The n e w e ng l a n d j o u r na l of m e dic i n e

C or r e sp ondence

Ivabradine in Catecholamine-Induced Tachycardia in a Patient

with Paraganglioma
To the Editor: A paraganglioma-related clinical tion, 60%) and functional status (New York Heart
sequela results from catecholamine secretion that Association class I) were excellent.
can cause hypertension, tachyarrhythmia, multi­
organ failure, and death.1 Radiolabeled lutetium- Figure 1 (facing page). Sites of Action for Heart-Rate
177 (177Lu)–Dotatate (Lutathera) is a systemic Control in Catecholamine-Induced Tachycardia.
therapy administered as a 30-to-60-minute intra- As shown in Panel A, heart rate is controlled by the
venous infusion at a dose of 7.4 GBq (200 mCi) ­autonomic nervous system, and the sinoatrial (SA)
every 8 weeks for four cycles. After binding as a node acts as the pacemaker. Sinus tachycardia that re-
sults from elevated levels of catecholamines released
somatostatin analogue to overexpressed soma-
from paragangliomas is one of the most prevalent cardio-
tostatin receptors on a tumor, 177Lu-Dotatate vascular manifestations of these tumors. Norepineph-
undergoes radioactive decay, releasing beta par- rine, epinephrine, or both are released from sympathetic
ticles that subsequently lead to cellular disrup- nerve terminals, the adrenal medulla, or catecholamine-
tion; this disruption causes profound catechola­ secreting tumors and bind to β1-adrenoceptors, β2 -
adrenoceptors, or both in the heart. A subsequent
mine release.2 A pharmacologic catecholamine
­cascade results, wherein a β-adrenoceptor coupled
blockade is achieved with α-adrenoceptor and with Gs-protein activates adenylate cyclase, which in-
β-adrenoceptor blockers, calcium-channel block- creases cyclic AMP (cAMP) levels and promotes ion-
ers, or both, with or without a catecholamine channel permeability, thereby increasing node activity,
synthesis inhibitor, metyrosine (Demser).1 Studies automaticity, and conduction velocity and leading to
sinus tachycardia. AV denotes atrioventricular, DOPA
of other medications for catecholamine-induced
3,4-dihydroxyphenylalanine, and HCN hyperpolarization-
sinus tachycardia are limited. activated, cyclic nucleotide–gated. As shown in Panel B,
Here, we report the case of a 54-year-old man traditional treatment options for sinus tachycardia in-
with an inoperable metastatic paraganglioma in clude β-adrenoceptor and calcium-channel blockers,
whom systemic targeted radiotherapy with 177Lu- which provide negative chronotropic effects on the SA
node, depression of the AV node, and decreased con-
Dotatate was indicated. He had hypertension
duction velocity and contractility in cardiomyocytes. In
and tachycardia that were well controlled with addition, metyrosine (Demser), an inhibitor of the rate-
the use of phenoxybenzamine, metoprolol, and limiting enzyme in catecholamine biosynthesis, tyrosine
metyrosine, and his cardiac status (ejection frac- hydroxylase, decreases catecholamine synthesis and
therefore decreases catecholamine-induced stimulation
this week’s letters of the heart. As shown in Panel C, a new drug, ivabra­
dine, works by targeting the If current in the SA node
1284 Ivabradine in Catecholamine-Induced Tachycardia through intracellular blockade of the HCN channel,
leading to reduced diastolic depolarization of the pace-
in a Patient with Paraganglioma
maker action potential and thus decreasing the heart
1286 Retraction: Steering CAR T Cells into Solid rate. In this manner, despite β-adrenoceptor activation
and cAMP production, an electrical impulse would not
Tumors. N Engl J Med 2019;380:289-91. be generated because of If current blockade. Ivabradine
acts solely on the SA node; therefore, catecholamine
1287 Fracture Prevention with Zoledronate in Older effects on the AV node and cardiomyocytes would not
Women with Osteopenia be mitigated by this drug. Nevertheless, the regulation
of the intrinsic pacemaker in the SA node is paramount
1289 Immune Escape of AML Cells after Transplantation in heart-rate control.

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 Correspondence

A Catecholamine Influence on Cardiac Conduction System

SA Node S Y MP A T H E T IC N E R V E T E R MIN A L

Tyrosine DOPA Dopamine

hydroxylase decarboxylase -hydroxylase
β-hydroxylase
Sympathetic
nerves
Tyrosine DOPA Dopamine Norepinephrine

Ca2+ Ca2+ Na+ HCN Adenylate

channel channel cyclase

Increased Gs protein β-adrenoceptor

cAMP
Protein kinase A

AV Node and Cardiomyocyte

Increased SA node activity

Norepinephrine

Increased AV node
Adenylate Ca2+
Ca2+ automaticity and Sinus Tachycardia
cyclase channel conduction velocity

Increased myocyte
β-adrenoceptor contractility, automaticity,
Increased Protein and conduction velocity
Gs protein cAMP kinase A

B Traditional Treatment Options (Metyrosine, β-adrenoceptor blocker, Ca-channel blocker)

Decreased Decreased sympathetic
Tyrosine DOPA Dopamine
norepinephrine response from each
point of the cardiac
Metyrosine Tyrosine DOPA Dopamine
conduction system
hydroxylase decarboxylase β-hydroxylase

Ca2+
Ca channel β-adrenoceptor
blocker blocker

Decreased
cAMP

C New Treatment Option (Ivabradine)

Direct SA node inhibition
Tyrosine DOPA Dopamine Norepinephrine

Tyrosine DOPA Dopamine

hydroxylase decarboxylase β-hydroxylase
Decreased impulse
conducted throughout
Na + the electrical system
HCN
of the heart, thereby
channel
achieving heart-rate
control
SA N O D E
Increased
Ivabradine cAMP

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Before the initiation of treatment with 177Lu-
Dotatate, his plasma norepinephrine level was
20,500 pg per milliliter (normal range, 84 to
794; 121 nmol per liter [normal range, 0.5 to 4.7]),
and his plasma epinephrine level was less than
20 pg per milliliter (normal range, 0 to 57;
<109 pmol per liter [normal range, 0 to 311.2]).
After one cycle of 177Lu-Dotatate, he had hyper-
tension and tachycardia, and he received occa-
sional 5-mg phentolamine intravenous pushes,
esmolol at a dose of 200 μg per kilogram of body
weight per minute, labetalol at a dose of 2 mg
per minute, and diltiazem at a dose of 15 mg per
hour to establish circulatory control. Despite
adequate medical management, the tachycardia
and hypertension became resistant to treatment.
As predicted, the norepinephrine level increased,
reaching 172,000 pg per milliliter (1020 nmol
per liter). Subsequently, systolic heart failure
(ejection fraction, 30%) and acute kidney injury
developed. Persistent tachycardia despite max­
imum doses of β-adrenoceptor and calcium-
channel blockers, as well as metyrosine, war-
ranted immediate consideration of additional
rate-control medications.
Ivabradine (Corlanor), which has an excellent
safety profile and benefit in patients with heart
failure,3 was administered orally at a dose of 5 mg
twice daily. Heart-rate control was achieved with
a decrease in the maximal pulse from 143 beats
per minute on the day before administration of
ivabradine to 92 beats per minute on the third
day of ivabradine use. When the dose of ivabra­
dine was tapered to 2.5 mg twice a day, tachy-
cardia developed, and the patient was therefore
sent home with instructions to take the drug at
a dose of 5 mg twice a day. His cardiac function
improved, and the ejection fraction increased to
45%. Because of the patient’s clinical course,
subsequent 177Lu-Dotatate cycles were deferred.
Catecholamines increase heart rate through
β-adrenoceptor stimulation (Fig. 1). β-adreno­
ceptor and calcium-channel blockers modulate
this effect by inhibiting the signal cascade. Al-
though β-adrenoceptor desensitization occurs with
prolonged catecholamine stimulation,4 tachycardia
persists despite maximal β-adrenoceptor blockade.
Ivabradine is a commercially available If cur-
rent inhibitor that acts directly in the sinus node
without adverse cardiovascular events.5 The If
current acts in the hyperpolarization-activated,
cyclic nucleotide–gated (HCN) channel of the
sinoatrial node; this current increases with sym-
pathetic stimulation, resulting in the generation
and modulation of cardiac rhythmicity.5 Thus,
regulated impulse generation with ivabradine is
one possible approach in managing sinus tachy-
cardia in patients who have persistently elevated
catecholamine levels and β-adrenoceptor desen-
sitization and therefore diminished responses to
β-adrenoceptor blockers.
Gelinemae Malaza, M.D.
Alessandra Brofferio, M.D.
Frank Lin, M.D.
Karel Pacak, M.D., Ph.D.
National Institutes of Health
Bethesda, MD
karel@​­mail​.­nih​.­gov
Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
1. Pacak K. Preoperative management of the pheochromocy-
toma patient. J Clin Endocrinol Metab 2007;​92:​4069-79.
2. Makis W, McCann K, McEwan AJ. The challenges of treating
paraganglioma patients with (177)Lu-DOTATATE PRRT: catechol-
amine crises, tumor lysis syndrome and the need for modification
of treatment protocols. Nucl Med Mol Imaging 2015;​49:​223-30.
3. Koruth JS, Lala A, Pinney S, Reddy VY, Dukkipati SR. The
clinical use of ivabradine. J Am Coll Cardiol 2017;​70:​1777-84.
4. Tsujimoto G, Manger WM, Hoffman BB. Desensitization of
beta-adrenergic receptors by pheochromocytoma. Endocrinology
1984;​114:​1272-8.
5. DiFrancesco D. The role of the funny current in pacemaker
activity. Circ Res 2010;​106:​434-46.
DOI: 10.1056/NEJMc1817267

Retraction: Steering CAR T Cells into Solid Tumors.

N Engl J Med 2019;380:289-91.
To the Editor: Because the authors of the Marion H. Brown, Ph.D.
­Nature article entitled “A Homing System Tar- Michael L. Dustin, Ph.D.
University of Oxford
gets Therapeutic T Cells to Brain Cancer”1 have Oxford, United Kingdom
retracted it owing to issues with figure pre­ This letter was published on February 20, 2019, at NEJM.org.
sentation and underlying data, we hereby 1. Samaha H, Pignata A, Fousek K, et al. A homing system tar-
wish to retract our commentary on that arti- gets therapeutic T cells to brain cancer. Nature 2018;​561:​331-7.
2. Brown MH, Dustin ML. Steering CAR T cells into solid tumors.
cle, entitled “Steering CAR T Cells into Solid N Engl J Med 2019;​380:​289-91.
Tumors.” 2
DOI: 10.1056/NEJMc1902526

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