Heart Transplant

Updated: April 10, 2020

Cardiac Pacemaker

https://link.springer.com/chapter/10.1007/978-3-319-43773-6_8

In addition, the depolarization of the remaining native heart is not transmitted beyond the anastomotic suture line to the donor heart.

Postoperative Cardiovascular Physiology

Heart Rate

Immediately post-operatively, the transplanted heart is bradycardic likely from sinus node

dysfunction (myocardial ischemia and surgical manipulation) and can last for 1-2 weeks. 

The sinus node dysfunction is usually transient but a 2-5% prevalence of permanent pacemaker

placement has been report (1).

In time, the transplanted heart will have a higher heart rate, between 90-110 beats per minute, likely related to the loss of vagal tone from denervation (134). With exercise, heart rate may increases slightly (likely due to Bainbridge reflex). 

Stroke Volume (Diastolic Dysfunction)

  • due to reperfusion stunning usually for the first 24 hours

  • causes impaired filling

  • filling pressures of 10-15 mmHg may be required

  • if does not resolve within 1 week, suspect acute rejection in your differential diagnosis

Cardiac Output

Because of the impaired heart rate and diastolic dysfunction, adequate heart rate and

atrio-ventricular synchrony are often required to maintain cardiac output. 

A minimum heart rate of 90 beats per minute is usually maintained using:

  • epicardial pacing

  • isoproterenol infusion

In addition, Frank-Starling mechanisms and its affect on end-diastolic volume are further implored to maximize the cardiac output. Because of this, heart transplant patients become preload dependent with higher filling pressures needed a concept that is very important especially before the use of anesthesia. 

 

Maximizing the heart rate and stroke volume ensures an adequate cardiac output. 

The normal response to changes in position (eg. sitting, standing, walking) are lost as are the variations in response to stimuli such as valsalva maneuver, carotid sinus massage, body position as well as normal response to laryngoscopy and intubation.

Additionally, especially with exercise, left ventricular end-diastolic volume remains the main mechanism of increasing stroke volume and thus cardiac output. Relying on circulating catecholamines would have a delayed chronotropic response and thus not an adequate compensatory mechanism. Remember, normally an innervated heart that undergoes a sudden reduction in intravascular volume will have a simultaneous increase in both heart rate and contractility. In the denervated heart, the initial response is only dependent on Frank-Starling mechanisms.

Certain medications that will not work:

  • phenylephrine

  • atropine

  • amyl nitrate 

  • digoxin

  • neostigmine

Adenosine has an exaggerated response - use 1 mg

Reference: (1) Chinnock et al, Pacing Clin Electrophysiol, 1996, (134) Beck, Circulation, 1969

Donor-Recipient Size Mismatch

Mismatch can affect cardiovascular function

Immune System

Histocompatibility complexes: protect an individual from organism or toxins that might cause damage (77-78). All cells and toxins possess specific antigens that uniquely identify them. Antigens provoke the immune system and once activated it functions in two different pathways:

  • innate immune system

  • adaptive (acquired) immune system - this is responsible for allograft rejection

    • cell-mediated​ immune system (T cells)

    • humoral-mediated immune system (B-cells)

Innate Immune System

  • Complement system consists of 3 pathways:

    • Classical

    • Lectin

    • Alternative

Adaptive Immune System

T lymphocytes are activated by antigen which causes a proliferation and release of a

vast quantity of different types of T cells (helper T, cytotoxic T, and suppressor

T cells).

  • Helper T cells predominate and are primarily responsible for regulating

immune function by producing lymphokines (eg. IL, IF). Its these lymphokines

that facilitate or inhibit both B and T cells. 

  • Cytotoxic T cells directly attack the offending antigen (especially foreign cells)

  • Suppressor T cells are believed to modulate by releasing chemicals that turn "off" the immune reactions; might also play a role in autoimmune disorders

Antigen can directly activate B lymphocytes (plasma cells) which are responsible

for antibody production and activation of the complement system (C3-->C3b) which

will be responsible for neutralizing the antigens by means of: agglutination,

precipitation, opsonization or lysis. 

 

Allograft Rejection

Almost all cardiac transplant recipients will experience episodes of graft rejection at some point. 

Immune activation, unless suppressed, will damage and ultimately destroy the transplanted donor heart. 

Acute cardiac rejection manifestations is quite variable: 

  • malaise

  • reduced exercise tolerance

  • low grade fever

Rejection is best diagnosed by means of periodic endomyocardial biopsies. After the initial biopsy, routine biopsies are performed biweekly for the first three months, monthly for 6 months and then every 3 months; after the first 2 years, biopsies are performed on an annual basis. Episodes of rejection can alter this schedule and the number of biopsies that may be required. 

 

Chronic rejection manifests as an accelerated graft atherosclerosis. Incidence is about 10-15% by the end of the first year and 35-50% by the fifth year. Evidence suggests that denervation causes an up-regulation of muscarinic receptors that promotes an influx of calcium in the transplanted hearts coronary arteries causing a circumferential, diffuse narrowing of the intraluminal diameter. Calcium channel blockers may ameliorate this problem. 

Immunosuppressive Therapy

Most centers use a "triple-drug" regimen which consists of:

  • glucocorticoids

  • antiproliferative

    • mycophenolate​

    • azathioprine

    • cyclophosphamide

    • chlorambucil

    • methotrexate

  • calcineurin inhibitors

    • tacrolimus (prograf, FK506)

    • cyclosporin

References: (77) Barry et al, Cirulation, 1999, (78) Hanto et al, Surgery Scientific Principles and practices, 1993, 

Infection​

Infection is the leading cause of death among cardiac transplant patients, between 1 month and 1 year, and is usually caused by:

  • mediastinitis

  • pneumonia

  • urinary tract infection

  • central-line induced sepsis

The most frequent infecting organism is cytomegalovirus.

Despite advances in antimicrobial prophylaxis, infection continues to be one of the most important barriers for long-term survival. Methods to identify heart recipients at risk of infection could allow physicians to make targeted adjustments to immunosuppressive strategy and prophylaxis aimed at decreasing patient morbidity (2). 

Immunoglobulin G (IgG)

  • investigated as a risk factor for infection 

  • < 400 mg/dL is a risk factor for infection with:

    • respiratory infection​

    • cytomegalovirus (CMV)

    • aspergillus and other fungal infections

References: (2) Carbone et al, J Neurol Neurosurg Psychiatry, 1999

Complications

  • primary graft failure

  • rejection

Primary Graft Failure

  • poor cardiac output with adequate filling pressures

Rejection

  • hyperacute 

    • usually happens within the first few hours of transplant​

    • antibody mediated

  • acute

    • usually happens after the first week​

    • T-mediated

  • Treatment

    • high dose methylprednisolone pulse therapy ​

complement system.PNG

Physiology after Heart Transplant

  • cardiac response to demand is greatly altered secondary to permanent sympathetic & parasympathetic denervation

  • heart rate increases very slowly from circulating catecholamines (B receptors upregulated)

  • to maintain cardiac output, patient rely on stroke volume instead of HR - thus, they are preload dependent

  • denervation prevents patient from experiencing myocardial ischemia chest pain

  • ephedrine, atropine are mediated via sympathetic and parasympathetic and will have minimal effects

  • digitalis will have no effect on atrioventricular nodal conduction but retains its direct inotropic effect

  • beta adrenergic agonists and phosphodiesterase inhibitors are unaffected

  • nitrates are unaffected but reflex tachycardia is depressed

  • vasoconstrictors are unaffected but less reflex bradycardia

  • orthostatic hypotension can be avoided by sitting up in increments and eventually standing slowly (if not patients will become afraid of doing physical therapy)

Complications

- affected by donor characteristics and operative technique chosen

- bicaval vs. biatrial technique has resulted in less atrioventricular valve dysfunction, arrhythmia, improvements in hemodynamics, exercise capacity and overall survival

  • right heart failure

  • left heart failure

  • pulmonary hypertension

  • systemic hypertension

  • heart block

  • bradycardia

  • tachycardia

  • early graft failure

  • allograft rejection

  • accelerated allograft coronary artery disease

  • renal dysfunction

  • infection

  • malignancy

Post-Operative Management

  • pacing and/or beta-adrenergic agonist (dopamine, dobutamine, epinephrine, isoproterenol)

  • further depressed cardiac function

    • IABP

    • ECMO

    • ventricular assist device

 

  • preload dependence

    • sensitive to positive pressure ventilation

    • bleeding

    • tamponade

    • pneumothorax

 

  • Right Ventricular Failure / High Pulmonary Vascular Resistance

    • inhaled Nitric Oxide

    • prostacyclin

    • nitroglycerine IV

    • nitroprusside IV

    • atrial pacing

    • beta adrenergic agonist

    • phosphodiesterase inhibitors

    • ECMO

    • RVAD

 

  • Arrhythmias

    • atrial/ventricular tachyarrhythmias are common after transplant

    • atrial arrhythmias maybe associated with allograft rejection

 

  • Left Ventricular Dysfunction after Heart Transplantation

    • Early Left ventricular Dysfunction (Primary Graft Failure)

      • occurs within hours to days of heart transplantation

      • can be apparent in the OR

      • usually due to one of three causes:

        • hyperacute rejection

        • reperfusion injury

        • suboptimal donor

    • Late Left Ventricular Dysfunction

      • usually due to:

        • allograft rejection

        • ischemia caused by allograft coronary artery disease

        • infectious myocarditis

        • unknown cause

 

  • Endomyocardial biopsy

    • serial biopsies are performed after surgery to detect any signs of rejection

    • cellular rejection relies mainly on endomyocardial biopsy especially when vague clinical symptoms and no reliable serological markers available

    • antibody-mediated rejection difficult to diagnose (usually detected by rising donor-specific antibody titers when other causes have been excluded

Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial

  • in patients with end-stage heart failure, LVADs reduce all-cause mortality, as compared to optimal medical therapy

Immunology / Immunosuppression

Immunosuppression

  • methylprednisolone 125mg IV x 3 doses, then 75mg IV x 3 doses, then 50mg IV x 3 doses

 

Induction:

  • IL-2 receptor antagonists (eg. Basiliximab, Simulect)

    • prevents T cells from replicating and activating B cells

    • given 4 days apart

    • may be used if holding tacrolimus for renal insufficiency

  • Polycolonal anti-thymocyte antibodies (eg. ATGAM or Thymoglobulin)

 

Antiproliferatives

  • Mycophenolate

    • 1500mg PO q12 hours

    • metabolised in the liver to the active moiety mycophenolic acid

    • reversibly inhibits inosine monophosphate dehydrogenase, the enzyme that controls the rate of synthesis of guanine monophosphate in the de novo pathway of purine synthesis used in the proliferation of B and T lymphocytes

    • other cells are able to recover purines via a separate salvage pathway and are thus able to escape the effect

Calcineurin Inhibitors

  • Cyclosporine

  • Tacrolimus

    • dosage forms: 0.5, 1, 5

    • hold if renal insufficiency present

    • can start > 6 hours post transplant

    • Side effects

      • posterior reversible encephalopathy ​syndrome (PRES)

      • diarrhea

      • hypertension

      • low phosphate

      • low magnesium

Biopsy

  • tells us about cell-mediated rejection

Donor Specific Antibodies (DSA)

  • tells you about antibody mediated rejection

  • these are antibodies directed against antigens expressed on donor organ; when not treated clinically, results in an immune attack against the transplanted organ and increases the risk of graft loss/rejection

  • DSA attacks the endothelium of the allograft resulting in antibody mediated rejection (AMR); complement activation ??? 

IgG level

  • <500 needs repletion

Prophylaxis

  • TMP-SMX (bactrim)

    • pneumocystis pneumonia prevention (10-14% rate in US transplant centers)

    • listeria monocytogenes prophylaxis

    • toxoplasma gondii prophylaxis

References

UpToDate, Pham, October 16, 2013

... but I would more especially commend the clinician who, in acute diseases, by which the bulk of mankind are cutoff, conducts the treatment better than others.
 
Hippocrates, 400 BC