor
Donor Selection:
Donor Evaluation:
Donor Management:

Donor Selection

Donor Selection
Concept of irreversible brain death is accepted both legally and
medically.
Patients with irreversible brain injury accompanied by the intent
to withdraw life support are considered to be potential organ
donors.
Brain dead is defined as irreversible cessation of all functions of
the entire brain. The heart does not need to stop for a valid
declaration of death.
Most common causes of brain death are
Intracranial haemorrhage
Blunt trauma
Penetrating trauma
Anoxic brain injury

CRITERIA FOR DETERMINING BRAIN DEATH
Clinical Evaluation:
 Mechanism of brain injury is sufficient to account for irreversible loss of brain
function.
 Absence of reversible causes of CNS depression:
CNS depressant drugs
Hypothermia (<32°C [85°F])
Hypotension (MAP <55 mmHg)
 Absence of neuromuscular blocking drugs that may confound the results of the
neurologic examination.
 No spontaneous movements, motor responses, or posturing
 No gag or cough reflexes
 No corneal or pupillary light reflexes
 No oculo-vestibular reflex (cold calorics)

CRITERIA FOR DETERMINING BRAIN DEATH
Confirmatory tests:
Apnea test for minimum of five minutes showing:
No respiratory movements
PCO2 >55 mmHg
pH <7.40
No intracranial blood flow

Donor Evaluation

Donor Evaluation
After identification of potent donor, contact local or host OPO
[Organ Procurement Organization]
Functions of OPO:
Organ donation consent
Verification of brain death
Evaluation & maintaining the donor
Allocation of donor organs
Detail history
Physical examination
Past medical history
Height & weight
Clinical course

Donor Evaluation
Lab investigations:
CBC
Metabolic panel
ABO
Viral: HBV, HCV, HIV, HTLV, EBV,CMV, West Nile Virus.
ECG, ECHO, CXR.
Pulmonary artery catheter evaluation.
Coronary angiogram to exclude significant CAD in male donor > 45
yrs & female donors > 50 yrs.

Donor Evaluation: Suitable donor criteria
1. Age <55 years
2. Absence of significant structural abnormalities
LVH (wall thickness >13 mm by echocardiography)
Significant valvular dysfunction
Significant congenital cardiac abnormality
Significant coronary artery disease
3. Adequate physiologic function of donor heart:
(LVEF) ≥45%
(MAP) >60 mmHg
(PCWP) 8–12 mmHg
Cardiac index >2.4 L/min x m2
CVP 4–12 mmHg
SVR 800–1200 dyne/seccm5

Donor Evaluation: Suitable donor criteria
4. No inotropic dependence:
Dopamine or dobutamine requirement <10 g/kg/min
5. Donor – recipient body size match:
Usually within 20-20% of height & weight.
6. Negative HBsAg, HCV & HIV.
7. Absence of active malignancy or overwhelming infection

Donor Management

Donor Management
Volume resuscitation
Optimizing cardiac output
Normalizing systemic vascular resistance
Maintaining adequate oxygenation
Correcting anemia, acid base, and electrolyte abnormalities
Correcting hormonal imbalances that occur after brain death and
that can impair circulatory function.

Donor Management
Optimal cold ischemic period of 4 to 6 hours in adult hearts is
generally considered safe.
DCD: Donation after Circulatory Death
Death of patient is confirmed with cardio-respiratory criteria
Asystole for at least 5 min. & Apnoea for at least 5 min. with
or with out brain death.
Donor hearts are preserved with either
Standard cold solution
Or
Organ Care System [Portable] Ex-vivo heart perfusion:
Maintains the donor heart warm & beating.

Organ Care System [Portable] Ex-vivo heart perfusion

donor-Recipient cross-matching
ABO compatibility: Mandatory.
Rh factor: It is not required as cardiac myocytes do not express the Rh antigen.
Overall body size: Donor should be at least 80% of the recipient’s weight.
HLA matching:
Because of relative scarcity of donor organs it is not routinely performed.
HLA cross-matching is performed only if recipient has significant anti-
HLA antibody titre.
Multiple pregnancy
Multiple blood transfusion
MCS
Previous transplant
Increased anti-HLA antibody is associated with rejection & CAV.

donor-Recipient cross-matching
Prospective cross-match
Gold standard
Virtual cross-match
Less reliable
Donor cells are mixed with
recipient’ serum to determine the
cell mediated cytotoxicity prior to
transplant
Recipient's anti-HLA antibodies are
compared to the donor’s HLA type.
Donor with HLA type that
corresponds to the presence of HLA
antibodies in recipient are avoided.

cardiac transplantation: technique
Heterotopic Transplantation
Orthotopic Transplantation
Biatrial
Bicaval
Living Organ Transplant
Dead Heart Transplant

Heterotopic cardiac transplantation
“Piggyback” transplantation
“Double heart”
Donor heart is connected in parallel with the recipient heart
by four surgical anastomoses at the level of:
RA
LA
Aorta
Pulmonary trunk

“Piggyback” transplantation
“Double heart”

 It accounts of less than 0.3% of heart transplants.
 It is beneficial if the patient :
Pulmonary hypertension.
Reversible HF (myocarditis)
 The negative aspects of this approach:
A difficult operation.
No angina relief.
Need for anticoagulation (the native heart can cease to
function and thrombosis).
 Contraindicated if the native heart has significant tricuspid or
mitral regurgitation.

orthotopic cardiac transplantation
[Greek: Orthos, straight + topos, place]

Biatrial Technique

Biatrial Technique
It is the original surgical technique, was described by Lower &
Shumway in 1960.
Heart is harvested in both donor & recipient by same technique.
Heart is removed by transecting the atria at the midatrial level,
leaving the pulmonary venous connections intact on the posterior
wall of LA.
Aorta & pulmonary artery are transected just above the semilunar
valves.
Harvested heart is cooled by placing it in iced preservation
solution & then placed in a secure container for transport.
Cold ischemic time: 3-4 hours.

Biatrial Technique
Heart is implanted in orthotopic position.
Reanastomosis: At midatrial level, beginning with the atrial
septum.
Great vessels are connected just above the semilunar valves.
Two asynchronous P waves on ECG:
One P wave from SA node of donor heart.
One P wave from SA node of native heart.

Biatrial Technique
Two asynchronous P waves on ECG

Biatrial Technique
The ischemic time & operative time is shorter.
Complications include:
Distortion of atrio-ventricular geometry
Atrio-ventricular regurgitation
Atrial & ventricular dysfunction
Atrial arrhythmias
Right atrial thrombus
Donor SA node dysfunction
Heart block that necessitate PPM implantation in 10-
20% of patients.

Bicaval Technique

Bicaval Technique
Donor atria intact
Anastomoses is done at SVC, IVC, & pulmonary veins.
Recipient atria are removed intact except small left atrial
cuff.
Ischemic time & operative time is prolonged.
Less chances of complications as compared with Biatrial
technique.
However narrowing of the SVC and IVC make biopsy
surveillance difficult.

Immediate post-operative care
Immunosuppression
Chronotropic support of donor SA node for first 2-3 post-
operative days:
TPI
IV B agonist infusion
Post-operative bradycardia: SA node dysfunction
Surgical trauma
Ischemia to SA node
Drugs, Amiodarone
Spontaneous recovery or requires PPI 10-20% in
Biatrial & < 10% in Bicaval technique.
Patient with uncomplicated course can be discharged
from hospital as early as 7-10 days after heart
transplantation.

Living Organ Transplant
In February 2006, at the Bad Oeynhausen Clinic for Thorax and
Cardiovascular Surgery, Germany, surgeons successfully transplanted a
'beating heart‘ into a patient.
Rather than cooling the heart, the living organ procedure keeps it
at body temperature and connects it to a special machine called an Organ
Care System that allows it to continue pumping warm, oxygenated blood.
This technique can maintain the heart in a suitable
condition for much longer than the traditional method.

Dead Heart Transplant
In October 2014, Australian surgeons have recently
successfully transplanted dead hearts into patients for the first
time.
According to Surgeon Kumud Dhital, the incredible
development of the preservation solution with this technology
of being able to preserve heart, resuscitate it and to assess the
function of heart has made this possible.

Physiology of the transplanted heart
Transplanted heart is completely denervated.
Both afferent [from heart to CNS] & efferent [from CNS to
heart] nerve supply is lost.
Loss of afferent nerve supply:
No chest pain
Loss of efferent nerve supply:
Normal resting HR is faster usually between 90-110 bpm.
It is due to loss of vagal tone.

Effects of exercise on Transplanted heart
Loss of efferent nerve supply
Recipient must rely on circulating catecholamine
to respond to exercise
Blunting of HR response to exercise
[Slow rise & fall of HR after exercise because of slow rise &
decline of circulating catecholamine to baseline]

No reflex tachycardia in response to hypotension/ hypovolemia.
Diurnal changes in BP are abolished.
Biatrial anastomoses causes less atrial contribution to SV.
Diastolic dysfunction is common.
ECG has two P waves.
Re-innervation:
Variable
Possible angina
Improvement in HR response & exercise tolerance to exercise
Decreases the resting HR

Lack of baroreceptor reflex:
Orthostasis
Carotid sinus massage is not effective in terminating re-entrant
tachycardia.
Direct sympathomimetic drugs: EFFECTIVE.
Isoproterenol
NE
Epinephrine
Phenylephrine
Dopamine
Indirect sympathomimetic drugs: NOT EFFECTIVE.
Anticholinergics
Anticholinesterase
Pancuronium
Ephedrines

Response to drugs:
Digoxin:
Little effect on SA & AV node
Unable to control rate in AF [loss of vagal tone]
However, inotropic effects are persistent.
Atropine:
Will not increase the HR.
Isoproterenol:
Increases both inotropy & chronotropy.
Vasodilators:
Will not cause the reflex tachycardia.
B-blocker:
Transplanted heart is more sensitive.

Post operative treatment
Induction immunosuppression
Maintenance immunosuppression
Induction immunosuppression:
3 drug regimen
CNI: Calcineurin inhibitors: Tacrolimus/ Cyclosporine
Anti-metabolite/ Anti-proliferative: MMF/Azathioprine
Corticosteroids:
Augmented Induction immunosuppression:
3 drug regimen
+/-
ATG or IL-2 inhibitors[Dacilizumab/ Basilizumab]

Maintenance immunosuppression:
3 drug regimen
Or
2 drug regimen
Or
1 drug regimen: Tacrolimus
Following early withdrawal of MMF & steroids.
High dose is required & associated with high serum
creatinine after 1 year.

CNI: Calcineurin inhibitors: Tacrolimus/ Cyclosporine
Tacrolimus is preferred
Inhibit Calcineurin
Decreases the IL=2, TNF-alpha, INF-beta, & GM-CSF
Decreases the T- cell activation & proliferation
Tacrolimus: 0.02-0.04 mg/kg/day in 2 divided doses.
Cyclosporine: 3-6 mg/kg/day in 2 divided doses.

Tacrolimus & Cyclosporine: Toxicity
Both:
Nephrotoxicity
Neurotoxicity
HTN [LVH]
Hyperlipidaemia
Hypomagnesaemia
Tacrolimus:
New onset DM
Hyperkalaemia
Cyclosporine:
Hirsutism
Gingival hyperplasia
Hyperuricemia
Hypokalaemia

Anti-metabolite/ Anti-proliferative: MMF/Azathioprine
MMF is preferred
Decreases the T- cell & B- cell activation & proliferation
MMF: 2000-3000mg/day in 2 divided doses.
Azathioprine:1-3.5mg/kg/day, titrated to keep WBC 3000.
MMF & Azathioprine can potentiate each others toxicity.
MMF Toxicity:
GIT [Nausea & Diarrhea]
Azathioprine Toxicity:
BM suppression
Hepatitis
Pancreatitis
Malignancy

Corticosteroids
Induction/ Maintenance/ DOC in Acute Rejection
Non-specific anti-inflammatory
Decreases the antigen presentation
Decreases the cytokines
Decreases the proliferation of lymphocytes
Dose: 1 mg/kg/day in 2 divided doses, usually rapidly tapered to
0.05 mg/kg/day by 6-12 months.

Corticosteroids: Toxicity
Weight gain
HTN
Hyperlipidaemia
Hyperglycaemia
Poor wound healing
Osteopenia
Salt & water retention
Proximal myopathy
Cataract
Peptic ulcer
Growth retardation

Augmented Induction immunosuppression:
3 drug regimen
+/-
ATG:
Decreases the early rejection but increases the risk of infection.
IL-2 inhibitors[Dacilizumab/ Basilizumab]:
Decreases the early rejection with out increasing the risk of
infection.
Dacilizumab with MMF: Increases the Fungal infections.

PSI: Proliferation Signal Inhibitors
mTOR Inhibitors
Sirolimus/ Everolimus
Inhibit the T- cell, B- cell, Fibroblast,&
Endothelial cells activation & proliferation
Used as induction therapy instead of CNI.
Prevents or improve CNI induced renal dysfunction &
reverses the LVH.
Used as maintenance therapy.
Used in place of MMF:
In c/o, Rejection, CAV, Malignancy, CMV infection.
Sirolimus: 0.5-2 mg/kg/day.
Everolimus: 1.5 mg/day in 2 divided doses.

Sirolimus/ Everolimus: Toxicity
Poor wound healing [Decrease in fibroblast]
Oral ulcerations
LL oedema
Hyperlipidaemia: CHL & TG
Pleural & Pericardial effusion
Pulmonary toxicities: interstitial pneumonia/ haemorrhage.
BM suppression: Pancytopenia

Post operative complications
Pericardial effusion: With or without tamponade.
Bleeding:
Primary graft failure/ Early graft dysfunction: RV & LV systolic/
diastolic dysfunction
Ischemia
Reperfusion injury
Prolonged cold ischemic time
Pulmonary HTN
Severe RVR
Treatment:
Inotropes
Vasodilators
MCS [Mechanical Circulatory Support]
Emergent re-transplant.

Cardiac arrhythmias:
Sinus tachycardia: Donor heart is denervated.
SA node injury: Biatrial technique/ CAV.
Spontaneous recovery.
PPI
AV node injury: AV Blocks
RBBB: Prolonged cold ischemic time/ Endomyocardial biopsy.
AF:
Early… during healing of atrial anastomoses.
Late… due to rejection.
AFL:
Typical cavo-tricuspid isthmus dependent, requires RFA between
TV annulus & RA suture line.
APCs & VPCs:
VT& VF: SCD
CAV/ rejection.

Transplant rejection: MC cause of death after transplantation
Hyperacute rejection:
Acute rejection:
ACR [Acute Cellular Rejection] Cell mediated.
AMR [Antibody Mediated Rejection] Acute humoral.
Chronic rejection:

Hyperacute
rejection
Acute
rejection
Chronic
rejection
Minutes to hours Weeks to months Months to years
Pre-existing antibody
T cell mediated
or
Antibody mediated
Antibody mediated
or
Ischemia
Previous organ grafts
Multiparity
Multiple BT
Intravascular
thrombosis
Younger
Female donor
CMV
Black race
HLA mismatch
Early tolerance to
immunosuppression
Transplant CAD
CAV

Clinical manifestations of transplant rejection:
Asymptomatic
Nonspecific symptoms: Fatigue, low grade fever.
Heart failure
Hypotension
Pericardial effusion
Atrial arrhythmias
Diagnosis of transplant rejection:
No reliable serological markers
Anti-HLA antibodies in recipients
Donor cell free DNA in blood & urine of recipients
GEP [Gene Expression Profile]
“Endomyocardial biopsy” is gold standard.

Endomyocardial biopsy
Right internal jugular vein or femoral vein
Bioptome in RV
5 pieces of endomyocardium
from RV septum.
Every weekly for 4-6 weeks,
then every 3 monthly for 1 year,
then 4-6 monthly up to 5 years.

Endomyocardial biopsy [ISHLT]
Grade Description
0 No rejection
1 Mild
Interstitial &/or perivascular
infiltrates with up to one focus of
myocyte damage
2 Moderate Two or more foci
3 Severe
Diffuse damage/ edema/ vasculitis/
hemorrhage

Treatment of transplant rejection:
 Steroids
 Higher CNI
 MMF=> PSI
 IV Immunoglobulins
 Cytolytic therapy [ATG]
 Plasmapheresis
 Inotropic agents
 Heparin
 IABP/ ECMO support

CAV: Cardiac Allograft Vasculopathy
Post transplant panvascular CAD
More aggressive
Worst prognosis
Etiology:
Neointimal proliferation of vascular smooth muscle cells
Risk factors:
Younger females
HLA mismatch
CMV infection
Ischemia & reperfusion injury
Rejection
Traditional risk factors like, DM, HTN, Smoking, Obesity, &
Dyslipidemia.

Non-transplant Atherosclerosis Cardiac Allograft Vasculopathy
Epicardial vessels
Panvascular [Epicardial & micro
vessels]
Focal Diffuse
Eccentric lesion Concentric lesion
Lipid rich Lipid poor
Slow progression Rapid progression
Early calcification
Late calcification

Coronary Angiography: Every yearly

IVUS: Gold standard

Clinical manifestations of CAV:
Typical chest pain is absent. [Denervated heart]
Chest pain can be present in c/o re-innervation.
Ischemia & infarction
HF
Arrhythmias
SCD
Treatment:
Aspirin
Control of HTN & hyperlipidaemia
Statins
PSIs: Sirolimus/ Everolimus
PCI & DES
CABG
Re-transplantation

Post Transplant infection:
Early: within 1st month
Late: 2 months to 1 year
Indwelling catheters, wound infections, mechanical ventilation,
MCS.
Sternal wound infection/ Mediastinitis/ Pneumonia/ UTI.
Nosocomial & Opportunistic infections:
Bacterial: E.coli,Klebsiella,Proteus,Staph,Legionella.
Fungal: Aspergillus, Candida.
Viral: CMV.
Mycobacterial
Nocardia
Toxoplasma

Post Transplant infection:
Investigations to detect the focus
Immune monitoring assay:
To measure the ATP release from activated lymphocytes.
< 200 ATP/ mL s/o risk of infection.
Decrease the dose of CNI& MMF [Immunosuppression]
Anti-microbial prophylaxis:
Oral candidiasis,Toxoplasmosis,Pneumocystis,CMV during 1st year.
Role of vaccination: Controvesial
Live vaccines are contraindicated.
In some centres, dead vaccines for Pneumococci & Influenza
after 6 months of transplant.

Post Transplant malignancy:
Skin malignancy is MC: Human papilloma virus
Squamous cell ca
Basal cell ca
EBV: PTLD, MC is B cell lymphoma.
HHV 8:Kaposis sarcoma.
Solid organ malignancy: Ca lung, breast & prostate.
Screening:
Mammography
PAP smear
Colonoscopy
Prostate & skin examination
Treatment:
Decrease the immunosuppression
PSIs [Sirolimus/ Everolimus] instead of CNI & MMF.

Post Transplant Hyperlipidaemia:
Usually within 1st 3 month & then decreases after 1 year.
Related to immunosuppressive drugs.
CVA/ PAD/ CAV
Treatment:
Statins: Pravastatin & Simvastatin.
Post Transplant Renal insufficiency:
CNI induced vasoconstriction, increased endothelin-1, & decreased
NO.
Treatment:
Decreased the dose of CNI
Replace CNI with PSIs.

Post Transplant New onset DM/ worsening underlying DM:
Usually with CNI: Tacrolimus >> Cyclosporine.
Treatment:
Avoid Metformin
Sulphonylureas are DOC.
Post Transplant HTN:
Usually with CNI: Cyclosporine >> Tacrolimus.
Difficult to control, requires multidrug therapy.
Treatment:
Avoid B-blockers
ACEI/ ARBs: may not be tolerated because of Renal
insufficiency.
CCBs: Nifedipine & Amlodipine are often effective.

Post Transplant Osteoporosis:
Usually with Corticosteroids.
Treatment:
Calcium, D3,& Bisphosphonates.
Post Transplant Gout:
Drug-drug interactions:

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