Pathophysiology and Acute Management of Tachyarrhythmias in Pheochromocytoma: JACC Review Topic of the Week

Abstract

Pheochromocytomas, arising from chromaffin cells, produce catecholamines, epinephrine and norepinephrine. The tumor biochemical phenotype is defined by which of these exerts the greatest influence on the cardiovascular system when released into circulation in high amounts. Action on the heart and vasculature can cause potentially lethal arrhythmias, often in the setting of comorbid blood pressure derangements. In a review of electrocardiograms obtained on pheochromocytoma patients (n = 650) treated at our institution over the last decade, severe and refractory sinus tachycardia, atrial fibrillation, and ventricular tachycardia were found to be the most common or life-threatening catecholamine-induced tachyarrhythmias. These arrhythmias, arising from catecholamine excess rather than from a primary electrophysiologic substrate, require special considerations for treatment and complication avoidance. Understanding the synthesis and release of catecholamines, the adrenoceptors catecholamines bind to, and the cardiac and vascular response to epinephrine and norepinephrine underlies optimal management in catecholamine-induced tachyarrhythmias.

Keywords: blood pressure; catecholamines; pheochromocytoma; sinus tachycardia; tachyarrhythmias; ventricular tachycardia.

FIGURE 1. Management of Catecholamine-Induced Tachyarrhythmias

General management of catecholamine-induced tachyarrhythmias (A), management of ST (B), and VT (C). Refer to text for elaboration. BP = blood pressure; EP = electrophysiologist; EPI = epinephrine; HR = heart rate; IV = intravenous; NE = norepinephrine; PO = oral; VT = ventricular tachycardia. *If ivabradine is unavailable or too expensive, agents like diltiazem, verapamil, and metoprolol or atenolol after α-adrenoceptor blockade can be used but beware of hypotension *Sotalol, propafenone and procainamide can also be used as add on agents in the management of ventricular tachycardia

FIGURE 1. Management of Catecholamine-Induced Tachyarrhythmias

General management of catecholamine-induced tachyarrhythmias (A), management of ST (B), and VT (C). Refer to text for elaboration. BP = blood pressure; EP = electrophysiologist; EPI = epinephrine; HR = heart rate; IV = intravenous; NE = norepinephrine; PO = oral; VT = ventricular tachycardia. *If ivabradine is unavailable or too expensive, agents like diltiazem, verapamil, and metoprolol or atenolol after α-adrenoceptor blockade can be used but beware of hypotension *Sotalol, propafenone and procainamide can also be used as add on agents in the management of ventricular tachycardia

FIGURE 1. Management of Catecholamine-Induced Tachyarrhythmias

General management of catecholamine-induced tachyarrhythmias (A), management of ST (B), and VT (C). Refer to text for elaboration. BP = blood pressure; EP = electrophysiologist; EPI = epinephrine; HR = heart rate; IV = intravenous; NE = norepinephrine; PO = oral; VT = ventricular tachycardia. *If ivabradine is unavailable or too expensive, agents like diltiazem, verapamil, and metoprolol or atenolol after α-adrenoceptor blockade can be used but beware of hypotension *Sotalol, propafenone and procainamide can also be used as add on agents in the management of ventricular tachycardia

FIGURE 2. Catecholamine Synthesis and Interfering Agents

Catecholamines (dopamine, NE, and EPI) are produced in chromaffin cells through a common synthetic pathway (left), beginning with tyrosine hydroxylase (TH) regulating the conversion of tyrosine to dihydroxyphenylalanine, the rate-limiting step. Dihydroxyphenylalanine is converted to dopamine, which is converted to NE; phenylethanolamine-N-methyltransferase (PNMT) converts NE to EPI. Common foods and medications interfere with 3 mechanisms in catecholamine synthesis and turnover that are relevant to triggering and worsening of tachyarrhythmias. First, synthesized NE and EPI sequestered into storage vesicles can be displaced by prescribed drugs (e.g., sympathomimetics) and tyramine found in fermented, aged, and smoked foods (cheese, wine, beer, soy sauce, avocado, banana, and so on). Second, reuptake inhibitors (serotonin and/or NE-related antidepressants) block catecholamine reuptake. Third, following reuptake, NE and EPI are deactivated by monoamine oxidase and are eventually metabolized to dihydroxyphenylglycol (DHPG). Monoamine oxidase is inhibited by monoamine oxidase inhibitors, including oxazolidinedione antibiotics (linezolid). Additional agents also contribute to catecholamine excess by alternative, multiple, or less-well-known mechanisms and are not shown. These agents include opiates, peptide hormones (vasopressin, glucagon, steroids), neuromuscular blockers, anesthetics, and antiemetics (notably metoclopramide). Ultimately, catecholamines enter the circulation and act upon the heart and vasculature via adrenoceptors (right). Glucocorticoids and thyroid hormones either increase the number of adrenoceptors or their affinity to catecholamines. AV = atrioventricular; SA = sinoatrial; other abbreviations as in Figure 1.

FIGURE 3. Catecholamine Binding Affinities and Adrenoceptor Actions

α(1,2), β(1,2) adrenoceptors present on end organs bind EPI and NE with differing affinities. α1-adrenoceptors are present on vascular smooth muscle and result in vasoconstriction and hypertension when activated by NE or EPI. α2-adrenoceptors are present on synaptic nerve terminals and inhibit the release of NE. β1-adrenoceptors are present on the heart and kidney and, when activated by EPI or NE, result in increased heart rate, inotropic force, and conduction velocity within the heart, and renin release from the kidney. β2-adrenoceptors, present on certain vessels and lung smooth muscle; when activated by EPI, result in vasodilation and in excess can lead to hypotension. Abbreviations as in Figure 1.

FIGURE 4. Core Principles in Treatment of Catecholamine-Induced Tachyarrhythmias

The principal treatment strategy for sinus tachycardia (ST) and ventricular tachycardia (VT) include ß1-adrenoceptor blockade especially in hypertensive patients (bottom). In ST, diltiazem, verapamil, and ivabradine are useful add-on agents (left). In VT, lidocaine and amiodarone are useful add-on agents (right). The order in which these agents are used should be considered in the context of comorbid BP derangements (center). Metyrosine (top) can also be considered as an adjunctive treatment in decreasing catecholamine synthesis. If ST and VT remain refractory after adding on these agents, consider consultation with a cardiologist or an electrophysiologist.

FIGURE 5. Learning Points in our Clinical Experience

Timelines detailing patient care and learning points for 5 patients cared for at our institution. Abbreviations as in Figures 1 and 4.

CENTRAL ILLUSTRATION. Tachyarrhythmias in Catecholamine Excess

Pheochromocytomas produce excess catecholamines, which bind adrenoceptors and act on the sinoatrial node (SAN), atrioventricular node (AVN), His-Purkinje system, and myocardium (top). Cardiac β1-adrenoceptor stimulation leads to stimulatory guanine triphosphate protein-coupled receptor (Gs) activation, which activates adenylate cyclase (AC) to convert adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA). Nodal cells of the SAN and AVN have slow APs (bottom left). In the SAN, cAMP activates the HCN channel. This increases the slope of diastolic depolarization in phase 4 (green) and increases chronotropy (dashed line vs. solid line). Ivabradine opposes this. In the AVN, cAMP-activated PKA phosphorylates L-type calcium channels, which increases the slope of phase 0 (orange) and increases dromotropy (dashed line vs. solid line). Nondihydropyridine calcium channel and β1-adrenoceptor blocking agents oppose this. In fast-action potentials of the myocardium (bottom right), β1-adrenoceptor stimulation increases conduction velocity, enhances automaticity, and shortens refractoriness (phase 0 to the end of phase 3) by a variety of mechanisms mediated by an elevation in cAMP. β1-adrenoceptor blockade prolongs refractoriness and may decrease spontaneous depolarization (dashed line vs. solid line). Class IA-C antiarrhythmics acting on phase 0 (purple) of depolarization prolong refractoriness, while class III antiarrhythmics do so by acting on phase 3 (pink) of depolarization (dashed line vs. solid line). Ryanodine 2 receptors (RyR2) present on the sarcoplasmic reticulum (SR) of cardiac myocytes and cells of the His-Purkinje system are phosphorylated by PKA and cause calcium efflux into the cytosol; calcium binds the troponin-tropomyosin complex revealing myosin binding sites on actin, enhancing cross-bridge cycling, and increasing inotropy (not shown).