Medications:

Aspirin 80 mg daily

Tacrolimus 5 mg PO BID

Mycophenolate Mofetil 1000 mg PO BID

Prednisone 10 mg BID

Diltiazem 60 mg PO TID

Pravastatin 40 mg daily

Allergies: NKA

Past Medical History:

Cardiac:

Nonischemic cardiomyopathy status post orthotopic heart transplant 18 months prior

Hypertension

Hypercholesterolemia

Endocrine:

Diet controlled diabetes mellitus

Physical Exam:

Vital Signs: BP 145/92, HR 95, RR 20, oxygen saturation 99% on room air

Cardiac: Regular tachycardia without murmurs, rub, or gallop. JVP 3 cm. Left leg bandaged but no pedal edema on right leg

Respiratory: Lungs clear to auscultation bilaterally

Otherwise: Insignificant

An EKG that was performed in the ED is notable for the presence of two distinct P waves and right bundle branch block.

Autonomic regulation of cardiac chronotropy (heart rate) and dromotropy (conduction velocity) is achieved through a balance of sympathetic and parasympathetic signaling to cardiac pacemaker tissue. Autonomic control of cardiac inotropy (contraction) and lusitropy (relaxation), on the other hand, is primarily mediated through sympathetic signaling to cardiac myocytes [1, 2].

When activated, preganglionic neurons of both the sympathetic and parasympathetic nervous system release acetylcholine from their nerve terminals in the autonomic ganglia. Acetylcholine then diffuses across the synaptic cleft where it binds to nicotinic acetylcholine receptors located on the postsynaptic neurons, ultimately promoting depolarization and signal propagation in these cells. In the parasympathetic system, stimulated postganglionic fibers release acetylcholine which binds to muscarinic acetylcholine receptors on the heart. In the sympathetic system, stimulated postganglionic fibers release norepinephrine which binds to cardiac adrenergic receptors.

Autonomic nerves are transected in the process of transplantation, disrupting autonomic influence on cardiac function in the early postoperative period. Autonomic reinnervation of the transplanted heart can occur over time, but its extent and time course are highly variable and therefore unpredictable [3–10].

In the healthy, resting individual both sympathetic and parasympathetic nerve fibers regulate automaticity in the pacemaker cells of the sinus node [1, 2]. Usually in adults, vagal parasympathetic influence predominates, resulting in an overall slowing of the rate of depolarization of these cells and therefore slowing of the resting heart rate. Disruption of autonomic signaling to the heart during the process of transplantation attenuates this parasympathetic-heavy influence, often leading to a significant elevation in resting heart rate. Resting rates of 80–110 are common, though rates as high as 130 or greater have been reported [3, 7, 9–11].

Though neither sensitive nor specific, alterations in hemodynamic parameters such as heart rate and blood pressure due to sympathetic nervous system activation can serve as an indicator of insufficient anesthetic depth. In patients who have undergone heart transplant, this sympathetic response may be blunted or absent, highlighting the importance of having a heightened awareness of anesthetic depth in this patient population [6].

Cardiac output is equal to the product of heart rate and stroke volume. Accordingly, decreases in stroke volume must be corrected or accompanied by a proportional increase in heart rate in order to maintain stable cardiac output. Reflex signaling through the autonomic nervous system plays a central role in this compensatory response, increasing heart rate and/or contractility when required to maintain cardiac output. This reflex signaling is disrupted in the denervated heart leaving only intrinsic adaptive cardiac responses such as the Frank–Starling mechanism intact [3, 7]. This mechanism describes the heart’s ability to increase contractility in response to increased cardiac muscle stretch due to increased filling, i.e., preload.

Drugs that produce hemodynamic changes through modification of vascular tone such as phenylephrine and nitroglycerin will produce relatively normal, dose-dependent alterations in preload and systemic vascular resistance. The compensatory bradycardia or tachycardia that would typically be seen with use of these medications, on the other hand, is largely dependent on the autonomic nervous system and may be disrupted [2]. Overall, the hemodynamic effect of these drugs will be preserved if not slightly augmented via loss of these compensatory changes. Similarly, drugs such as atropine that exert their effect indirectly by altering autonomic signaling will typically be less efficacious or completely ineffectual depending on the level of autonomic reinnervation that has occurred post-transplantation [7, 10]. Hemodynamic effects of drugs like epinephrine that directly binds to receptors on cardiac tissues will not only be maintained but may be exaggerated [7, 9, 10, 12, 13]. Finally, drugs with mixed direct and indirect activity such as ephedrine will typically retain only their direct effects.

In the denervated heart, bradycardia typically would not respond to the indirect effects of atropine and glycopyrrolate, so the provider must be prepared to treat with pacing or direct acting medications such as isoproterenol or epinephrine. The denervated heart’s response to adenosine, however, is exaggerated and so use of an alternate medication such as amiodarone is preferred when treating tachyarrhythmias [9, 10].

While disruption of autonomic input most commonly results in elevation of the resting heart rate in individuals who have undergone cardiac transplantation, factors such as sinus node tissue injury related to graft ischemia, surgical trauma or reperfusion injury occasionally cause post-transplant bradycardia [7, 9]. Treatment with a permanent pacemaker is typically only undertaken when symptomatic bradycardia is persistent, with rates of pacemaker placement for this indication most commonly reported at <10% [3, 9]. While there are no clear guidelines surrounding the implantation of ICDs in these patients, common reasons for placement include unexplained syncope, frequent nonsustained ventricular arrhythmia, graft failure, and graft vasculopathy with associated left ventricular dysfunction [9, 14].

Two of the most common surgical approaches to cardiac transplantation include the atrial to atrial cuff technique and the bicaval technique. In the atrial to atrial cuff technique, a part of the recipient’s right and left atria remains in situ and is sutured to the atria of the donor heart. This may leave the recipient with active sinus node tissue from both their native heart as well as their newly transplanted heart. While these suture lines serve as a barrier to prevent widespread conduction of pacemaker potentials originating in retained recipient sinus nodal tissue, this electrical activity can still be seen on an EKG as a second P wave [3, 6, 9, 15]. A lower rate of pacemaker implantation and a slight mortality benefit have been shown with the bicaval technique and thus most centers have moved away from the atrial to atrial cuff technique when possible [16]. Despite this fact, this phenomenon can still be seen in the operating room in patients who had their transplant prior to the more recent shift in practice. Additionally, technical limitations occasionally prohibit the use of the bicaval approach necessitating use of the atrial to atrial cuff technique.

First degree AV block, right bundle branch block and atrial flutter are common [3, 9, 10, 17].

Isolated, stable right bundle branch block is likely of little clinical significance. Higher rates of sudden cardiac death, however, have been noted in the setting of progression of bundle branch block on serial EKGs [9].

Development of one of these arrhythmias in a patient with a transplanted heart may be a marker for significant underlying cardiac pathology such as rejection, LV dysfunction, or cardiac allograft vasculopathy. Identification of these arrhythmias should prompt a full workup to evaluate for the presence of these serious conditions and to ensure that cardiac function is optimized before the patient is taken to the operating room [9]. From a treatment standpoint, use of beta-blockers and calcium channel blockers for rate control may be limited by the risk of bradycardia and interactions with immunosuppressive medication. Despite the fact that amiodarone also has the potential to interfere with pharmacokinetic processing of certain immunosuppressants, it is frequently the drug of choice for treatment of atrial tachyarrhythmia in this patient population [9, 10]. Radiofrequency ablation may also be used to treat sustained arrhythmias.

Cardiac allograft vasculopathy is the result of endothelial damage from both immune and nonimmune factors. It causes diffuse vascular remodeling, which can result in progressive and potentially rapid occlusion of affected vessels [4, 18].