JACC: CARDIOVASCULAR IMAGING VOL. 14, NO.

11, 2021

ª 2021 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

STATE-OF-THE-ART REVIEW

Cardiac Imaging in Carcinoid

Heart Disease
Tomasz Baron, MD, PHD,a,b Johannes Bergsten, MD,b Anders Albåge, MD, PHD,c Lennart Lundin, MD, PHD,b
Jens Sörensen, MD, PHD,d Kjell Öberg, MD, PHD,e Frank A. Flachskampf, MD, PHDb

ABSTRACT

Carcinoid disease is caused by neuroendocrine tumors, most often located in the gut, and leads in approximately 20% of
cases to specific, severe heart disease, most prominently affecting right-sided valves. If cardiac disease occurs, it de-
termines the patient’s prognosis more than local growth of the tumor. Surgical treatment of carcinoid-induced valve
disease has been found to improve survival in observational studies. Cardiac imaging is crucial for both diagnosis and
management of carcinoid heart disease; in the past, imaging was accomplished largely by echocardiography, but more
recently, imaging for carcinoid heart disease has increasingly become multimodal and warrants awareness of the
particular diagnostic challenges of this disease. This paper reviews the pathophysiology and manifestations of carcinoid
heart disease in light of the different imaging modalities. (J Am Coll Cardiol Img 2021;14:2240-2253) © 2021 by the
American College of Cardiology Foundation.

C arcinoid disease is caused by neuroendocrine

tumors most often located in the gut and may
lead to specific, severe cardiac complications,
most prominently valve disease (1–3). Cardiac compli-
originate mostly in the gastrointestinal tract, espe-
cially the small intestine and particularly the ileum.
The clinical presentation is dominated by the effects
of vasoactive substances secreted by the tumors,
cations, if they occur, determine the patient’s prog- especially serotonin (5-hydroxytryptamine [5-HT]),
nosis more than local growth of the tumor. Therefore, tachykinins, prostaglandins, histamine, and kalli-
cardiologists need to know about the specific chal- krein. The effects of these substances lead to the
lenges to diagnosis and management of carcinoid heart classic symptoms of carcinoid disease: flushing,
disease. Cardiac imaging is crucial for both diagnosis diarrhea, and bronchospasm.
and management and are reviewed here in depth. The neuroendocrine tumors are well differentiated
CARCINOID DISEASE: EPIDEMIOLOGY, and grow slowly. The biologically active secreted
PATHOPHYSIOLOGY, AND substances are metabolized and inactivated by the
CLINICAL PRESENTATION liver if they arrive through the portal circulation, but
if tumors metastasize to the liver or produce large
Neuroendocrine tumors, with an estimated popula- amounts of these substances, their products reach the
tion prevalence of 5 in 100,000 population (4), inferior vena cava through the hepatic vein. From

From the aUppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; bDepartment of Medical Sciences, Cardiology,
and Clinical Physiology, Uppsala University, Uppsala, Sweden; cDepartment of Cardiothoracic Surgery and Anesthesiology,
d
University Hospital, and Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Department of Surgical
Sciences, Nuclear Medicine, and PET, Uppsala University, Uppsala, Sweden; and the eDepartment of Endocrine Oncology,
Uppsala University Hospital, Uppsala, Sweden.
Sherif Nagueh, MD, served as Guest Editor for this paper.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received September 30, 2020; revised manuscript received December 22, 2020, accepted December 23, 2020.

ISSN 1936-878X/$36.00 https://doi.org/10.1016/j.jcmg.2020.12.030

JACC: CARDIOVASCULAR IMAGING, VOL. 14, NO. 11, 2021 Baron et al 2241
NOVEMBER 2021:2240–2253 Baron, Imaging in Carcinoid

there they proceed to the right heart, typically detected and quantified by the plasma level ABBREVIATIONS

affecting the tricuspid and pulmonary valves. or urinary excretion of 5-hydroxyindoleacetic AND ACRONYMS

Because tumor-secreted substances are largely inac- acetate (5-HIAA), which therefore is used as
5-HIAA = urinary 5-
tivated during the lung passage, usually only low an activity marker of the disease and can hydroxyindoleacetic acid
concentrations reach the left heart, where they pro- monitor therapeutic efforts. Another prog- 5-HT = 5-hydroxytryptamine
duce no or minor effects. This is different in the rare nostically relevant biomarker of carcinoid is (serotonin)

case of pulmonary metastases or the, likewise rare the serum level of the glycoprotein chro- CaHD = carcinoid heart disease
instance, of primary pulmonary tumor location, mogranin A. Natriuretic peptides are elevated CMR = cardiac magnetic
which expose the left heart to the typical pathological and carry prognostic weight in patients with resonance

changes of carcinoid heart disease (CaHD). CaHD (8). Cardiac manifestations of carcinoid CT = cardiac computed
In a report on 52 patients with CaHD, tricuspid, tumors limit prognosis stronger than intesti- tomography

pulmonary, mitral, and aortic valve disease was nal tumor progression; thus, cardiac imaging ECG = electrocardiogram

found in 47 (90%), 36 (69%), 15 (29%), and 14 (27%) is crucial (Central Illustration). LV = left ventricle

patients, respectively (5), which included mild le- General treatment options for advanced PET = positron emission
sions. In most series, the fraction of patients reported metastatic carcinoid are: 1) agents that block tomography

to have left-sided valve disease is lower. In the pre- the biologically active mediators (long-acting RegF = regurgitant fraction

sent report, aortic and mitral valve disease were more somatostatin analogs); 2) in highly prolifera- RegVol = regurgitant volume

frequent in the presence of a patent foramen ovale, tive tumors, cytotoxic treatment (e.g., strep- RV = right ventricle
suggesting a role for right-to-left shunting of active tozotocin and 5-fluorouracil); 3) somatostatin TAPSE = tricuspid annulus
tumor products. receptor-based peptide radionuclide therapy; plane systolic excursion

CaHD occurs in approximately 20% of all carcinoid and 4) transcatheter embolization of the tumors or
patients under contemporary somatostatin analog surgical removal of the tumors and liver metastases
therapy (6). The typical cardiac lesions of CaHD are (3). Relatively little evidence from controlled treat-
believed to be due to local action of 5-HT mediated by ment trials exists (9), especially comparing the major
specific receptors in the heart (5-hydroxytryptamine options. Several newer therapeutic agents are being
receptor 2B [5-HT2B]), which induce endothelial pla- evaluated. Cardiac surgical therapy for CaHD is dis-
que formation mainly on the valve cusps but also on cussed below.
the subvalvular apparatus and the endothelium of the PROGNOSIS. Prognosis in patients with CaHD is pri-
cardiac chambers (7). The plaque formations consist marily determined by cardiac involvement not tumor
of myofibroblasts, smooth muscle cells, and extra- progression. In a prospective study of 252 patients
cellular material including collagen. The valve cusps with carcinoid disease, recruited from 2006 to 2010,
thicken, stiffen, and retract (diminish in cusp area with a median follow-up of 29 months, 41 patients
and length) due to the effect of 5-HT, leading to had CaHD at baseline, and 44 developed new or
combined regurgitation and stenosis. Regurgitation worsening valve disease, and progression was pre-
typically is functionally more important, at least in dicted by high 5-HIAA levels and more frequent
the tricuspid valve, where true stenosis is rare. The flushing episodes (10). In a recent retrospective,
pulmonary valve may develop both regurgitation and single-center analysis of patients who underwent
stenosis, which are difficult to evaluate due to the valve replacement due to CaHD, survival rates at 1, 5,
reduced right ventricular (RV) stroke volume reach- and 10 years were 69%, 35%, and 24%, respectively
ing the pulmonary valve as a consequence of the (11).
universally present severe tricuspid regurgitation.
CARDIAC IMAGING. Echocardiography. Echocardio-
Thus, pulmonary valvular lesion severity is prone to
graphic examination is the diagnostic mainstay in
be underestimated. Rarely, carcinoid tumors may
CaHD (12–14). Tricuspid valve disease, RV size and
metastasize to the heart, causing intramural mass
function, and right atrial size can be well assessed in
lesions (5).
nearly all patients and in the rare cases of left-sided
DIAGNOSIS AND TREATMENT. Patients with CaHD valvular lesions (mostly aortic). However, assess-
present most often with signs of right heart failure, ment of the pulmonary valve, particularly of pulmo-
apart from the noncardiac carcinoid symptoms of nary regurgitation, is difficult and often inconclusive.
flushing, wheezing, diarrhea, and abdominal pain due Echocardiography of the tricuspid valve. The tricuspid
to intestinal tumor growth. Thus, liver enlargement valve is well visualized in parasternal, apical, and
(which may also be due to metastases), venous subcostal views. The typical appearance in CaHD is
congestion, peripheral edema, and pleural effusion characterized by a dilated annulus and diffusely
are common. Tumor production of serotonin can be thickened, retracted leaflets, which do not close in
2242 Baron et al JACC: CARDIOVASCULAR IMAGING, VOL. 14, NO. 11, 2021

Baron, Imaging in Carcinoid NOVEMBER 2021:2240–2253

C E NT R AL IL L U STR AT IO N Schematic of Carcinoid Heart Disease and Imaging Modalities Used for Diagnosis

o
release of vasoactive ech
substances (serotonin etc.)

hepatic CMR
metastases

CT
carcinoid heart disease

neuroendocrine
tumor in the gut Evaluate:
PE
• tricuspid and pulmonary valve disease
T
• right ventricular size/function
• left-sided valves
• PFO
• cardiac metastases ?

Baron, T. et al. J Am Coll Cardiol Img. 2021;14(11):2240-2253.

CMR ¼ cardiac magnetic resonance; CT ¼ computed tomography; PET ¼ positron emission tomography; PFO ¼ patent foramen ovale.

systole, leaving open an often considerable central continuous-wave Doppler in pronounced cases is
gap, and do not completely open in diastole, thus saturated and, instead of being parabolic, shows an
exhibiting limited mobility (Figure 1). The leaflets early peaking, triangular shape (sometimes called
display a loss of pliability. Typically, all leaflets are “dagger-shaped”), due to the rapid decrease of the
affected. Moreover, chordae may be thickened and driving pressure during systole caused by a rapid
shortened, and occasionally the papillary muscles increase in right atrial pressure (Figure 2). The
may be affected. Identification of involved tricuspid maximal regurgitant velocity typically is relatively
valve leaflets and of affected subvalvular structures low (<2 m/s), indicating that systolic pressures in the
may be improved by 3-dimensional (3D) echocardi- RV are not elevated. Other important signs of severe
ography (5). Functionally, the effect in full-blown tricuspid regurgitation such as systolic reversal of
disease is severe tricuspid regurgitation (Figure 1C), hepatic vein flow and a dilated, noncollapsing inferior
making the RV and right atrium effectively 1 chamber; vena cava are usually present; for a complete list of
in contrast, tricuspid stenosis is extremely rare. Mean features of severe tricuspid regurgitation, the reader
gradients across the tricuspid valve are is referred to current guidelines (15,16).
often <5 mm Hg, and reflect mostly increased trans- Echocardiography of the pulmonary valve. Assessment
valvular flow volume. The regurgitation signal on of the pulmonary valve represents the most difficult
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F I G U R E 1 Carcinoid Disease of the Tricuspid Valve

A B

(A) Parasternal right ventricular inflow view in systole. Note position of tricuspid leaflets with wide gap, increased echogenicity of leaflets,
and increased size of the right atrium (Video 1). (B) Apical modified 4-chamber view, in systole, with the same tricuspid leaflet characteristics
as in (A). The RV and the right atrium are dilated, with the ventricular septum bulging to the left side (Video 2). (C) Color Doppler image of
apical modified 4-chamber view with severe (“torrential”) tricuspid regurgitation (Video 3). RV ¼ right ventricle.

task for echocardiography in CaHD. Visualization and regurgitation. Because in pulmonary regurgitation
Doppler interrogation should be carefully sought the duration of diastolic backward flow is inversely
from the standard windows (i.e., parasternal and proportional to regurgitation severity, in severe
subcostal RV outflow views). Similar to the appear- regurgitation, the color Doppler signal also becomes
ance of the tricuspid valve, the pulmonary valve shorter in time, therefore appearing less severe. Vena
leaflets in CaHD exhibit thickening, retraction, and contracta measurements are often difficult to make
restricted mobility, although no fusion or calcifica- with confidence due to limited image quality. Addi-
tion (Figure 3). Combined pulmonary regurgitation of tionally, the proximal jet width of the pulmonary
all degrees and stenosis with reported peak flow ve- regurgitant jet by color Doppler in the upper para-
locities up to 3.8 m/s (5) are the typical functional sternal (or subcostal) short-axis view is affected by
consequences. Apart from the difficulty of visualizing the lateral spatial resolution of ultrasonography. The
the pulmonary valve in many adults, the particular most informative measurement, therefore, is the
pathophysiology of CaHD with its 2 serial, often se- continuous-wave Doppler profile of pulmonary
vere regurgitant valvular lesions, render functional regurgitation, obtained in a parasternal or subcostal
assessment difficult. Given that there is often short-axis view (15,16). A regurgitant signal ending
“torrential” tricuspid regurgitation, the stroke vol- before the beginning of the next forward flow signal
ume reaching the pulmonary valve is substantially is a sign of severe pulmonary regurgitation; the ratio
reduced, mitigating stenotic gradients and regur- of the duration of pulmonary regurgitation to the
gitant volume. This is particularly vexing for the interval between 2 forward flow signals has been
echocardiographic assessment of pulmonary termed the pulmonary regurgitation index and
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F I G U R E 2 Representative Doppler Tracings of Severe Tricuspid Regurgitation in Carcinoid Tricuspid Disease

V
A 5 .62

10

2
-.62

[m/s]

-1

-2

-3
-2 -1 50 mm/s 0
cw PW +61.6
B 50%
1.8MHz C 50%
1.6MHz
WF 225Hz WF 125Hz
SV4.0mm
12.5cm

-61.6
cm/s

200
80

100
40
cm/s

cm/s
-100

-200 -40

-300
-80
75mm/s 81bpm 75mm/s 84bpm

(A) Apical continuous-wave Doppler of low diastolic forward and systolic backward velocities across the tricuspid valve in extremely severe
regurgitation and atrial fibrillation with severely depressed right ventricular function. Forward flow ceases before the end of diastole due to
early diastolic pressure equalization. (B) Triangular regurgitant systolic flow velocity profile by apical continuous-wave Doppler. In this case,
regurgitation is not as extreme as in (A), and sinus rhythm is preserved. Note elevated diastolic forward velocities due to high regurgitant
volume. (C) Pulsed-wave Doppler of hepatic vein flow shows substantial systolic backward flow as a sign of severe tricuspid regurgitation.

values <0.77 are suggestive of severe regurgitation Regarding pulmonary valve stenosis, velocities and
(Figure 4). The steepness of the decline in regurgitant gradients also underestimate the severity of the
velocities over diastole can be quantified by pressure lesion (Figure 5). The ratio of subvalvular to trans-
halftime, by analogy to aortic regurgitation; a pres- valvular velocity-time integral would be a theoreti-
sure halftime <100 ms is considered indicative of cally more adequate measurement than transvalvular
severe pulmonary regurgitation. It should be noted, gradients but lacks validation.
however, that these indices were originally mostly Echocardiography of the right ventricle and right
derived from patients with congenital pulmonary atrium. RV remodeling according to the volume load
valve disease and postoperative Fallot patients and from tricuspid and pulmonary regurgitation leading
have not been specifically validated for CaHD and its to dilation, diastolic ventricular septal flattening,
peculiar pathophysiology characterized by a severely and initially increased indices of systolic function
decreased RV forward stroke volume. As a conse- (e.g., tricuspid annulus plane systolic excursion
quence of those difficulties, in the present authors’ [TAPSE]), which decrease over time with failure of the
experience, pulmonary regurgitation severity is not volume-overloaded RV. Standard echocardiographic
graded reliably by echocardiography in CaHD and assessment of the RV should be performed, with
there is a tendency to underestimate severity. careful acquisition of dedicated, RV-optimized
JACC: CARDIOVASCULAR IMAGING, VOL. 14, NO. 11, 2021 Baron et al 2245
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(“focused”) and RV-modified views. The most

F I G U R E 3 Carcinoid Disease of the Pulmonary Valve
reproducible echocardiographic size measurement is
the basal minor dimension in the RV-focused apical
4-chamber view, often termed “D1.” Systolic RV
pressure is mostly normal. Functionally, TAPSE, the
systolic peak longitudinal tissue velocity at the base
of the RV free wall (S0 ), RV fractional area change,
and longitudinal strain are helpful (note that free- RVOT
wall strain and “global” RV strain are based on 3
and 6 RV segments, respectively, and have different
normal values). RV strain is decreased in individuals
with CaHD. Interestingly, RV strain has been found
slightly decreased even in patients with elevated 5-
HIAA levels but without clear valvular disease (19%
vs. 22%, respectively, for RV free wall strain; 17). Ao asc
Given sufficient image quality, 3D echocardiography
can provide a useful estimate of RV ejection
MPA
fraction. Doppler recordings from the RV outflow
tract or the pulmonary valve often show prominent
late-diastolic antegrade flow, especially during
inspiration, after the electrocardiographic P wave
(i.e., coinciding with atrial systole) (Figure 4B). This
suggests the presence of a “restrictive physiology” Modified parasternal short-axis view of the ascending aorta in systole. The
pulmonary valve leaflets have an increased echo-density. The RVOT is
of the RV, which due to its high diastolic stiffness
dilated. Accompanying 2-dimensional Video 4 shows that the leaflets do not
conveys the atrial “kick” to the pulmonary
close in diastole and color Doppler video (Video 5). Ao asc ¼ ascending
circulation, although this has not been systematically aorta; MPA ¼ main pulmonary artery; RVOT ¼ right ventricle outflow
explored in carcinoid disease. Together with the RV, tract.
the right atrium increases in size, and atrial
fibrillation may ensue, additionally increasing (left
and right) atrial size. For standard assessment of the goal of assessing disease progression. These scores
RV and atrium, see current recommendations (18) are based on right-sided valvular disease and RV size
including assessment of RV strain. Presence of an and function and have been shown to correlate with
open foramen ovale, facilitated by high right atrial 5-HT and N-terminal pro–B-type natriuretic peptide
pressure and right atrial dilation, should be levels (see Dobson et al. [21] for details). However,
ascertained (see below). Right-to-left shunting may beyond descriptive accuracy with the ability to sem-
occur through such a foramen, enabling active iquantify disease progression, no prospective value
substances released into the inferior caval vein by (e.g., for deciding which patients should undergo
the metastatic tumor to bypass deactivation during surgery) has been shown for any score. Trans-
pulmonary passage (19) and thus affect the left-sided esophageal echocardiography should be considered
valves. in case of prohibitive transthoracic echo windows but
Echocardiography of left-sided valves. Left-sided is not necessary in the most patients. Notably, carci-
valve disease, mostly aortic and/or mitral regurgita- noid crisis may be triggered by transesophageal
tion, is relatively rare and mostly not severe, and gross echocardiography (22).
morphological abnormalities of left-sided valve are Nuclear imaging. Due to its superior ability to esti-
uncommon. Assessment follows standard guideline mate cardiac chamber volumes, to obtain unob-
criteria. It has been suggested that patients with a structed images in any desired plane orientation, and
patent foramen ovale are more likely to develop to measure volumetric forward and backward flow
left-sided disease, that it may be a risk factor for across valves by phase-contrast techniques, cardiac
right- and left-sided CaHD progression (5), and that magnetic resonance (CMR) plays an increasing role
assessment of patency by transthoracic contrast in the diagnostic work-up of patients with CaHD as
echocardiography with right-heart contrast should be a fallback option where echocardiography is
part of the work-up of patients with CaHD (20). insufficient or inconclusive (23,24). The most
Several echocardiographic scores have been commonly used technique is a retrospective
developed to quantify the severity of CaHD with the electrocardiogram (ECG)-triggered registration of
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F I G U R E 4 Carcinoid Disease of the Pulmonary Valve

59.1 cm/s
0.299 s
0 cm/s

M3 M4 M3 M4
cw cw +56.2
B 20%
1.8MHz
+56.2
C 55%
1.8MHz
WF 150Hz WF 150Hz

-56.2
cm/s
-56.2
200
cm/s

60 160

120

cm/s
80
-56.3 cm/s
40
-60
cm/s

-120 -40
75mm/s 90bpm

(A) Continuous-wave Doppler of pulmonary valve (same patient as in Figure 3). a short pulmonary regurgitant flow Is seen which ends 299 ms
before the next ejection (heart rate was 48 beats/min). See Video 3 to appreciate the visual impression of mild regurgitation due to its brief
duration. With a pressure half-time of 53 ms and a pulmonary regurgitation index of 61%, this represents severe pulmonary regurgitation.
Systolic forward flow velocities are mildly increased (Vmax, 1.8 m/s). (B) Carcinoid pulmonary valve disease. Continuous-wave Doppler signals
of moderate-to-severe pulmonary regurgitation show diastolic pulmonary regurgitant flow ending 100 ms before the onset of systolic
forward flow (blue arrows). Note also prominent antegrade a wave, suggesting “restrictive physiology” of the right ventricle. (C) Short
pressure half time of pulmonary regurgitant flow (63 ms).

contiguous axial or short-axis images (slices) diastolic and end-systolic RV volumes and sub-
throughout the cardiac cycle using steady-state free tracting forward flow through the pulmonary valve
precession sequences to assess chamber morphology (measured by phase-contrast immediately above the
and function in CaHD, especially the RV, and of the pulmonary valve). The result of the subtraction is
valves (25) (Figures 6 and 7). tricuspid regurgitant volume (RegVol), which,
Quantification of valvular regurgitation is one of related to total right ventricular stroke volume,
the major strengths of CMR. Evaluation of pulmo- yields tricuspid regurgitant fraction.
nary regurgitation by CMR is important in CaHD, Tricuspid regurgitation is considered severe if
given the difficulties in assessment of this valve by RegVol >60 ml or RegF >40%, moderate if RegVol is
echocardiography. Pulmonary regurgitation assess- 31 to 60 ml or RegF is 21 to 40%, and mild below these
ment is based on directly measuring through-plane values. Recommended ranges for pulmonary regur-
flow using phase-encoded sequences (Figure 6). gitation are RegVol >40 ml or RegF >30% for severe,
The ratio of diastolic backward stroke volume to RegVol of 21 to 40 ml or RegF of 16 to 30% for mod-
systolic forward stroke volume provides pulmonary erate, and below these values for mild pulmonary
regurgitant fraction (RegF). Assessment of tricuspid regurgitation (26).
regurgitation by CMR is rarely clinically necessary CMR results provide a unique opportunity for tis-
because the valve is excellently evaluated by sue characterization using conventional noncontrast
echocardiography but can be done by calculating (T1- and T2-weighted sequences with or without fat
total right ventricular stroke volume from end- saturation) and contrast-enhanced (late gadolinium
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F I G U R E 5 Carcinoid Pulmonary Stenosis

+69.3

PV Vmax
Vmax 278 cm/s
Max PG 31 mmHg

-69.3
cm/s

cm/s

-100

-200

-300

-400

75mm/s 77bpm

Although maximal velocity is <3 m/s, because of low stroke volume, this represents at least moderate pulmonary stenosis (Video 6).

F I G U R E 6 CMR Estimation of Tricuspid and Pulmonary RegV in a Carcinoid Patient With Involvement of Both the Tricuspid and
Pulmonary Valve

(A) Calculation of RV stroke volume using short-axis cine stack with SSFP sequence. Example of contouring of the ventricles in short axis in
end-diastole (left) and end-systole (right) with corresponding 4-chamber images. (B) Measurement of pulmonary stroke volumes using
phase-contrast imaging. Magnitude image for anatomy (left) and corresponding phase-contrast image (middle) with a section of main
pulmonary artery in the center (red contour). Flow time curve is shown across the main pulmonary artery (right). The part of the curve below
the baseline illustrates backflow in the pulmonary artery during diastole (yellow arrow). Total RV stroke volume was 156 ml; pulmonary
forward flow volume, 72 ml; calculated tricuspid, RegVol, 84 ml; and RegF, 54%. Pulmonary RegVol 21 ml and RegF 30%. Tricuspid
regurgitation was considered severe and pulmonary regurgitation moderate. CMR ¼ cardiac magnetic resonance; RegF ¼ regurgitant fraction;
RegVol ¼ regurgitant volume; RV ¼ right ventricle; SSFP ¼ steady-state free precession.
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F I G U R E 7 Tricuspid and Pulmonary Valve Assessment in Carcinoid Valve Disease Using CMR and ECG-Triggered CT

A B

C D

(A) CMR four-chamber cine image with SSFP sequence in end-systole. Thickened tricuspid valve leaflets with a wide central gap (yellow
arrow). (B) CMR four-chamber cine SSFP sequence in end-diastole. Longitudinal section over pulmonary valve showing thickened cusps and a
large coaptation defect (red arrow). (C) CT image taken in diastole at 75% of cardiac cycle. Cross-section of thickened pulmonary valve with a
large regurgitation area of 2.3 cm2 measured by planimetry. In the center of the image, a long-axis view of the aortic valve, which is closed
during diastole. (D) CT image taken in diastole at 75% of the cardiac cycle. Open tricuspid valve (yellow arrow) and thickened pulmonary
valve with a coaptation defect (red arrow). CMR ¼ cardiac magnetic resonance; CT ¼ computed tomography; ECG ¼ electrocardiography;
SSFP ¼ steady-state free precession.

enhancement) techniques for identifying localized acquisition covers a full cardiac cycle, restricted
pathologies, such as cardiac metastases. Figures 8 mobility can be demonstrated. Regurgitant orifice
and 9 illustrate CMR findings in patients with cardiac area may be directly measurable by planimetry
metastases of carcinoid disease. (Figure 7). Detection of cardiac carcinoid metastases
Cardiac computed tomography. In addition to allowing by CT is another strength. The main limitation
for pre-operative, noninvasive coronary angiography associated with CT scans is radiation exposure in the
in candidates for cardiac surgery, computed tomog- range of 5 to 10 mSv for an ECG-gated CT covering 1
raphy (CT) is rarely performed to study CaHD le- whole cardiac cycle.
sions. However, due to its excellent spatial Nuclear imaging. Several radiolabeled somatostatin
resolution, retrospective electrocardiographically analogs, such as gallium-68- or indium-111-labeled
(ECG)-gated CT allows good visualization of diseased octreotide, which are taken up by neuroendocrine
valve leaflets, which is particularly welcome for the tumor cells, are routinely used to detect and localize
otherwise difficult-to-visualize pulmonary valve neuroendocrine tumors and their metastases by
(3,24,27). The leaflets appear thickened, and, if CT positron emission tomography (PET) and can
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F I G U R E 8 Multimodality Imaging of Cardiac Carcinoid Metastases

A B
MV

LV

LV
Metastases

Metastases

C D

(A) Transesophageal echocardiogram demonstrating large mass in mid to distal inferior wall of the left ventricle. (B) 3-dimensional TTE shows
rounded mass (arrow) in the posterior wall of the LV. (C) CMR demonstrating 2 masses in the mid inferolateral wall extending to the apex
(arrows). Masses are limited to myocardium with no extra cardiac extension. (D) Gallium-68-labeled octreotide PET demonstrates avid focal
uptake of tracer in the region of the 2 masses (arrow), suggesting metastatic carcinoid tumor. Reprinted with permission from Bhattacharyya
et al. (5). CMR ¼ cardiac magnetic resonance; LV ¼ left ventricle; PET ¼ positron emission tomography; TTE ¼ transthoracic
echocardiogram.

occasionally detect metastatic cardiac lesions (Fig- ROLE OF CARDIAC IMAGING IN THE DECISION FOR
ures 9 and 10). The somatostatin analogs are superior CARDIAC SURGERY. Deciding when to intervene in
to [ 18F]fluorodeoxyglucose-based markers for the valvular CaHD is based on the severity of (mostly
detection of neuroendocrine tumors. Furthermore, right-sided) valvular heart disease. Once the presence
PET is better than single-photon emission tomogra- of severe valvular heart disease is established, the key
phy imaging in this regard, showing higher sensitivity issues are RV function and heart failure symptoms
to small lesions, especially when performed together despite fluid and salt restriction and diuretic therapy.
with CT (28). Cardiac metastases may occur more In accordance with the current recommendations for
frequently than originally believed and may be valvular heart disease guidelines (31,32) about severe
detected particularly well by PET/CT after adminis- tricuspid and pulmonary regurgitation, progressive
tration of monoamine precursor tracers such as [ 11C]5- deterioration of RV function and persistent heart
hydroxytryptophan (Figure 10) and the radiophar- failure symptoms caused by CaHD favor surgical
maceutical [18 F]fluoro-L-DOPA (29). One study found therapy, if tumor progression and comorbidity allow
a prevalence of 13% myocardial metastases in for an expected survival over 1 year. Thus, in most
patients with CaHD (30). Occurrence of cardiac me- cases, establishment of severe tricuspid regurgitation
tastases did not seem to correlate with valvular CaHD. with RV dilation and persistent symptoms or begin-
Note, however, that the valvular lesions typical of ning deterioration of RV function is the crucial
CaHD do not take up somatostatin analogs, and thus finding indicating the need for surgical intervention.
nuclear imaging plays no routine role in evaluating Tricuspid valve replacement is always performed. As
valvular CaHD. discussed, apart from tricuspid valve replacement,
pulmonary valve replacement is increasingly
2250 Baron et al JACC: CARDIOVASCULAR IMAGING, VOL. 14, NO. 11, 2021

Baron, Imaging in Carcinoid NOVEMBER 2021:2240–2253

F I G U R E 9 CMR Images From a Patient With Cardiac Carcinoid Metastases of a Pulmonary Carcinoid

A B

C D

Initial evaluation with echocardiography revealed mild concentric LV hypertrophy without valve engagement. CMR showed normal chamber
dimensions with both left and right ventricular function. In the LV walls, multiple round masses, 6 to 23 mm in diameter, were seen, involving
the septum, apex, and lateral wall, localized both intramurally, subepicardially, and subendocardially; and 1 single mass of 5-mm diameter was
observed in the mid RV free wall (red arrows). (A and B) 4-chamber and short-axis views, respectively. The masses displayed a hyperintense
signal compared to that of neighboring myocardium on T2-weighted sequences (C) and an isointense signal on T1-weighted sequences (D).
CMR ¼ cardiac magnetic resonance; LV ¼ left ventricle.

performed at the same time (11). Because in the past not justify use of mechanical prostheses per se for
pulmonary valve assessment was largely performed right-sided lesions. In one of the largest published
by echocardiography, which has substantial short- cohorts of 195 patients who underwent cardiac sur-
comings, it is unclear which degree of pulmonary gery for CaHD, of 8 patients who had a reoperation for
valve involvement should trigger replacement of this tricuspid bioprostheses, only 1, in whom a bio-
valve. However, underestimation of the pulmonary prosthesis had been implanted 8 years earlier, had
valve dysfunction at the time of surgery and leaving a signs of typical carcinoid plaque (11). Post-
significantly leaking valve untreated is likely to affect operatively, similar to post-operative care for other
future RV function, surgical outcomes, and patient prosthetic valves, echocardiography should be per-
prognosis. formed early (within 30 days) and yearly or if new
In case of at least moderate left-sided disease, symptoms arise.
these valves should also be considered for replace- POST SURGICAL IMAGING SURVEILLANCE. Current
ment. Several cases of quadruple-valve replacement recommendations (3,40) advise, apart from the
due to cardiac CaHD have been published (33–39). routine in-hospital early post-operative echocardiog-
Currently, replacement using a bioprosthetic valve raphy, an echocardiographic examination 3 to
is preferred by most centers, as life expectancy is 6 months post-operatively and at least yearly there-
limited in patients with CaHD, and chronic warfarin after, with particular attention to transprosthetic
therapy may not be well tolerated. In patients who gradients due to possible leaflet thrombosis if anti-
have undergone reoperation for CaHD, CaHD-specific coagulation is terminated or suboptimal. No other
degeneration of biologic prostheses is rare and does routine imaging is generally recommended.
JACC: CARDIOVASCULAR IMAGING, VOL. 14, NO. 11, 2021 Baron et al 2251
NOVEMBER 2021:2240–2253 Baron, Imaging in Carcinoid

HIGHLIGHTS F I G U R E 1 0 PET/CT Diagnosis of Cardiac Carcinoid Metastasis

 Carcinoid heart disease is a complication

of metastatic neuroendocrine tumors of
the gut affecting mainly the tricuspid and
pulmonary valves and rarely also the
mitral and aortic valves.
 Adequate cardiac imaging is crucial for
diagnosis and for the decision to inter-
vene surgically, which has been shown to
improve prognosis in severe carcinoid
heart disease.
 Carcinoid heart disease displays specific,
well-recognized features which should be
systematically sought in patients with
known tumors or right-sided valvular
heart disease.
 Pulmonary valve involvement is frequent,
tends to be underestimated by echocar-
diography, and may require cardiac
magnetic resonance for complete
evaluation.
 Cardiac computed tomography and nu-
clear imaging can contribute to improved
evaluation in some cases.

SUMMARY

The prognosis of carcinoid heart disease (CaHD) has

improved considerably over the last decades. One of
the drivers of this improvement is the better man-
agement of cardiac complications of metastasized Small pericardial metastasis from midgut carcinoid tumor visualized with
carcinoid disease, and the foundation for such man- [11C]5-hydroxytryptophan (5-HTP) PET/CT. 5-HTP is the precursor of se-
agement is better diagnosis through state-of-the-art rotonin which accumulates in serotonin-producing tumors, and PET identifies
cardiac imaging (Table 1). CaHD is mainly a disease lesions with high accuracy. Note the absence of uptake in normal
myocardium. CT ¼ computed tomography; PET ¼ positron emission
of right-sided heart valves. The tricuspid valve is
tomography.
nearly invariably affected, resulting in torrential
regurgitation. Coexisting pulmonary valve disease
has probably long been underestimated and under-
treated. The reason for this lies in the limited acces- substantially more severe instances of pulmonary
sibility of the pulmonary valve for echocardiography regurgitation have been found by CMR than were
and the difficulty of accounting for 2 serial regur- apparent by echocardiography. Cardiac computed
gitant lesions, which leads to severely reduced stroke tomography (CT) plays an ancillary role in anatomic
volume reaching the pulmonary valve, masking the valve evaluation where the quality of echocardiog-
severity of the pulmonary lesion. In most patients raphy is insufficient. In contrast to the crucial role of
with CaHD whose treatment plan is to undergo positron emission tomography (PET) for detection of
tricuspid valve replacement, the authors’ present neuroendocrine tumors, nuclear imaging has no
practice is to use cardiac magnetic resonance (CMR) routine role in CaHD, although the rarely occurring
to better assess pulmonary valve pathology, and cardiac metastases may be detected best by PET/CT.
2252 Baron et al JACC: CARDIOVASCULAR IMAGING, VOL. 14, NO. 11, 2021

Baron, Imaging in Carcinoid NOVEMBER 2021:2240–2253

T A B L E 1 Suggested Cardiac Imaging Approach to Patients with Carcinoid Disease

Patients with carcinoid disease and symptoms or signs of heart disease or increased natriuretic peptides or urinary or plasma levels of 5-HT should be screened by
echocardiography for valvular heart disease, particularly in cases of tricuspid and pulmonary valve disease and other abnormalities (e.g., left-sided valve disease)
(2,3,5,17,19,40,41).
If right-sided carcinoid heart disease is present, particular attention should be paid to right ventricular size and function.
If valve disease or right ventricular size and function are not adequately assessed by echocardiography, consider CMR (23,24), especially in cases of pulmonary
regurgitation, right ventricular volumes, and ejection fraction. CT images can add morphologic details of valves not sufficiently assessed by echocardiography,
especially the pulmonary valve (3,27) and right ventricular size and function.
Patients with confirmed advanced carcinoid heart disease should be examined every 3–6 months by echocardiography, because symptoms may be misleading.
Increased natriuretic peptide levels or urinary or plasma levels of 5-HT are markers of disease progression and change in symptoms, which should prompt repeat
echocardiography and additional imaging if necessary (3,8,10,40).
Especially if surgical therapy is considered, evaluate the patency of the foramen ovale by using contrast (agitated saline) echocardiography for possible intra-
operative closure. An open foramen ovale may be associated with left-sided valve disease (5,8,20,40).
After valve surgery for carcinoid heart disease, apart from immediate post-operative echocardiography, an echocardiographic examination 3–6 months post-
operatively and thereafter yearly are recommended in the absence of new symptoms. A focus of post-operative surveillance should be on the evolution of
transprosthetic gradients, as an increase may indicate thrombosis or structural degeneration of the prosthesis (3,40).
PET imaging is crucial for diagnosing endocrine tumor and metastasis location but generally not helpful for carcinoid heart disease. However, PET imaging has the
best ability to identify the rare occurrence of cardiac carcinoid metastases (3,28–30,40).

5-HT ¼ 5-hydroxytryptamine (serotonin); CMR ¼ cardiac magnetic resonance;PET ¼ positron emission tomography.

FUNDING SUPPORT AND AUTHOR DISCLOSURES

ADDRESS FOR CORRESPONDENCE: Dr Frank A.
The authors have reported that they have no relationships relevant to Flachskampf, Uppsala University Hospital, Ingång 40,
the contents of this paper to disclose. plan 5, 751 85 Uppsala, Sweden. E-mail: frank.
flachskampf@medsci.uu.se.

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