A rare cause of graft dysfunction after a heart transplant

Abstract

1. Case report

A 39-year-old 65 kg man with idiopathic dilated cardiomyopathy and progressive worsening had episodes of ventricular tachycardia 20 months prior to transplantation.

His ventricular tachycardia was initially treated with amiodarone. He underwent placement of an automatic implantable cardioverter-defibrillator (AICD). Recurrent episodes of ventricular tachycardia were treated with sotalol and procainamide. He developed side effects to this therapy, including: blue discoloration of his skin (from chronic amiodarone therapy), dizziness, nausea, blurred vision, and intermittent episodes of heart block.

Because of those side effects (amiodarone, 400 mg daily; procainamide, 2 g three times a day; and sotalol, 160 mg twice a day), we hospitalized him while awaiting a heart transplant. His EKG showed sinus bradycardia at a rate of 47 beats/min. His procainamide level was 10.8 μg/ml (normal: 4–8). Amiodarone and sotalol levels were not done. Fortunately, a donor heart became available shortly thereafter and he underwent an orthotropic heart transplant. The donor heart was reported to be normal, with a normal ejection fraction. The quality of cardiac preservation was excellent during cardiectomy, transportation, and the transplant. The ischemic time was 195 min. The classic atrial cuff technique was used for the transplant.

Intraoperatively, in spite of the usual attempts to resuscitate the heart including moderately high doses of dobutamine and epinephrine, his heart remained asystolic. We were not able to pace the transplanted heart. Blood chemistries and arterial blood gases including pH were entirely normal. It remained soft and well perfused at electromechanical rest. Because the donor heart was normal in every respect, the donor was on no antiarrhythmic drug, and the preservation technique using 1.5 l of Celsior was our standard protocol, we suspected pharmacological myocardial depression secondary to the chronic high doses of multiple antiarrhythmics that had been used in our patient. Finally, we implanted an Abiomed BVS 5000 biventricular assist device (Abiomed, Danvers, MA, USA) as a bridge to recovery. Troponin was not measured. Over the next two days, he showed subtle improvement in cardiac function. On the fourth postoperative day, under transesophageal echocardiography guidance, we gradually weaned him off the biventricular assist device and explanted it. His remaining postoperative course was uneventful.

On the most recent sixth anniversary of his transplant, he successfully participated in a 30 mile bicycle race. As of 2009, he is NYHA class I and has had a normal coronary angiogram, normal right and left sided pressures, cardiac output at rest of 4.0 l/min. His cardiac graft had an ejection fraction of 69%. His renal and hepatic function are normal.

2. Discussion

Graft failure accounts for 44% of mortality in the first 30 days postoperatively. This case demonstrates reversible graft failure related to: (1) a denervated transplanted heart, (2) immediate redistribution to the graft of the antiarrhythmic agents from extracardiac tissues, and (3) altered elimination of the antiarrhythmic drugs following cardiopulmonary bypass (CPB).

Orthotropic heart transplantation results in a donor heart that is anatomically and functionally denervated. Immediately after transplantation native heart bradycardia is seen in upto 50% of recipients.

The pretransplant use of antiarrhythmic drugs may contribute to the occurrence of post-transplant sinoatrial (SA) node dysfunction. Amiodarone pretransplant at a mean daily dose of 247 mg was associated with post-transplant SA-nodal chronotropic dysfunction necessitating prolonged atrial pacing [1, 2]. However, a higher average dose of 392 mg daily, showed an association with bradycardia, lower cardiac index for 24 hours postoperatively, and increased postoperative mortality. Konertz et al. noted that pretransplant use of amiodarone, propafenone, sotalol, mexiletine or quinidine, correlated with greater difficulty in weaning from CPB and increased requirements for postoperative inotropic support [3].

Based on these reports, the antiarrhythmic drugs in this case probably redistributed from peripheral tissues in the recipient to the new graft causing asystole. Following long-term treatment amiodarone and its active metabolite, desethylamiodarone (DEA), are found in the myocardium at concentrations exceeding those in plasma and in most other peripheral tissues except adipose tissue [4]. Post-transplantation, amiodarone redistributes from the peripheral tissues to the donor heart [5] and can be detected for upto 12 weeks post-transplant. Sotalol concentrations have been detected in the ventricles of explanted hearts after transplantation [6]. Sotalol is also found in skeletal muscle, kidney, liver and lung [7]. Procainamide and its active metabolite, N-acetylprocainamide (NAPA), are also found throughout the myocardium at concentrations that exceed those in plasma, though the myocardial to plasma concentration ratios are lower than those of amiodarone and DEA [8].

Following redistribution to the transplanted heart, the antiarrhythmic drugs would be expected to exert acute pharmacological effects that mimic those described in isolated cells. When administered acutely amiodarone principally manifests sodium and calcium channel blocking effects as well as non-competitive beta-adrenergic blocking effects. Due to amiodarone's lipophilicity and consequential deep tissue penetration, the recovery of the sodium current from inactivation may be significantly delayed. Thus, excitability and conduction throughout the atria and ventricular myocytes and the His–Purkinje system would be suppressed. The calcium channel blocker effects result in impaired depolarization and pacemaker function in the SA node as well as depressed atrioventricular (AV) nodal conduction. The acute effects of sotalol would consist of competitive, non-selective beta-adrenergic blockade, resulting in depressed SA nodal depolarization and AV nodal conduction, combined with repolarization and refractoriness throughout the heart. Procainamide would be expected to block depolarizing sodium channels and repolarizing potassium channels [9], therefore slowing conduction within the AV node and His–Purkinje system.

In addition to their electropharmacological effects, these three antiarrhythmics cause important negative inotropic effects in the denervated heart by altering excitation-contraction coupling. The blockade of the sodium channels is the predominant effect of the class I antiarrhythmics, amiodarone and procainamide, resulting in a net efflux of calcium and a reduction in myocardial contractility. Lastly, both amiodarone and sotalol possess beta-adrenergic blocking effects that indirectly decrease intracellular calcium accumulation thereby contributing to the overall negative inotropism.

The electropharmacological and hemodynamic effects of the antiarrhythmic drugs persisted for several days post-transplant largely due to the lipophilicity and deep tissue penetration of amiodarone and DEA. Delayed elimination of amiodarone, DEA, sotalol, procainamide and NAPA may also have resulted from the impact of CPB on hepatic and renal function.

In summary, our patient experienced acute, graft non-function probably as a consequence of the electropharmacological and negative inotropic effects of three anti-arrhythmic drugs, amiodarone, sotalol and procainamide. The drugs and their active metabolites likely redistributed from peripheral tissues into the transplanted heart, mimicking a collective overdose. Mechanical circulatory support salvaged the heart and the patient. This case raises the question of stopping very high dose antiarrhythmic medications before transplantation and using of mechanical circulatory support instead.

References