A 6-year-old, 37.5-kg, castrated male Golden Retriever was presented with intermittent
coughing and cardiac murmur. Physical examination revealed a grade III/VI systolic
heart murmur at the mitral valve area, tachycardia, and a resting respiratory rate
(RRR) of 24 breaths/min. Blood pressure was within normal range (systolic pressure
129 mmHg, diastolic pressure 104 mmHg, and mean arterial pressure 112 mmHg [Cardell
9402 Veterinary Monitor; Midmark, Tampa, FL, USA]). Complete blood count and serum
chemistry results were within normal range. Thoracic radiography demonstrated left-sided
cardiomegaly and a moderate broncho-interstitial pattern in the perihilar region.
The electrocardiography (ECG) revealed a mean electrical axis of 86˚, sinus tachycardia
(168 bpm), a widened P wave (0.06 s, [reference value, ≤0.05 s]) (Martin 2015), increased
R amplitude (5.2 mV, [reference value, 2.61 ± 0.55 mV]) (Sato et al. 2000), and depressed
ST segment in lead II.
On two-dimensional (2D) echocardiography (EPIQ 7 ultrasound system, Philips Medical
Systems, Andover, MA, USA), a class-2 subaortic stenosis (SAS) was identified, characterized
by a linear fibrous structure on the left ventricular outflow tract and severe post-stenotic
dilation of the aorta (Figure 1A). Color flow Doppler imaging of the left ventricular
outflow tract showed turbulent subvalvular systolic flow (Figure 1B). An increased
flow velocity across the left ventricular outflow tract was measured by continuous-wave
Doppler (4.34 m/s, [reference value, 1.29 ± 0.22 m/s], pressure gradient 75 mmHg)
(Chetboul et al. 2005), and aortic regurgitation was documented by color Doppler and
continuous-wave Doppler (3.07 m/s; pressure gradient 38 mmHg). Furthermore, a dilated
cardiomyopathy (DCM) was diagnosed which is characterized by a dilated left ventricle
(LV) and left atrium {E point to septal separation 31 mm, [reference value, 1–10 mm],
LV internal diameter in diastole (LVIDd) 74.9 mm, LVIDd indexed to body weight 2.58,
[reference value, 1.35-1.73], LV internal diameter in systole (LVIDs) 67.8 mm, LVIDs
indexed to body weight 2.16, [reference value, 0.79–1.14], end diastolic volume index
(EDVI) 258 mL/m2, [reference value, 54.16 ± 1.86 mL/m2], left atrial to aortic root
dimension ratio 2.6, [reference value, 1.23 ± 0.03]} (Figure 1C), with poor systolic
function {end systolic volume index (ESVI) 207 mL/m2, [reference value, 21.53 ± 1.15 mL/m2],
fractional shortening (FS) 9.48%, [reference value, 27–55%], ejection fraction (EF)
in Simpson’s method 8.0%, [reference value, 61.00 ± 1.24%]} (Morrison et al. 1992;
Saini et al. 2017; Cornell et al. 2004) (Figure 1D). The sphericity index of LV was
1.15 (<1.65 represents increased sphericity) (Dukes-McEwan et al. 2003). A central
jet of mitral regurgitation was documented by color Doppler and continuous-wave Doppler.
Figure 1.
(A) B-mode and (B) color-flow Doppler echocardiography of the left apical five-chamber
view in a dog with SAS and DCM showing class-2 SAS characterized by a linear fibrous
structure on LVOT (arrow head) and turbulent subvalvular systolic flow (white arrow).
Mitral regurgitation was also observed (yellow arrow). (C) Two-dimensional echocardiogram
(right parasternal long-axis view) showing DCM characterized by dilated chambers.
Note the enlargement of LV and LA (double arrowed lines) and the thin walls of the
ventricle (arrow heads). (D) Poor systolic function (fractional shortening 9.48%)
documented on M-mode (right parasternal short-axis view). Note the lack of contractility
(double arrowed lines). Ao, Aorta; DCM, dilated cardiomyopathy; LA, left atrium; LV,
left ventricle; LVOT, left ventricular outflow tract; SAS, subaortic stenosis.
The dog was administered pimobendan (0.3 mg/kg BW, PO q 12 h), furosemide (1 mg/kg
BW, PO q 12 h), ramipril (0.125 mg/kg BW, PO q 24 h), diltiazem sustained-release
(3 mg/kg BW PO, q 12 h), spironolactone (1 mg/kg BW PO, q 12 h), and digoxin (0.005 mg/kg
BW PO, q 12 h). To minimize the risk of myocardial damage, taurine (1 g/dog, PO q
12 h) and L-carnitine (2 g/dog, PO q 12 h) were supplemented to the cardiac medication
described above. The dog’s owner refused to perform interventional approach to SAS,
such as balloon valvuloplasty.
The serum concentration of N-terminal pro B-type natriuretic peptide (NT-proBNP) (IDEXX
Laboratories Inc., Westbrook, ME, USA), conventional echocardiography, and 2D speckle
tracking echocardiography (2D-STE) were serially evaluated in addition to other clinical
examinations {heart rate (HR), heart rhythm on ECG, and RRR} on days 0, 7, 60, and
180. The serial changes of serum NT-proBNP concentration, bull’s eye map by 2D-STE,
and echocardiographic results are shown in Figures 2 and 3, and Table 1, respectively.
The images for 2D-STE analysis were obtained and analyzed using a QLAB 7.0 system
(cardiac motion quantification; Philips Medical Systems, Best, the Netherlands). 2D
cine loops of parasternal or apical view with three or more consecutive cardiac cycles
and high frame rates (40-60 frames/s) were stored digitally for subsequent offline
analysis. LV myocardium was sufficiently visualized by careful acquisition of 2D views.
The software automatically selected a starting reference image which began with the
R-wave of the electrocardiogram. Then, the bilateral annuli and the apex of the LV
myocardial wall were manually selected by the investigator. The endocardial border
of the myocardium was automatically traced by the software, designating a region of
interest (ROI). If necessary, the investigator manually corrected the ROI to incorporate
the entire endocardial surface without any artifacts. The investigator ensured that
myocardial movement was visually synchronized with the ROI for the entire cardiac
cycle. The ROI was divided into six segments and the segmental values were averaged
to obtain mean LV strain and strain rate. The velocity, strain and strain rate values
in this case were the peak values on the respective mean curves. The LV radial velocity
(RV) and radial FS (RFS) were analyzed by 2D-STE from standard right-parasternal short-axis
view at the mid-ventricular level (papillary muscle level). The LV circumferential
strain (CS) and circumferential strain rate were evaluated from the same view used
in the radial evaluation. The LV longitudinal strain (LS) and longitudinal strain
rate were evaluated from three different views (standard left-apical four-chamber,
three-chamber, and two-chamber views), and the average was calculated for global LS
and longitudinal strain rate. A bull’s eye map was created for complete analysis of
the LV longitudinal function.
Figure 2.
Serial evaluation of serum NT-proBNP concentration in a dog with SAS and DCM. DCM,
dilated cardiomyopathy; NT-proBNP, N-terminal pro B-type natriuretic peptide; SAS,
subaortic stenosis.
Figure 3.
Serial evaluation of bull’s eye map of longitudinal strain by two-dimensional speckle
tracking echocardiography performed in a dog with SAS and DCM. On day 7, segmental
dyskinesia (blue region) in the apical region was detected, even though the overall
results in radial and circumferential evaluations were improved after treatment. This
deterioration of cardiac function in a specific segment was undetectable with conventional
echocardiography and serum NT-proBNP evaluation. The segmental dyskinesia gradually
worsened with disease progression. DCM, dilated cardiomyopathy; NT-proBNP, N-terminal
pro B-type natriuretic peptide; SAS, subaortic stenosis.
Table 1.
Serial evaluation of conventional echocardiography and 2D-STE in a 6-year-old Golden
Retriever dog with subaortic stenosis and dilated cardiomyopathy.
Variable
Day 0
Day 7
Day 60
Day 180
Heart rate (bpm)
168
134
131
132
Conventional echocardiography
FS (%)
9.48
12.7
16.7
13.5
EF (%)
8.0
14.5
19.5
16.4
EDVI
258
240
252
253
ESVI
207
177
173
173
2D-STE
Radial
Velocity (cm/s)
3.4
4.5
5.4
4.0
FS (%)
7.3
8.2
9.7
7.5
Circumferential
St (%)
−7.2
−8.2
−9.6
−7.5
SRS (1/s)
−1.0
−1.5
−1.6
−1.4
Global longitudinal
St (%)
−9.6
−9.7
−8.0
−5.4
SRS (1/s)
−1.7
−1.7
−1.4
−1.2
EDVI, end diastolic volume index; EF, ejection fraction in Simpson’s method; ESVI,
end systolic volume index; FS, fractional shortening; SRS, strain rate in systole;
St, strain.
On day 0, the serum NT-proBNP concentration was 7829 pmol/L [reference value, 0 to
900 pmol/L] (Figure 2). The 2D-STE results showed a clear reduction in the CS (−7.2%,
[reference value, −25 to −19%]), circumferential strain rate in systole (CSRS) (−1.0/s,
[reference value, −2.9 to −2.3/s]), global LS (−9.6%, [reference value, −23 to −14%]),
and global longitudinal strain rate in systole (LSRS) (−1.7/s, [reference value, −2.8
to −1.9/s]) (Suzuki et al. 2013) (Table 1).
On day 7, the clinical sign of intermittent coughing disappeared and the clinical
examination showed RRR of 18 breaths/min and sinus rhythm (134 bpm). The serum NT-proBNP
concentration decreased to 6912 pmol/L [reference value, 0 to 900 pmol/L] after treatment
(Figure 2). In conventional echocardiography and 2D-STE evaluation, FS, EF, EDVI,
ESVI, RV, RFS, CS, and CSRS were improved, and global LS and LSRS remained similar
to day 0 (Table 1). However, segmental dyskinesia in apical region was detected on
a bull’s eye map of LS (Figure 3).
On day 60, the dog showed RRR of 24 breaths/min and sinus rhythm (131 bpm). The serum
NT-proBNP concentration increased to 7711 pmol/L [reference value, 0 to 900 pmol/L],
indicating worsened myocardial damage (Figure 2). The conventional echocardiography
and 2D-STE results showed improvements in FS, EF, RV, RFS, CS, CSRS, and ESVI, but
deteriorations in EDVI, global LS, and global LSRS compared to day 7 (Table 1). The
bull’s eye map of LS demonstrated progression of myocardial dyskinesia (Figure 3).
On day 180, the dog showed RRR of 24 breaths/min and sinus rhythm (132 bpm). The serum
NT-proBNP concentration increased continuously to 8976 pmol/L [reference value, 0
to 900 pmol/L] (Figure 2). The FS, EF, RV, RFS, CS, CSRS, global LS, and global LSRS
worsened, while EDVI and ESVI remained similar to day 60 (Table 1). The bull’s eye
map of LS identified even more intensified myocardial dyskinesia than that on day
60 (Figure 3).
On day 229, the dog exhibited vomiting, hyporexia, and severe tachycardia (240 bpm).
Electrocardiography revealed atrial fibrillation with notched R wave. Without response
to esmolol (constant rate infusion of 0.1–0.2 mg/kg BW/min) and sotalol (2 mg/kg BW
PO, q 12 h), the atrial fibrillation persisted and the dog died the following day.
Subaortic stenosis (SAS) is one of the most common congenital cardiac diseases in
dogs (Kleman et al. 2012), which results in LV concentric hypertrophy by pressure
overload (O’Grady et al. 1989). Dilated cardiomyopathy (DCM) is also one of the most
common cardiomyopathies in dogs (Borgarelli et al. 2001), characterized by LV dilation,
impaired systolic function, and hemodynamic state of volume overload (Dukes-McEwan
et al. 2003; Tidholm et al. 2001). However, concurrence of the two diseases has been
rarely reported in dogs. There is one retrospective study reporting two dogs with
SAS and concurrent DCM among 195 dogs with confirmed diagnosis of SAS, but no detailed
description and evaluation of cardiac function and disease progression were made (Kienle
et al. 1994). To the authors’ knowledge, this is the first case report describing
a serial change of cardiac function and myocardial damage during monitoring period
in a dog with SAS and DCM, which is a rare condition with two different hemodynamic
properties.
The dog in this case mainly exhibited characteristics of DCM rather than those of
SAS. However, due to concomitant SAS, myocardial dysfunction and cardiac remodeling
of the dog were clearly worse than those of the previously reported DCM dogs (Pedro
et al. 2017; Bélanger et al. 2005). In addition, the median survival time of pimobendan-treated
DCM dogs were 1037 days in five Cocker Spaniels and 329 days in five Doberman Pinschers
(Fuentes et al. 2002), whereas the dog in this case with DCM and SAS died much earlier.
In veterinary medicine, it is known that SAS can develop to show LV dilation and reduced
EF in end-stage (De Madron et al. 2016), similar to the “low-flow, low gradient (LF-LG)
aortic stenosis (AS)” in humans (Pibarot and Dumesnil 2012). However, no case of SAS
has been reported in dogs that have caused myocardial changes to meet the diagnostic
criteria of canine DCM (Tidholm et al. 2001), and the exact diagnostic criteria or
characteristic features of LF-LG AS are not well demonstrated in dogs. The dog in
the present case showed clear myocardial dysfunction and cardiac remodeling which
fulfilled all proposed major and minor criteria for diagnosis of canine DCM (Dukes-McEwan
et al. 2003). Nevertheless, since the histopathology of this case was not available,
there is also a possibility of LF-LG AS, like in humans. Therefore, “LF-LG AS-like
disease” should be considered as a differential diagnosis of the dog in this case.
Further studies on end-stage SAS and establishment of criteria for LF-LG AS are required
in dogs.
For a precise assessment of cardiac function and identification of myocardial damage,
serum NT-proBNP concentration and 2D-STE were used to monitor the dog of the present
case over time. The NT-proBNP is considered to be one of the most specific and widely
used cardiac biomarkers in dogs, especially in volume overload conditions where stress
or stretch of the myocardium occurs (Oyama 2015; Wess et al. 2011; Singletary et al.
2012). Nevertheless, combination of NT-proBNP with other methods are required for
detection of early cardiac disease (Oyama 2015; Singletary et al. 2012). In human
heart diseases, the 2D-STE has been evaluated in combination with NT-proBNP and showed
significant correlation with NT-proBNP (Mornos et al. 2011; Wang et al. 2012; Meimoun
et al. 2011). However, in veterinary medicine, there are no reports comparing the
changes of NT-proBNP and 2D-STE in heart diseases during treatment period. This case
delineates how 2D-STE can be applied in combination with NT-proBNP to monitor a dog
with myocardial injury.
The most notable point of this case is that the 2D-STE measurement was able to detect
cardiac dysfunction in a specific segment which was undetectable by clinical examinations
and NT-proBNP measurement. On day 7, clinical signs, HR, LV contractility and myocardial
damage were improved after treatment, which were confirmed by the results of clinical
examinations, conventional echocardiography, 2D-STE, and NT-proBNP. However, despite
the improvement of overall myocardial function, a segmental dyskinesia in apical segment
was detected in bull’s eye map of LS. This suggests that improvement of the overall
myocardial injury does not mean improvement of all myocardial segments, and some of
the myocardial segments may be exacerbated in spite of increased contractility. Therefore,
the combined use of biomarkers such as NT-proBNP with 2D-STE in dogs with myocardial
damage may be useful for accurate assessment of myocardial status.
Regarding the response to therapy on day 7, the possibility of tachycardia induced
cardiomyopathy (TIC) as a primary cause of DCM can arise because clinical signs and
myocardial function were improved simultaneously with resolution of tachycardia in
response to the therapy (Shinbane et al. 1997; Zupan et al. 1996). It is known that
TIC can mimic DCM on echocardiography and is characterized to be largely reversible
by resolution of tachycardia (Martin 2015, p. 102–111, Shinbane et al. 1997; Zupan
et al. 1996). However, the tachycardia might have been secondary to the primary cardiac
disorders since the dog showed sinus tachycardia with evidence of congestive heart
failure (CHF), rather than supraventricular or ventricular tachycardia (Martin 2015).
In addition, the results of global LS and NT-proBNP concentration deteriorated even
though the HR remained stable at day 60 and 180, which also indicates that the tachycardia
was not the primary cause of the myocardial dysfunction (Packer et al. 1986). The
improvement of clinical signs and myocardial function on day 7 could be due to improvement
of secondary TIC (resolution of tachycardia), however the improvements including the
reduction of HR might also be due to resolution of CHF and increased cardiac output
by cardiac medications. Therefore, TIC was not considered as a primary cause of DCM,
although TIC secondary to primary cardiac disorders could be a possible differential
diagnosis in this dog.
Of the various 2D-STE indices used in this case, the longitudinal deformations (global
LS and global LSRS) were the most sensitive and accurate indicators of the myocardial
damage detected by NT-proBNP. From day 7 to day 180, the values of longitudinal deformations
decreased as serum NT-proBNP concentration increased. The high sensitivity of the
longitudinal deformations to myocardial damage has also been reported in human studies
(Mizuguchi et al. 2008; Kouzu et al. 2011). The three-directional 2D-STE results in
patients with cardiovascular risk factors and diastolic dysfunction showed lower LS
and LSRS than those of control patients (Mizuguchi et al. 2008). In another study
on three-directional 2D-STE in hypertension patients with eccentric cardiac hypertrophy,
a significant decrease was observed only in longitudinal deformation (Kouzu et al.
2011). The longitudinal fibers of the heart consist mainly of subendocardial fibers,
which are the most vulnerable fibers to interstitial fibrosis and ischemia, and therefore,
it is known that the longitudinal function is most sensitive to the initial changes
of cardiac disease (Kouzu et al. 2011). Thus, also in veterinary medicine, the longitudinal
deformations have possibility to be the most sensitive and useful indicator of myocardial
damage, especially in dogs with DCM. However, in the prior study on 2D-STE in DCM
dogs (Pedro et al. 2017), longitudinal deformations were not measured. Therefore,
further investigation on the directional difference of 2D-STE in DCM dogs is required.
Meanwhile, radial and circumferential deformations (RV, RFS, CS, and CSRS) were the
most sensitive indicators of myocardial contractility. Both radial and circumferential
deformations, as well as FS and EF increased on day 7 and day 60. The increase on
day 7 is thought to be a response to pimobendan administration, and the increase on
day 60 may be a compensation for the decrease in longitudinal deformation. In both
humans and dogs (Suzuki et al. 2013; Mizuguchi et al. 2008; Kouzu et al. 2011), it
is reported that the myocardial contractility is mainly exerted on radial and circumferential
directions, and the radial and circumferential deformations increase in compensation
for longitudinal dysfunction. This suggests that radial and circumferential deformations
in 2D-STE can be used as an accurate indicator of contractility in DCM dogs. However,
as observed on day 60, an increase in contractility does not indicate improvement
of the myocardium. Therefore, for precise assessment of myocardial function in dogs
with myocardial damage, monitoring using all three directions of 2D-STE will be necessary.
In this case, segmental dyskinesia on day 7 occurred initially in the apical region.
It is reported in human DCM patients that myocardial shortening in the apex precedes
that in the middle and basal regions, and thus the apical region was affected most
by the wall stress (Fujita et al. 1993). Therefore, also in dogs, the apical region
may be the first site of injury in cardiomyopathies such as DCM. Additional retrospective
studies in large number of dogs with cardiomyopathies are expected to clarify this.
In conclusion, this is the first reported case of a dog with DCM and SAS, which described
and compared serial changes of NT-proBNP and 2D-STE with disease progression. The
2D-STE was able to detect segmental dyskinesia which was undetectable by NT-proBNP
measurement. In addition, longitudinal deformations were the most sensitive 2D-STE
indices to show the myocardial damage, while radial and circumferential deformations
were accurate indices to show myocardial contractility. Therefore, monitoring with
NT-proBNP and 2D-STE is expected to have great diagnostic and prognostic utility in
dogs with heart diseases. Further large-scale studies on the comparison and clinical
application of cardiac biomarkers with 2D-STE are recommended.