Heart transplantation associated arrhythmias

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Syed rizvi, M.B.B.S[2] Associate Editor(s)-in-Chief: José Eduardo Riceto Loyola Junior, M.D.[3]

Overview

Patients with end-stage cardiac disease can be managed with heterotopic heart transplantation, which is the most effective long term therapy, while implantable left ventricular assisted devices have also shown desirable outcomes. The short term mortality in these patients has been decreasing due to more refined surgical techniques, as well as the use of more advanced immunosuppressive regimen, but the morbidity in these patients has increased due to repeated transplant rejection episodes, and Cardiac allograft vasculopathy, which usually manifests as arrhythmia.

Historical Perspective

• Performed by a team led by Dr Christiaan Barnard in 1967, at the Groote Schuur Hospital and the University of Cape Town.
• Subsequent orthotopic HTs were reported by Brink J et al. (2009) as:
  • Barnard performed  10 more orthotopic HTs between 1967 to 1974, two of whom survived for 13 and 23 years respectively.
  • Dr. Shumway from Stanford University and Dr. Juro Wada at Sapporo Medical University in Japan performed the first HT in the United States (US) and Japan respectively, in 1968.
  • 166 transplants were performed globally between 1968 to 1970, however, due to complications such as severe graft rejection reaction and infection, the 2-year survival rate was reported to be only 11%.
• Heterotopic HTs:
  • Due to poor survival rate post orthotopic HT Barnard considered heterotopic (piggy-back)  HT as a possibility to improve patient survival rate in 1974.
  • Heterotopic heart transplantation allows the recipient's heart to maintain circulation while rejection reaction is reversed with immunosuppressive therapy.
  • Advent of cyclosporine in 1980 was a much needed addition to post-operative management which contributed greatly to reduce incidence of severe life-threatening rejection episodes, hence Barnard’s group was able to resume orthotopic heart transplantation(OHT).

Techniques of HT

• John, R et al.  guide about techniques of HT:
  • Preoperative preparation:
    • Successful HT requires very close coordination between the donor and recipient surgical team.
    • Preoperative assessment includes: following considerations are critical to success of HT
      • Assessing compatibility of the donor heart.
      • Surgical team ensures optimum health of the recipient by ruling out any ongoing coagulation defect or infection.
  • Intra-operative phase is planned to limit donor ischemic time to less than six hours; preferably less than four hours in case of old donor or increased pulmonary vascular resistance.
• John, R et al. report  Bicaval and Biatrial anastomosis are two most common techniques of HT
  • Biatrial method:
    • Part of the recipient right and left atria is retained which is sutured to respective atrial of the donor.
    • This allows surgeons to preserve the recipient's sinus node, however due to disruption of  blood supply and denervation this is rendered non-functional.
    • There is a complete conduction block across the suture line in the right atrium.
  • Bicaval method:
    • Anastomosis is made at the level of two vena cavae, the great vessels and the left atrial cuff around the pulmonary vein.
    • There is less sinus nodal injury, tricuspid regurgitation, and atrial dilatation making it the preferred technique of the current times.
    • Potential advantages: associated with reduced hospital stay,decreased incidence of atrial dysrhythmias and conduction disturbances, less mitral and tricuspid incompetence secondary to atrioventricular (AV)  geometry distortion and right ventricular failure.
    • Potential disadvantages: increased ischemic time and the possibility of narrowing of the caval anastomosis.  

Classification

Types of Arrhythmias			Occurrence	Common mechanism	Treatment
Tachyarrhythmias	Supra-ventricular tachy- arrthymia (SVT)	Atrial fibrillation	Common in early postoperative period Over all frequency 47.3% (Elkaryoni et al.)	1. Graft manipulation (primary graft failure)	1. Evaluate and manage the trigger 2. Persistent cases: Catheter ablation
				2. Inflammatory changes (pericardial inflammation)
				3. Autonomic hypersensitivity
				4. Ischemia
				5. Denervation
				6. Early rejection
				7. Inotropes
		Atrial flutter	Common in immediate  postoperative period (>1 month) Over all frequency 7.6% (Elkaryoni et al.)	1. AR - 28% cases 2. Remodelling of atria (late onset ) 3. Atrial suture lines - conduction barriers 4. Recipient to donor atrial conduction 5. Increased risk with bi-atrial method 6. Increased risk with older donor age	1. Evaluate and manage the trigger 2. Persistent cases: Radiofrequency ablation
	Other SVTs	Focal atrial tachycardia		Formation of depolarization foci near the atrial scar that take control of the heart rhythm. Foci can be found in donor atrium or in the atrial remnant of recipient which passes into the donor.	Focal catheter ablation
		Atrial reenterant tachycardia & Nodal reenterant tachycardia		Requires a preexisting route in the donor that allows a macroreentrant.	Radiofrequency ablation (RFA)
		Atrial macro-reentrant tachycardia		site of origin is mostly in the upper right atrium, around the native and donor suture line	Radiofrequency ablation (RFA)
		Recipient-to-donor atrial conduction tachycardia		Site of origin usually right atrial anastomosis.	Radiofrequency ablation (RFA)
	Ventricular tachycardias Over all frequency 7.6% (Elkaryoni et al.)	Non-sustained	Early post-transplat period	Acute rejection Graft vasculopathy Severe cardiac allograft vasculopathy (in symptomatic cases)	ICD placement (in symptomatic cases)
		Sustained	Early post-transplat period	1. Acute rejection (if presenting during immediate post operative period) 2. Allopathic vasculopathy 3. LV dysfunction	Prompt for coronary angiography and cardiac biopsy
		Ventricular fibrillation	1.1%	Transplant coronary artery disease
Bradyarrhytmia		Sick sinus syndrome (SSS)	0.5  % (Elkaryoni et al.)	1. Sympathetic denervation 2. Ischemic injury to the sinus node 3. Graft ischemia or rejection 4. Drug effects
		Sudden cardiac arrrest	3.7% (Elkaryoni et al.)	1. SSS 2. Cardiac allograft vasculopathy 3. Transplant coronary artery disease
		Heart Block	0.3% (Elkaryoni et al.)	1. Postoperative injury 2. Progressive conduction system disease associated with coronary artery disease 3. LV dysfunction 4. Chronic rejection 5. Injury from endomyocardial biopsies.

• Post heart transplant arrhythmias can be divided into tachyarrhythmias (heart rate > 100/min)  and bradyarrhythmia (heart rate < 60 /min).

Tachyarrhythmias

• Tachycardias are further classified based on place of origin, such as supraventricular arrhythmias originate between sinus node and the AV node, where as ventricular arrhythmias originate below the AV node at the ventricular level.

Supraventricular tachyarrhythmias (SVT)

• Are most common POA noticed after HT.
• Overall AF is reported to be more common as compared to AFl (47.3% vs 7.6%).
• However older studies report AF (0.3 to 24%)  second after AFl (2.8 to 30%)

Supraventricular tachyarrhythmias (SVT)
	EKG	Path
Atrial Fibrillation (AF)	EKG findings: irregularly irregular rhythm, absent P waves, ventricular rate of 100-180 beats/minute, variability in QRS complexes intervals, narrow QRS complexes.  Mechanism: Early postoperative period: associated with pericardial inflammation, graft manipulation, primary graft failure, allograft rejection (AR) (37.5%), and autonomic changes(such as due to denervation), ischemia, and inotropes. Postoperative period (> 1 month): seen to be associated with allograft vasculopathy (in 21% cases), rejection (in 46% cases) or infection. Occurrence: In relation to technique of heart transplantation: meta-analysis reports pooled estimated incidence of AF: Biatrial technique: 18.7% (95%CI: 10.3%-31.5%) Bicaval technique: 11.1% (95%CI: 6.5%-18.4%) Frequency in relation to timing of onset postoperative period: POAF (</= 1 month): 6.2% POAF (> 1 month): 4%
Atrial Flutter	EKG findings: regular rhythm at the rate of 200 to 300 beat per minute, accompanied with flutter waves (saw-tooth pattern) Mechanism: AR - 28% cases Remodelling of atria (late onset ) Atrial suture lines - conduction barriers Recipient to donor atrial conduction Increased risk with bi-atrial method Increased risk with older donor age Occurrence: POAFl (</= 1 month): 2.9% POAFl (> 1 month): 7.4%

Other supraventricular Tachycardia : reported in patients with stable OHT these SVTs are diagnosed on electrophysiological testing.

• Focal atrial tachycardia:
  • Mechanism:  
    • Formation of depolarization foci near the atrial scar that takes control of the heart rhythm.
    • Foci can be found in donor atrium or in the atrial remnant of the recipient which passes into the donor.
    • Areas of slow electrical conduction are formed by scars and fibrosis, that leads to the formation of macro reentrant and development of focal atrial tachycardia
• Atrial reentrant tachycardia: Rare in transplanted patients
  • Mechanism:
    • Require a pre-existing route in the donor that allows a macro reentrant.
    • They are uncommon in transplanted patients.
• AV and AV nodal reentrant tachycardia: originates from transplanted heart due to changes in autonomic tone affecting the substrate are likely to be the mechanism of tachycardias in the recipient patient. This has been reported even if the donor never experienced any tachycardias.
• Atrial macro-reentrant tachycardia: site of origin is mostly in the upper right atrium, around the native and donor suture line. Managed successfully with ablation.  

• Recipient-to-donor atrial conduction tachycardia: site of origin usually right atrial anastomosis

• Ventricular tachyarrhythmia:
  • Types:
    • Sustained VT
    • Non-sustained VT

• Occurrence: early post-transplant period
• Mechanism:
  • Acute rejection
  • Graft vasculopathy

Bradyarrhythmias

• Can be manifested due to node dysfunction or AV block, preoperative amiodarone use, angiographic nodal artery abnormality, prolong donor heart  ischemic time and rejection, denervation of autonomic nerves.
• The risk of bradyarrhythmia is also associated with  type of HT.  likely to occur due to the biatrial HT technique.
• In June 2021 a case report described a patient who had a recent heart transplant (biatrial procedure, keeping the native sinus node and blocking electrical conduction at the suture lines so that the recipient's right atrium impulses could not be conducted to the donor heart) and presented with transient loss of consciousness with asystolia that lasted 8 seconds.
  • His ECG showed regular ventricular bradycardia at 40 bpm with AV dissociation, which suggested transient complete AV block. Patient was referred to implant a permanent pacemaker. During the procedure an ECG was performed, which showed regular R-R interval with retrograde P waves just prior to the QRS suggesting a junction escape rhythm. A few seconds into the ECG and the morphology changes, the QRS is still narrow but there are P waves which vary in morphology preceeding the QRS - which suggested that they were coming from the donor's sinus node. There were two patterns of P waves, one that was being conducted to the ventricles, coming from the donor's heart, and the other that was detected that was not being conducted, originating from the recipient's sinus node, which could falsely suggest a diagnosis of complete AV block.
  • The conclusion stated that most of the heart transplant recipients undergo pacemaker implantation, but that complete AV block, which can develop in the long term, are uncommon. Most of the patients that develop bradycardia soon after a heart transplant are due to sinus node dysfunction (which can be due to sympathetic denervation, ischemia, tachycardia-bradycardia syndrome, and chronotropic negative drugs).
  • They also concluded that the sinus node dysfunction in the donor's heart was the responsible for the patient's asystolia.

• Complete AV block:
  • Common causes are postoperative injury, progressive conduction system disease associated with coronary artery disease, LV dysfunction, chronic rejection, and injury from endomyocardial biopsies.

• Sick sinus syndrome:
  • Transplant coronary artery disease accounts for most sudden cardiac death in OHT patients; these patients mainly present as asystolic heart and very rarely ventricular fibrillation in patients with moderately depressed or preserved left ventricular ejection fraction.

Epidemiology and Demographics

• The International Society for Health and Lung Transplantation (ISHLT) reports over 5,500 annual transplants (all ages) performed globally, most in  North America. Increased number of deaths due to drug overdose in the US, an improvement in reporting of transplants globally and increasing use of “higher-risk” donor hearts are thought to be the main reasons for annual increase in number of reported HTs. Figure 1: Number of heart transplants (adult and pediatric) by year (transplants: 1988−2017) and geographic region.
• Age & gender breakdown: 36th report of ISHLT estimates that:
  • Median recipient age for HT is 55 years.
  • Donor median range falls in the range of 28 years in North America to 45 years in Europe.
  • Gender breakdown amongst donor and recipient groups is reported to have  67.9% and 74.4% male population respectively.
• HT outcome:
  • Survival rate amongst 1-year survivors is reported to be 14.8 years, which is relatively higher for patients with primary diagnosis of  congenital heart disease followed by non-ischemic and ischemic cardiomyopathy, as worse for patients with diagnosis of re-transplants.
  • Higher recipients and donor age are also associated with early post operative mortality.
  • Female gender is associated with significantly higher post-transplant survival than men (median survival 12.2 years in women, 11.4 years in men).
  • Stehlik et al. report that most of the patients during the immediate postoperative period patients undergoing HT do not require hospitalisation. The functional status of 80% of the HT recipients is ≥80% on the Karnofsky Score (range, 10%–100%). Many HT recipients return to work. Figure 2 : 5 Kaplan-Meier survival by era (adult heart transplants: January 1982−June 2017). NA, not available.

• Elkaryoni et al analysed Nationwide Inpatient Sample 2002-2014 to identify OHT recipients by using ICD-9 codes. Out of the 175,845 HT, 21,613 patients (12.3%)  recipients presented with arrhythmia
  • Mean age was 60.8 ± 13.8 years, 73.1% were males and 63.8% were white.
  • Overall most common POA reported was Atrial fibrillation (AF) (47.3%) followed by atrial flutter (AFl) (7.6%), ventricular tachycardia (4.7%), Paroxysmal supraventricular tachycardia (1.6%), sudden cardiac arrest (3.7%) and ventricular fibrillation (1.1%), sick sinus syndrome (0.5%), complete heart block (0.3%) and other dysrhythmias (33.2%). Frequencies reported are not associated with timing of onset.
  • Congestive heart failure (CHF) and Orthotopic HT complications  such as cellular rejection and cardiac allograft vasculopathy were the most predictors for POA (OR 2.33, OR 1.65 respectively).

• The international Society of Heart and Lung Transplant (ISHLT) reports over 5,500 annual transplant Heart transplant performed globally, most in North America. Increased number of deaths due to drug overdose in the US, an improvement in reporting of transplant globally and increasing use of "high-risk" donor hearts are thought to be the main reasons for annual increase in number of reported heart transplants.

Mechanism and Risk Factors

• Various risk factors are involved in both Bradyarrhythmias and Tachtarrhythmias. some of them are-

• Denervation and reinnervation :
  • Average resting heart rate in HT patients increases due to  denervation of the parasympathetic system of the donor heart. Denervation of the sympathetic system causes decrease and delay in exercise or stress-induced augmentation of SA node automaticity, resulting in a decreased maximum heart rate with exercise.
  • Reinnervation (of both parasympathetic and sympathetic systems) process is incomplete, nonuniform and can be variable among patients, and heterogenous within the same patient.
  • A study led by Uberfuhr  in Germany found that 22 out of 38 (58%) patients with orthotopic heart transplantation had some degree of sympathetic reinnervation.

• Cardiac Allograft Vasculopathy:
  • Common occurrence in late postoperative heart transplantation period which can lead to ischemia. This is turn leads to ventricular arrhythmia and sudden cardiac death.
  • Trigger: heterogeneous factors (alloimmune, autoimmune and non-immune mediated responses) leading to inflammation, endothelial injury.

• Biopsy findings:  
  • Diffuse, pan-arterial involvement (unlike atherosclerosis - patchy distribution)
  • Affects mid to distal portion of the coronary artery
  • Donor-transmitted lesions are detectable early after transplant and tend to be focal and proximal
  • Late lesions can occur with both CAV and atherosclerotic disease

• Inflammation and ischemic injury:
  • Triggers: hypoxemia hypercarbia, endogenous or exogenous catecholamines, acid-base imbalances, and drug effects, as well as mechanical factors such as instrumentation
  • Timing: inflammation peaks around day 2-3

• Graft rejection:
  • Prevalence: approximately 20-30% of patients are reported to have experienced graft rejection during first year after HT.
  • Routine surveillance of transplant coronary artery disease is required, typically with annual coronary angiograms. Ischemia from graft vasculopathy should be considered a cause of arrhythmias, particularly 6 months or more after transplantation
  • Biopsy is of diagnostic value. Presence of inflammatory infiltrates in the transplanted tissue signifies graft rejection.
  • Empiric augmentation of immunosuppressant therapy can be considered.
  • Prognosis:
    • Cardiac fibrosis leading to compromised diastolic function can occur due to recurrent moderate to severe acute rejections.
    • Poor prognosis in long term

• Sinus node dysfunction:
  • Trigger: injuries during the surgical procedure such as trauma, nodal ischemia due to nodal artery injury or prolonged ischemia
  • Decrease incidence with bicaval surgical technique

• Biopsies as a diagnostic intervention to rule out acute rejection of the graft:
  • Endo-Myocardial Biopsy (EMB) utilised to evaluate cardiac AR or dilated and restrictive cardiomyopathies can lead to arrhythmias.

• Infections:
  • Recipient is at increased risk of acquiring infection due to use of immunosuppressive therapy
  • Immunosuppressive therapy and timings of infection are associated with cause of infection
  • “Estimations indicate that about 1.5% of cardiac transplant patients are infected with infectious endocarditis (IE), mostly by Staphylococcus aureus and Aspergillus fumigatus. Risk factors include the use of central catheters in the perioperative period and frequent endomyocardial biopsies”
  • The Infective endocarditis can lead to post HT arrhythmia.

• Drugs:
  • As the average effect of amiodarone is prolonged. If early  sinus node dysfunction occurs in a transplanted heart , the effect of amiodarone may further compromise the electrical conduction of the transplanted heart.

• Surgical technique
  • Preliminary studies show that bicaval technique has less risk of developing POA as compared to biatrial method. Needs further research to establish as an association.

Treatment

• The Treatment of post transplant arrhythmias depends on the type of etiology.
• Cather ablation/ Radiofrequency ablation- employed in various tachyarrhythmia.
• Pacemaker insertion - Considered in persistent bradyarrhythmia and heart block,
• ICD insertion- for prevention of Sudden Cardiac Death (SCD).

Medical Therapy

• Emperic treatment of rejection with steroid therapy is done when the suspected etiology is rejection.
• Limited evidence is present but the use of antiarrhythmic therapy can be employed with the careful consideration of safety and tolerability.

Prevention

• Preventive care can be taken by targeting the etiology of the arrhythmia. This involves-
• Detection and prompt treatment of rejection.
• Prevention of Cardiac allograft vasculopathy.
• Limited data is available on ICD implantation for prevention of sudden cardiac death.