Small Animals
Epidemiological, clinical, and echocardiographic features
and survival times of dogs and cats with tetralogy
of Fallot: 31 cases (2003–2014)
Valérie Chetboul dvm, phd
Isabelle Pitsch dvm
Renaud Tissier dvm, phd
Vassiliki Gouni dvm, phd
Charlotte Misbach dvm, phd
Emilie Trehiou-Sechi dvm
Amandine M. Petit dvm
Cécile Damoiseaux dvm
Jean-Louis Pouchelon dvm, phd
Loïc Desquilbet phd
Eric Bomassi dvm
From the Unité de Cardiologie d’Alfort (Chetboul, Pitsch,
Gouni, Misbach, Trehiou-Sechi, Petit, Damoiseaux,
Pouchelon), Unité de Pharmacie-Toxicologie (Tissier),
and Department of Biostatistics and Clinical Epidemiology
(Desquilbet), Université Paris-Est, École Nationale Vété-
rinaire d’Alfort, Centre Hospitalier Universitaire Vétéri-
naire d’Alfort, 94704 Maisons-Alfort cedex, France; the
Centre Hospitalier Vétérinaire des Cordeliers, 29 avenue
du maréchal Joffre, 77100 Meaux, France (Pitsch, Bomassi);
and INSERM U955, Equipe 03, 51 avenue du maréchal
de Lattre de Tassigny, 94010 Créteil cedex, France
(Chetboul, Tissier, Pouchelon).
Address correspondence to Dr. Chetboul (valerie.
chetboul@vet-alfort.fr).
T etralogy of Fallot is a complex congenital heart dis-
ease that typically consists of a VSD, override of
the interventricular septum by the aortic root, obstruc-
tion of the right ventricular outflow tract, and second-
ary hypertrophy of the right ventricle.1,2 The disease
is caused by an anterior deviation and abnormal sep-
tation of the conal septum during the embryonic pe-
riod.3–5 This combination of conotruncal abnormalities
was first described in 1888 by Etienne-Louis Arthur
Fallot6 as la maladie bleue (“blue baby syndrome”).
ABBREVIATIONS
CI Confidence interval
∆P Doppler-derived trans-stenotic pressure gradient
HR Hazard ratio
IQR Interquartile range
LVFWs Left ventricular free wall in systole
PT:Ao Ratio of the diameter of the pulmonary trunk
to the diameter of the aorta
RVFWs Right ventricular free wall in systole
VSD Ventricular septal defect
VSD:Ao Ratio of the diameter of the ventricular septal defect
to the diameter of the aorta
JAVMA • Vol 249 • No. 8 • October 15, 2016
OBJECTIVE
To characterize the epidemiological, clinical, and echocardiographic fea-
tures of dogs and cats with tetralogy of Fallot (TOF) and determine their
survival times.
DESIGN
Retrospective case series.
ANIMALS
15 dogs and 16 cats with a diagnosis of TOF as determined via echocardiography.
PROCEDURES
Medical records of dogs and cats were reviewed to extract information on
signalment, clinical status at the time of TOF diagnosis, echocardiographic
findings, and any outcome data.
RESULTS
The most common canine breeds were terrier types (n = 7). Most animals
(28/31 [90%]) had clinical signs of TOF at the time of diagnosis, including
cyanosis (16/31 [52%]). Pulmonic stenosis was characterized by a variable
systolic Doppler-derived pressure gradient (median [range], 108 mm Hg
[26 to 255 mm Hg]). Most ventricular septal defects were large, with a
median (range) ratio of the diameter of the ventricular septal defect to that
of the aorta of 0.60 (0.18 to 1.15). Median age at cardiac-related death was
23.4 months, with no significant difference between dogs and cats. Median
survival time from TOF diagnosis to cardiac-related death was briefer for
animals with no or low-grade heart murmur (3.4 months) than for those
with higher-grade heart murmur (16.4 months). After adjustment for age
and sex, having a lack of or a low- to mild-grade systolic heart murmur was
significantly associated with a briefer survival time.
CONCLUSIONS AND CLINICAL RELEVANCE
With a few exceptions, cardiac-related death occurred predominantly in
young adult dogs and cats with TOF, and most animals had severe clinical
signs at the time of TOF diagnosis. (J Am Vet Med Assoc 2016;249:909–917)
Tetralogy of Fallot has been extensively studied
in humans, in whom it is considered the most com-
mon congenital cyanotic heart disease, with an in-
cidence of 3 to 5 cases/10,000 live births, account-
ing for 5% to 10% of all congenital heart diseases.7–9
Several genetic mutations such as those of the genes
ZFPM2 and NKX2.5 have contributed to sporadic
cases of TOF in humans.4,10
Similarly, TOF is the most common cyanotic heart
disease of dogs and cats, accounting for 0.6% to 6.9% of
all congenital heart diseases in these 2 species.11–15 The
predisposition of Keeshonds to TOF has a suspected ge-
netic basis,16–18 but to the best of the authors’ knowledge,
no specific genetic mutation has been identified in dogs.19
Other than the conotruncal malformations reported for
Keeshonds,16–18 TOF has been sporadically reported for
other canine breeds.20–24 Only a few cases have been re-
ported for cats.11,25–30 Data regarding a series of dogs and
cats with TOF are therefore lacking, and survival times
of dogs and cats with TOF remain unknown. The pur-
pose of the study reported here was to characterize the
909
 Small Animals

epidemiological, clinical, and conventional and Doppler echocardiographic findings (including measurements
echocardiographic features of dogs and cats with TOF and presence and types of concomitant congenital heart
and determine their clinical outcomes and survival times. disease), and any outcome data included in the records
were also extracted.

Materials and Methods Standard and Doppler echocardiography

Medical records review
Paper and electronic medical records were identi-
fied of client-owned dogs and cats that had received a
conventional (ie, M-mode and 2-D) and standard Doppler
echocardiographic examination resulting in a diagnosis
of TOF at the Cardiology Unit of Alfort at the National
Veterinary School of Alfort, France, and at the Centre
Hospitalier Vétérinaire des Cordeliers in Meaux, France,
between April 1, 2003, and June 30, 2014. All animals
with TOF confirmed by conventional and Doppler echo-
cardiography were included in the study. Animals with
equivocal echocardiographic findings were excluded.
Data were obtained from the medical records re-
garding patient species, breed, age, sex, and body
weight. Clinical status at the time of TOF diagnosis,
Standard 2-D, M-mode, and Doppler echocardio-
graphic examinations were performed while dogs and
cats were awake and standing by trained observers at
the Cardiology Unit of Alforta and the Centre Hospitalier
Vétérinaire des Cordeliers,b as described elsewhere.31,32
Continuous ECG monitoring was provided throughout
the examinations. Characteristics of the 4 components
of TOF (VSD, overriding aorta, right ventricular out-
flow tract obstruction, and secondary right ventricular
hypertrophy) were assessed on standard parasternal
views (Figure 1). Presence of VSD was assessed by

Figure 1—Representative M-mode (A), 2-D (B), and color-flow Doppler (C and D) echocardiographic views of a cat with TOF.
A—The M-mode image reveals severe right ventricular myocardial hypertrophy (double-headed arrow), with a high ratio of right
ventricular free wall (RVFW) to left ventricular free wall (LVFW) thickness (1.43). B—The 2-D left parasternal short-axis view at
the level of the aortic valve reveals severe hypoplasia of the pulmonary trunk (arrows), characterized by a PT:Ao of 0.52 without
any poststenotic dilatation. Notice also the enlarged right atrial (RA) chamber. This cat was characterized as having a high ∆P value
(169 mm Hg) as assessed by continuous wave Doppler mode. C—A right parasternal 5-chamber Doppler view shows the left-to-
right component of a bidirectional shunt through a large VSD, located just below the overriding aortic root. D—Another right
parasternal 5-chamber Doppler view shows the right-to-left component of the same bidirectional shunt. Ao = Aorta. IVS = Inter-
ventricular septum. LA = Left atrium. LV = Left ventricle. PT = Pulmonary trunk. RV = Right ventricle.

910 JAVMA • Vol 249 • No. 8 • October 15, 2016


examination of the interventricular septum on right
and left parasternal long-axis, short-axis and oblique
views.33–35 Transverse views of the heart base, just prox-
imal to the pulmonic valve within the right ventricular
outflow tract, were also examined. Color-flow Doppler
mode was used to identify and confirm the presence
of VSD.33–36 Both color-flow and continuous-wave Dop-
pler modes were used to assess the shunt direction
(left-to-right, right-to-left, or bidirectional), as described
elsewhere.33–36 Continuous-wave Doppler mode was
also used to measure the maximal velocity through the
defect.
Maximal size of the defect (ie, VSD diameter)
was measured from Doppler color-flow map echo-
cardiograms at the level of the defect through the in-
terventricular septum.33,35 As described elsewhere,35
color-flow Doppler images were analyzed frame by
frame to compute the maximum area of the VSD jet
signal. The largest color-flow VSD diameter was then
measured. Lastly, the transverse aortic diameter was
measured along the commissure between the non-
coronary and left coronary aortic valve cusps in late
diastole by use of a 2-D method, as described else-
where.31,32 The VSD:Ao was then calculated.
Right parasternal long-axis 5-chamber echocar-
diographic views were also used to confirm override
of the aorta, which was defined as a displacement
of the aorta to the right so that it appeared to have
a biventricular connection overriding the muscular
ventricular septum.2 Right ventricular outflow tract
obstruction and obstructive abnormalities of the
pulmonic valve and pulmonary trunk (all hereafter
referred to as pulmonic stenosis) were diagnosed by
means of right and left parasternal short-axis views at
the level of the aortic valve. Morphological features of
pulmonic stenosis (valvular, subvalvular, and supra-
valvular obstruction) were assessed from the same
views by use of 2-D and color-flow Doppler modes.
Measurements of the diameters of the aorta and
pulmonary trunk were obtained by means of a 2-D
method and a right parasternal transaortic short-axis
view, as described elsewhere.37 Briefly, the end-dia-
stolic diameter of the pulmonary trunk was measured
just under the closed pulmonic valve, the aortic diam-
eter was measured on the same view, and the PT:Ao
was then calculated. The PT:Ao was considered un-
remarkable when values in dogs were between 0.80
and 1.15,37 and hypoplasia of the pulmonary trunk
was diagnosed when the PT:Ao was < 0.80. A similar
cutoff was applied to cats.
Additionally, continuous-wave Doppler mode was
used to assess the maximal systolic velocity through
the pulmonic stenosis. The modified Bernoulli equa-
tion was then applied to calculate the peak ∆P and to
grade the severity of pulmonic stenosis. Pulmonic ste-
nosis was considered mild for ∆P values ≤ 50 mm Hg,
moderate for ∆P values between 50 and 80 mm Hg,
and severe for ∆P values > 80 mm Hg.38
Thicknesses of the RVFWs and LVFWs were
measured by means of 2-D–guided M-mode echo-
JAVMA • Vol 249 • No. 8 • October 15, 2016
Small Animals
cardiography on the right parasternal ventricular
short-axis view,39 in accordance with the recommenda-
tions of the American Society of Echocardiography.40
The ratio of the thickness of the RVFWs to that of the
LVFWs was then calculated to assess the severity of
right ventricular hypertrophy. Hypertrophy was con-
sidered severe when the ratio was ≥ 1.5. Concomitant
congenital heart diseases were also recorded.
Follow-up data collection
Follow-up data were collected by a review of
the paper and electronic records of only animals
with TOF without any other concomitant congenital
heart disease. At the time of diagnosis, dogs and cats
were classified as clinically or subclinically affected
(ie, with or without clinical signs attributed to TOF).
Clinical signs for this purpose included exercise in-
tolerance, dyspnea, syncope, and cyanosis. Owners
of dogs and cats for which an outcome could not be
found in the records at the time the study concluded
were contacted by telephone, mail, or email to de-
termine whether their animals were alive (clinically
or subclinically affected) or dead (date and cause of
death, if known). Dogs and cats for which the out-
come could not be obtained at the time the study con-
cluded were considered lost to follow-up and were
consequently censored at the time of their last exami-
nation on record.
Statistical analysis
Statistical analyses were performed by use of
statistical software.c Categorical data are reported as
proportions or percentages, and continuous or ordi-
nal data for all variables but survival time are report-
ed as median (range). The Kolmogorov-Smirnov test
was used to assess normality of distribution of heart
murmur grades and imaging values. Because none of
these variables was normally distributed, values were
compared between dogs and cats by means of non-
parametric Mann-Whitney analysis. Spearman anal-
ysis (rs) was used to evaluate correlations between
heart murmur grade and ∆P.
Two survival analyses were performed: one for the
interval from date of birth to date of cardiac-related death
to determine median age at cardiac-related death and
the other to assess potential risk factors for cardiac-
related death at the time of diagnosis of TOF. Univari-
ate and multivariate Cox proportional hazard model-
ing was performed to identify factors associated with
survival time. The Kaplan-Meier method was used to
estimate median times to cardiac-related death, and
these survival times were compared between dogs
and cats by use of the log-rank test. Because of the
low number of animals, separate multivariate mod-
els were developed for each factor hypothesized to
be associated with survival time and were systemati-
cally adjusted for confounding factors (age and sex).
The proportional hazard assumption was checked by
including a linear-dependent interaction term, and
results (P > 0.13) indicated no deviation from that
911
 Small Animals
assumption. Survival times are reported as median
(IQR). Values of P < 0.05 were considered significant
for all analyses.
Results
Epidemiological features
Fifteen dogs (8 males and 7 females) and 16 cats
(11 males and 5 females) with TOF were included in
the study, for a total of 31 animals. Twenty-one had
received a TOF diagnosis at the Cardiac Unit of Alfort,
and 10 had received their diagnosis at the Centre Hos-
pitalier Vétérinaire des Cordeliers.
Dogs were of 9 breeds, with terrier types pre-
dominating (n = 7; 3 Jack Russell Terriers, 2 Maltese
Terriers, and 2 Border Terriers), followed by French
Bulldog (2), Chihuahua (2), and English Bulldog, Box-
er, Cane Corso, and Malamute (1 each). Median body
weight of the dogs was 3 kg (6.6 lb), with a range of
0.5 to 15.2 kg (1.1 to 33.4 lb).
Cats were of 5 breeds, with domestic shorthair
predominating (n = 12). Other cat breeds included
Persian, Ragdoll, Siamese, and British Blue (1 each).
Median body weight of the cats was 3.2 kg (7.0 lb),
with a range of 1.2 to 5.2 kg (2.6 to 11.4 lb).
Overall median (range) age at the time of TOF di-
agnosis was 7.0 months (1.7 to 54.0 months). Median
(range) age at time of TOF diagnosis for dogs specifi-
cally was 3.6 months (1.7 to 49.4 months) and for cats
was 9.8 months (2.9 to 54.0 months).
Clinical features
One dog (French Bulldog) and 1 cat (Persian) had
concomitant congenital heart disease, consisting for
both of an atrial septal defect and subaortic stenosis;
values of ∆P were 64 mm Hg and 38 mm Hg, respec-
tively. The remaining 29 (94%) animals had no heart
disease other than TOF.
Data obtained from cardiac auscultation at the
time of TOF diagnosis were available for 27 (87%)
animals (12 dogs and 15 cats). A heart murmur was
detected in most (n = 25 [93%]) of these animals. A
left systolic basal or midthoracic heart murmur (me-
dian grade, 4 [2 to 6]) was detected in 24 (89%) ani-
mals, either alone (n = 17 [71%]) or associated with
another heart murmur (ie, right systolic midthoracic
heart murmur) with a median grade of 4 (2 to 5; n =
7 [29%]), including the dog and cat with concomitant
congenital heart disease. One cat had only a systolic
right midthoracic heart murmur (grade 5/6).
Most animals (28 [90%]) had clinical signs of TOF
at the time of diagnosis (Table 1). The most common
clinical signs were exercise intolerance, observed in
all clinically affected animals, respiratory signs (eg,
dyspnea and panting), and cyanosis.
Treatment status at the time of TOF diagnosis was
known for all animals. Twenty one (68%; 11 dogs and
10 cats) were not being treated, and 10 (32%; 4 dogs
and 6 cats) were receiving 1 or a combination of the
following drugs that had been previously prescribed
by referring veterinarians: benazepril or enalapril (4
912 JAVMA • Vol 249 • No. 8 • October 15, 2016
cats and 1 dog), furosemide (1 dog and 2 cats), ateno-
lol (2 dogs), pimobendan (1 cat), acetylsalicylic acid
(1 cat), and spironolactone (1 cat).
Echocardiographic features
The location of the pulmonary stenosis was
known for 28 of 31 (90%) animals (15 dogs and 13
cats). Subvalvular stenosis was identified in 9 (32%)
of these animals (2 dogs and 7 cats), valvular stenosis
was identified in 8 (29%) animals (5 dogs and 3 cats),
and supravalvular stenosis was identified in 1 (4%)
animal (1 cat). Both subvalvular and valvular stenosis
were identified in 4 of 28 (14%) animals (3 dogs and
1 cat), and both valvular and supravalvular stenosis
were identified in 1 (4%) animal (1 cat). Combined
subvalvular, valvular, and supravalvular stenosis was
identified in 5 (18%) animals (all dogs).
A description of the pulmonary trunk at the time
of TOF diagnosis was available for 28 of 31 (90%) ani-
mals (15 dogs and 13 cats). Hypoplasia of the pulmo-
nary trunk was present in 10 (36%) animals (5 dogs
and 5 cats). Values for PT:Ao were available for 13
(42%) animals (5 dogs and 8 cats), with a median
(range) value of 0.62 (0.31 to 1.22) for dogs and 0.82
(0.52 to 1.40) for cats. The difference between spe-
cies was not significant (P = 0.51). Three dogs and
4 cats had a PT:Ao < 0.80 (reference range for dogs,
0.80 to 1.1537; reference range for cats unknown).
Values for ∆P at the time of TOF diagnosis were
available for 22 of 31 (71%) animals (12 dogs and 10
cats), with median of 108 mm Hg (range, 26 to 255 mm
Hg) for all animals. The median value for dogs (106
mm Hg [range, 39 to 255 mm Hg]) did not differ signifi-
cantly (P = 0.62) from the median value for cats (108
mm Hg [range, 26 to 169 mm Hg]). Pulmonic stenosis
was considered mild for 1 dog and 2 cats, moderate
for 4 dogs and 2 cats, and severe for 7 dogs and 6 cats.
No significant (P = 0.24) correlation was detected be-
tween heart murmur grade and ∆P (rs = 0.29).
Data regarding the ratio of the thickness of the
RVFWs to that of the LVFWs at the time of TOF diag-
nosis were available for 17 of 31 (55%) animals with
TOF (9 dogs and 8 cats), with a median (range) value
of 1.42 (0.89 to 1.94). No significant (P = 0.67) differ-
ence in median ratio values was identified between
dogs (1.34 [range, 1.25 to 1.94]) and cats (1.42 [range,
Table 1—Number (%) of dogs (n = 15) and cats (16) with
various clinical signs of TOF at the time of diagnosis.
Clinical sign All animals Dogs Cats
Exercise intolerance 28 (90) 13 15
Dyspnea or panting 18 (58) 8 10
Cyanosis 16 (52) 10 6
Slow growth rate 6 (19) 3 3
Syncope 5 (16) 4 1
Weight loss 5 (16) 3 2
Cough 3 (10) 1 2
For 3 of 31 (10%) animals (2 dogs and 1 cat), no clinical signs were
reported.
 Small Animals

0.89 to 1.88]). All 9 dogs and most (6) cats had a ratio of worsening of the aforementioned clinical signs for 3
> 1, and 7 animals (4 dogs and 3 cats) had severe right cats, and sudden for 3 cats. The remaining cat died at
ventricular hypertrophy characterized by a ratio > 1.5 the age of 65 months because of infectious peritonitis.
(1.67 [range, 1.56 to 1.94]) and (1.79 [range, 1.51 to Kaplan-Meier curves of intervals between birth
1.88]) for dogs and cats, respectively). and cardiac-related death revealed that the median
A unique perimembranous and membranous VSD age at death for the 29 animals was 23.4 months,
was detected in all animals. Data regarding VSD diame- with no significant (P = 0.30) difference between
ter, assessed by color-flow Doppler mode, were available dogs (13.0 months) and cats (23.4 months; Figure 2).
for 26 (84%) animals (12 dogs and 14 cats), with median Median survival time after TOF diagnosis was 14.5
value of 6.1 mm (range, 1.7 to 15.0 mm). No significant months (IQR, 4.4 to 29.5 months), with no significant
(P = 0.64) difference in median values was identified be- (P = 0.73) difference between dogs (11.1 months) and
tween dogs (7.7 mm [range, 3.7 to 11.4 mm]) and cats (5.4 cats (15.3 months).
mm [range, 1.7 to 15.0 mm]). The median (range) VSD:Ao Univariate analysis revealed that animals with-
calculated for 24 of 31 (77%) animals (10 dogs and 14 out any heart murmur or with a low- to mild-grade
cats) was 0.60 (0.18 to 1.15), with no significant (P = 0.64) systolic heart murmur survived for a median (IQR)
difference between dogs (0.60 [range, 0.35 to 1.02]) and time of 3.4 months (2.9 to 4.4 months) after TOF di-
cats (0.58 [range, 0.18 to 1.15]). Twenty-one of 24 (88%) agnosis, compared with 16.4 months (10.6 to 29.5
animals (9 dogs and 12 cats) had a VSD:Ao > 0.40, and 17
(71%) animals (7 dogs and 10 cats) had a VSD:Ao ≥ 0.50.
The direction of the shunt, assessed by use of com-
bined color-flow and continuous-wave Doppler modes,
was available for 29 of 31 (94%) animals (15 dogs and 14
cats). The shunt was bidirectional for 15 (52%) of these ani-
mals (7 dogs and 8 cats), left-to-right for 7 (24%) animals
(3 dogs and 4 cats), and right-to-left for 7 (24%) animals (5
dogs and 2 cats). No animals with left-to-right shunt were
cyanotic. All but 1 animal had clinical signs at the time of
diagnosis, including exercise intolerance (2 dogs and 4
cats), dyspnea or panting (1 dog and 2 cats), weight loss (1
dog), and slow growth rate (1 dog and 1 cat).

Cardiac events and survival time

Two animals with TOF (1 French Bulldog and 1
Persian cat) were excluded from subsequent statisti-
cal analyses because of other concomitant congeni-
tal heart diseases (subaortic stenosis and atrial sep-
tal defect for each). The dog was euthanized at 75.4
months of age because of right-sided congestive heart
failure. The cat died suddenly at 12 months of age.
Of the remaining 29 animals (14 dogs and 15
cats), 25 received a follow-up examination after TOF
diagnosis. Eighteen (72%) of these animals remained
untreated, and treatment of the other 7 (28%) animals
remained unchanged. Hydroxyurea was occasionally
prescribed by the referring veterinarian for 1 dog,
and phlebotomy in response to Hct values was per-
formed for another dog.
For all dogs that died during the study period (n
= 9), death was related to cardiac events at between
3.5 and 92.9 months of age. Cause or nature of death
was spontaneous (associated with worsening of clini-
cal signs such as exercise intolerance, respiratory
distress, and inability to remain in the standing posi-
tion) for 4 dogs, euthanasia because of worsening of
the aforementioned clinical signs for 2 dogs, sudden Figure 2—Kaplan-Meier curves of intervals from birth to car-
for 2 dogs, and pulmonary embolism for 1 dog. Death diac-related death for dogs (n = 14) and cats (15) with a diag-
was related to cardiac events at between 6.2 and 83.5 nosis of TOF overall (A) and for each species separately (B).
months of age for 10 of the 11 cats that died during the Median (IQR) overall age at death was 23.4 months (12.8 to 83.5
months). Median age at death for dogs alone was 13 months
study period. Cause or nature of death was spontane- (8.0 to 23.9 months) and for cats was 23.4 months (20.5 to 83.5
ous (associated with exercise intolerance, tachypnea months). Circles denote censored observations. The difference
with marked cyanosis) for 4 cats, euthanasia because between cats and dogs was not significant (P = 0.30).

JAVMA • Vol 249 • No. 8 • October 15, 2016 913

 Small Animals
Figure 3—Kaplan-Meier estimates of survival times from
initial TOF diagnosis to cardiac-related death for 25 dogs and
cats that had a follow-up examination performed after diag-
nosis, according to whether at diagnosis they had no heart
murmur or just a low- to mild-grade heart murmur (from 1/6
to 3/6; grey line) or a moderate- to high-grade heart murmur
(from 4/6 to 6/6; black line). Median (IQR) survival time for
animals with no murmur or just a low-grade heart murmur
was 3.4 months (2.9 to 4.4 months), which was significantly
(P < 0.01) different from that for animals with a moderate-
to high-grade murmur (16.4 months [10.6 to 29.5 months]).
Circles denote censored observations.
months) for animals with a higher-grade heart mur-
mur (P < 0.01; Figure 3). The crude HR for this
comparison was 14.2 (95% CI, 2.6 to 76.7). Similarly,
animals with severe right ventricular hypertrophy
had a significantly (P = 0.02) briefer survival time
after TOF diagnosis than did animals without this
disease characteristic (crude HR, 7.3; 95% CI, 1.4 to
36.6). Males (crude HR, 2.6; 95% CI, 0.9 to 7.6; P =
0.08) as well as animals with cyanosis (crude HR,
2.5; 95% CI, 0.9 to 7.2; P = 0.09) had a briefer surviv-
al time after TOF diagnosis than did females or ani-
mals without cyanosis, respectively; however, these
differences were not significant. No significant (P >
0.21) association with survival time was identified
for species (dog vs cat), syncope, slow growth rate,
presence of severe stenosis, VSD:Ao ≥ 0.5, pulmo-
nary hypoplasia, or shunt direction.
After adjustment for age and sex, lack of or low-
to mild-grade systolic heart murmur remained signifi-
cantly (P < 0.01) associated with a briefer survival
time (adjusted HR, 13.8; 95% CI, 2.4 to 80.0) after
TOF diagnosis, but the association between severe
right ventricular hypertrophy and survival time (ad-
justed HR, 4.4; 95% CI, 0.8 to 23.5) was no longer sig-
nificant (P = 0.08).
Discussion
Although some reports11,13,15 describe TOF as
the first condition associated with cyanosis in dogs
and cats with congenital heart disease, few studies
have specifically focused on the natural history of
TOF in small animals, and most such studies are case
reports or case series with only a limited number of
914 JAVMA • Vol 249 • No. 8 • October 15, 2016
cases.20–30 The present study provided original data
regarding the comparative epidemiological, clinical,
and conventional and Doppler echocardiographic
features of 31 dogs and cats with TOF.
Terrier types were the most common canine
breeds in the study, accounting for nearly half of
the dogs with TOF. A similar breed predisposition
for VSD (20/56 [36%]), either alone or in combi-
nation with other congenital heart diseases, was
previously reported by our research group.35 These
results are in accordance with those of previous
studies,12,41,42 suggesting that terrier-type dogs
are predisposed to conotruncal malformations.
However, in contrast to other studies,16–18,20 no
Keeshonds, Collies, Shetland Sheepdogs, or Bea-
gles were included in the present study, whereas
French Bulldog and Chihuahua were the second
most commonly affected breeds. Regarding cats,
domestic shorthair breeds were overrepresented,
as previously reported.42
In the study reported here, most dogs and cats
with TOF (29/31 [94%]) had no other congenital
heart disease. In humans, a persistent fourth aortic
arch and abnormal coronary arteries are concomi-
tantly diagnosed with TOF in 25% and 4% to 5% of
cases, respectively.5,43 In the present study, at least
1 systolic heart murmur related to pulmonic steno-
sis or VSD was detected in most animals with TOF
(25/27 [93%]), with a median grade of 4 (6-point
scale), regardless of thoracic region where the mur-
mur was most pronounced. Additionally, the ma-
jority (90%) of animals had clinical signs (mainly
exercise intolerance, dyspnea, and cyanosis) at the
time of TOF diagnosis, thus confirming that TOF
has early major physiopathologic consequences in
both dogs and cats (at a median age of 4 and 10
months, respectively).
As recommended for human patients, 2-D echo-
cardiography combined with M-mode and color-flow
Doppler mode was chosen to confirm the presence of
TOF. These combined ultrasonographic techniques
are considered as the most sensitive method for non-
invasive diagnosis of TOF5,44 in humans, allowing
identification of the pulmonary stenosis and overrid-
ing aorta, determination of the type and size of the
VSD, assessment of right ventricular hypertrophy se-
verity and shunt flow direction, and calculation of ∆P
values.
As part of the definition of TOF, pulmonic ste-
nosis was diagnosed in all animals included in the
present study. For most of them (64%), pulmonic
stenosis was characterized by a single obstruction
(subvalvular, valvular, or supravalvular), whereas
for others (36%) at least 2 obstructive lesions were
identified. In humans with TOF, valvular and su-
pravalvular pulmonic stenosis are the most com-
monly described types of obstructive lesions.5,43
Conversely to the situation in humans, solitary or
combined valvular and subvalvular obstructive le-
sions predominated in the animals of the present

study (36 of all 43 [84%] described obstructions),
whereas supravalvular obstructions were less com-
mon (7/43 [16%]), which is in accordance with
other reports.34,45
The present study also revealed that hypopla-
sia of the pulmonary trunk, identified in more than
a third of all dogs and cats with TOF, was common.
Pulmonic stenosis was considered severe for most
included animals (59%), whereas the obstruction
was considered moderate or mild for only 27%
and 14% of animals, respectively. These results ex-
plained, at least in part, the high percentage of ani-
mals with clinical signs at the time of diagnosis as
well as the high prevalence of cyanosis (52%). In
addition, the degree of right ventricular hypertro-
phy was marked for most animals, as reflected by
a median value of 1.4 for the ratio of the thickness
of the RVFWs to that of the LVFWs. Although right
ventricular hypertrophy is part of the definition of
TOF, to the best of our knowledge, no published
data exist regarding the severity of such myocar-
dial remodeling, compared with that in the left
ventricle.
As was identified in other studies,38,46 a large and
unique membranous and perimembranous VSD was
detected in all animals in the present study. The large
size of the defect was confirmed by VSD:Ao values,
which involved normalization of the VSD diameter
and allowed comparison of VSD severity between
animals of different sizes.35 In dogs and cats with
a solitary VSD, a good prognosis can be achieved
when the VSD diameter is less than half of the aortic
root size.47 Similarly, we previously identified a sig-
nificant difference in VSD:Ao values between clini-
cally and subclinically affected dogs, with a median
value of 0.4 for dogs with clinical VSD.35 In the pres-
ent study, VSD:Ao values were > 0.4 for nearly 90%
of all animals, with a median value of 0.6 and with
no difference between dogs and cats. The large size
of these defects, together with the high prevalence
of severe pulmonic stenosis, would explain the high
percentage of clinically affected animals at the time
of TOF diagnosis.
All possible types of VSD shunt directions as-
sociated TOF have been reported for small ani-
mals,38,45,46,48 without any accurate description of
their respective prevalences. In the present study,
a VSD was associated with a left-to-right shunt in
only 24% of animals, which was consistent with the
overall predominance of severe pulmonic stenosis.
Finally, after exclusion of the 2 animals with
other concomitant congenital heart diseases,
Kaplan-Meier analysis revealed that the survival
time of animals with TOF was fairly brief for dogs
and cats alike, with all deaths but 1 during the study
period related to a cardiac event. The median age
at cardiac-related death was 2 years, and only 25%
of the animals survived to 7 years of age. Findings
therefore suggested a poor long-term prognosis for
most dogs and cats with TOF. Interestingly, lack of
JAVMA • Vol 249 • No. 8 • October 15, 2016
Small Animals
or low-to-mild-grade heart murmur (vs moderate-to-
severe-grade heart murmur) and severe right ven-
tricular hypertrophy were associated with briefer
survival times from TOF diagnosis to cardiac-related
death, and after adjustment for age and sex, only
lack of or low-to-mild-grade systolic heart murmur
remained significant. These results are in accor-
dance with clinical reports showing that the intensi-
ty and duration of the systolic ejection murmur vary
inversely with severity of subvalvular obstruction in
human patients with TOF (which is the opposite in
patients with isolated pulmonic stenosis).5
This present study had several limitations,
mainly related to its retrospective nature. Values
for several conventional (eg, VSD diameter or
PT:Ao) and Doppler (eg, ∆P) echocardiographic
variables were unavailable for some animals. Addi-
tionally, Hct and blood oxygen saturation were not
recorded in the medical records. Several animals
were also lost to follow-up. The low number of ani-
mals included in the study resulted in low statisti-
cal power, which may have limited the ability to
detect significant associations of certain variables
with survival time in univariate and multivariate
analyses despite high HR values. For example, al-
though severe right ventricular hypertrophy had
an HR of 4.4 after adjustment for age and sex, this
association was not found to be significant (P =
0.08). The ability to adjust for other potential con-
founders was prevented owing to the small sample
size, and findings should be interpreted with con-
sideration of this limitation. Lastly, only live ani-
mals evaluated at 2 referral clinics were included in
the study, excluding all animals that may have died
before they could be brought to the clinics.
Despite the aforementioned limitations, the
present study provided clinical, imaging, and long-
term survival data for dogs and cats with TOF, help-
ing to further characterize this complex congenital
heart disease and highlighting its severity, which
was reflected in the common combination of se-
vere pulmonic stenosis and large VSD. Most affect-
ed dogs and cats had major hemodynamic derange-
ments at the time of diagnosis and died of cardiac
causes at a young adult age, with a few exceptions.
Additional research is therefore required to de-
velop palliative or curative surgical procedures for
treatment of dogs and cats with TOF. The potential
genetic basis of TOF also needs to be investigated
in some specific breeds such as Terrier-type dogs.
Acknowledgments
This study was not supported by any grant or other funding.
Footnotes
a. Vingmed System 5, Vivid 5, Vivid 7, and Vivid E9, GE Health-
care Inc, Waukesha, Wis.
b. Megas and My Lab Twice, Esaote Biomedica, Firenze, Italy.
c. Systat, version 10.0, SPSS Inc, Chicago, Ill.
915
 Small Animals
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From this month’s AJVR

Estimation of time to peak contrast enhancement of the aorta and liver

for dual-phase computed tomography on the basis of contrast medium
arrival time, injection duration, and injection technique in dogs
Jennifer Chau et al

OBJECTIVE
To evaluate the accuracy of estimating time to peak enhancement (TPE) of the aorta and liver
parenchyma on the basis of contrast medium arrival time in the aorta, injection duration, and injection October 2016
technique in dogs.
ANIMALS
18 dogs of specific body weight categories (≥ 2 dogs/category) with no liver abnormalities detected via CT. See the midmonth
PROCEDURES issues of JAVMA
Dogs were randomly assigned within weight categories to receive contrast medium IV at a fixed for the expanded
injection rate (5 mL/s) or fixed injection duration (20 seconds). Time–contrast attenuation curves
were generated from dynamic CT scans acquired at the hepatic hilus. Data collected for contrast table of contents
medium arrival time and injection duration were used to estimate TPEs of the aorta and liver, and
results were compared with the observed TPEs for the aorta and liver.
for the AJVR
RESULTS or log on to
Contrast medium arrival time, injection duration, and injection technique were significantly avmajournals.avma.org
associated with observed values for aortic TPE and explained 96.1% of variation in TPE. For
the fixed rate technique, the regression equation for estimating aortic TPE was 0.8 X (injection for access
duration + contrast medium arrival time) + 1.6. For the fixed duration technique, the regression to all the abstracts.
equation changed by only the constant (–2.6). However, the hepatic TPE estimated from the 3
predictor variables was not significantly different from the mean of observed TPEs.
CONCLUSIONS AND CLINICAL RELEVANCE
Aortic TPE could be accurately estimated from contrast medium arrival time, injection duration, and
injection technique in dogs with apparently healthy livers. The regression equations derived from this
relationship can be used to improve the efficiency of dual-phase CT of the liver in dogs. (Am J Vet Res
2016;77:1093–1100)

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