This document summarizes a study on the survival characteristics and prognostic variables of dogs with myxomatous mitral valve disease (MMVD), the most common heart disease in dogs. The study included 558 dogs of varying breeds and severity of MMVD. Clinical exams, echocardiograms, and follow-up phone interviews with owners were conducted to evaluate survival times and prognostic factors. Variables found to be associated with reduced survival in univariate analysis included older age, syncope, increased heart rate and dyspnea, higher ISACHC heart failure class, diuretic use, increased end-systolic volume, enlarged left atrium, and higher transmitral flow velocities. Multivariate analysis identified syncope, enlarged left atrium

1. Survival Characteristics and Prognostic Variables of Dogs with
Mitral Regurgitation Attributable to Myxomatous Valve Disease
M. Borgarelli, P. Savarino, S. Crosara, R. A. Santilli, D. Chiavegato, M. Poggi, C. Bellino, G. La Rosa,
R. Zanatta, J. Haggstrom, and A. Tarducci
Background: There are few studies evaluating the natural history and prognostic variables in chronic mitral valve disease
(CMVI) in a heterogeneous population of dogs.
Objectives: To estimate survival and prognostic value of clinical and echocardiographic variables in dogs with CMVI of
varying severity. Five hundred and fifty-eight dogs belonging to 36 breeds were studied.
Methods: Dogs were included after clinical examination and echocardiography. Long-term outcome was assessed by tele-
phone interview with the owner.
Results: The mean follow-up time was 22.7 13.6 months, and the median survival time was 19.5 13.2 months. In univ-
ariate analysis, age48 years, syncope, HR4140 bpm, dyspnea, arrhythmias, class of heart failure (International Small Animal
Cardiac Health Council), furosemide therapy, end-systolic volume-index (ESV-I)430 mL/m2
, left atrial to aortic root ratio
(LA/Ao)41.7, E wave transmitral peak velocity (Emax)41.2 m/s, and bilateral mitral valve leaflet engagement were associated
with survival time when all causes of death were included. For the cardiac-related deaths, all the previous variables except
dyspnea and EDV-I4100 mL/m2
were significantly associated with survival time. Significant variables in multivariate analysis
(all causes of death) were syncope, LA/Ao41.7 m/s, and Emax41.2 m/s. For cardiac-related death, the only significant vari-
able was LA/Ao41.7.
Conclusions and Clinical Importance: Mild CMVI is a relatively benign condition in dogs. However, some clinical variables
can identify dogs at a higher risk of death; these variables might be useful to identify individuals that need more frequent
monitoring or therapeutic intervention.
Key words: Heart; Heart failure; Myxomatous mitral valve disease; Volume overload.
Mitral regurgitation attributable to myxomatous
valve disease, also known as chronic mitral valve
insufficiency (CMVI), is the most common heart disease
in dogs. It has been estimated that CMVI accounts for
75–80% of cardiac diseases in dogs.1
The disease is
caused by progressive myxomatous degeneration of
either the mitral valve alone or together with the
tricuspid valve,1,2
leading to incomplete coaptation of
the leaflets and valvular regurgitation. Myxomatous mi-
tral valve disease has been shown to be associated with
valve thickening and abnormal motion of the mitral
leaflets upon echocardiogram analysis in both humans
and dogs. The condition has been shown to represent the
most common cause of mitral regurgitation in dogs.2–4
Gross and histological findings are comparable to the
changes found in mitral valve prolapse (MVP) in hu-
mans,5
which is usually benign, although serious
complications may develop. An age older than 50 years,
depressed left ventricular function, moderate to severe
mitral regurgitation, atrial enlargement, mitral valve
thickness 5 mm, and atrial fibrillation have been re-
ported to represent significant risk factors for
cardiovascular events, including sudden death.6
In dogs,
the disease is characterized by a slow progression over
years, with many affected dogs that, because of the age of
onset, never progress to reveal clinical signs of overt
heart failure (HF) before death. Surprisingly, although
CMVI is the most common cause of HF, there are very
few studies evaluating the natural history and potential
risk factors for progression of the disease in this species.
Previously reported risk factors in dogs for progression
of disease include age, gender, intensity of heart murmur,
degree of valve prolapse, severity of valve lesions, and the
degree of mitral valve regurgitation.7–10
However, these
studies have generally been conducted on specific breeds
such as Dachsund or Cavalier King Charles; prognostic
data and survival analysis of a more heterogeneous pop-
ulation including large breed dogs are thus not available.
The aims of the present study were to estimate the sur-
vival times in dogs with varying severities of MR
attributable to CMVI and to assess the prognostic value
of clinical and echocardiographical variables on survival.
Material and Methods
Study Population
The medical records of dogs examined at 4 referral centers in
northern Italy between January 2000 and June 2005 were reviewed.
From these records, 722 cases diagnosed with CMVI were identi-
fied. All dogs had been presented for a cardiology consultation
because of previous identification of a heart murmur, because of the
presence of clinical signs possibly indicating cardiovascular disorder
including cough and exercise intolerance, or both. Out of the initial
From the Department Patologia Animale, Faculty Veterinary
Medicine, Grugliasco, Italy (Borgarelli, Savarino, Crosara, Bellino,
Rosa, Zanatta, Tarducci); Clinica Veterinaria, Malpensa, Italy
(Santilli); Clinica Veterinaria, Padova, Italy (Chiavegato); Centro
Veterinario Imperiese, Imperia, Italy (Poggi); and the Department of
Clinical Sciences, Faculty of Veterinary Medicine and Animal Sci-
ence, Uppsala, Sweden (Haggstrom). Preliminary results presented
at the American College Veterinary Internal Medicine Louisville,
USA 2006.
Corresponding author: Michele Borgarelli, DVM, PhD, Dipl.
ECVIM-CA (Cardiology), Department of Clinical Science, College
of Veterinary Medicine, 111B Mosier Hall, KS 66506; e-mail:
mborgare@vet.k-state.edu.
Submitted May 2, 2007; Revised July 9, 2007; Accepted
September 25, 2007.
Copyright r 2008 by the American College of Veterinary Internal
Medicine
10.1111/j.1939-1676.2007.0008.x
J Vet Intern Med 2008;22:120–128

2. 722 cases, 157 were eliminated from further evaluation as it was im-
possible to contact the owner to obtain follow-up information or
because echocardiographic examination had not been performed.
Inclusion Criteria
All dogs included in the study had to have undergone physical
workup and echocardiographic examination. Echocardiographic in-
clusion criteria were the combination of presence of MVP, any degree
of mitral valve leaflet thickening by 2-D echocardiography, and the
identification of any degree of mitral valve regurgitation by color
Doppler examination, with or without mitral valve thickening. The
left ventricular fractional shortening (FS) had to be more than 20%.
Finally, the owners had to be available for a telephone interview.
Exclusion Criteria
Dogs that presented with congenital heart disease or acquired
cardiovascular disorders that directly or indirectly affected the mi-
tral valve or its function, such as bacterial endocarditis or dilated
cardiomyopathy, were excluded from the study. Mitral endocarditis
was excluded based on clinical findings, and the lack of obvious
large vegetative lesions with heterogeneous appearance, as detected
by echocardiography.11
Dilated cardiomyopathy was excluded
based on the presence of valve changes consistent with myxomatous
mitral valve disease and MVP and the absence of echocardiographic
criteria such as an FSo20%.12
Baseline Data
The following data were obtained from case records: gender, age,
body weight, heart rate (HR), presence and intensity of heart mur-
mur, systolic blood pressure (SBP), presence of dyspnea, case
history of syncope, presence of arrhythmias, and baseline treat-
ment. Dyspnea was defined as labored or difficult breathing. Blood
pressure was measured noninvasively with Doppler
sphygmomanometry.a
The following echocardiographic data were
retrieved: end-diastolic and end-systolic volume indexes (EDV-I
and ESV-I), left atrial to aortic root ratio (LA/Ao), description of
mitral valve leaflet morphology (anterior, posterior, or both), and
transmitral flow data. The latter included peak E-wave (Emax) ve-
locity (early filling) and E-wave deceleration time (Edt). In each dog,
based on clinical signs and thoracic radiographs, the severity of HF
was classified according to the International Small Animal Cardiac
Health Council (ISACHC) recommendations.13
All clinical datasets
were reviewed by a single experienced investigator (MB).
Echocardiography
All dogs had previously undergone a complete echocardiograph-
ic examination, which included transthoracic 2-D, M-mode,
spectral, and color flow Doppler. Transducer arrays of 5.0–7.5 and
2.5–3.5 MHz were used.b
Examinations were performed in con-
scious, unsedated dogs. Right parasternal M-mode recordings were
obtained from short-axis views with the dogs positioned in right lat-
eral recumbency, and the 2-D echocardiograms were obtained in
accordance with techniques described elsewhere.14,15
The presence of MVP and mitral valve thickening was evaluated
from the right parasternal long-axis, the right parasternal 4-chamber
view, and left apical 4-chamber view. Mitral valve prolapse was de-
fined as any systolic displacement of one or both mitral valve leaflets
basal to the mitral annulus observed in at least two of these views.3
The presence of mitral valve regurgitation was evaluated by color
Doppler in the right parasternal long-axis and left apical views.
Echocardiographic Measurements
All echocardiographic measurements were made by 4 investiga-
tors (MB,RAS,MP,DC), and were reviewed by 1 experienced
investigator (MB) with videotape recordings. M-mode measure-
ments were obtained according to the leading-edge-to-leading-edge
method. The EDV and ESV were calculated by the Teicholz meth-
od: EDV 5 [7 (EDD)3
]/(2.4 1 EDD) and ESV 5 [7 (ESD)3
]/
(2.4 1 ESD)16
and values were successively indexed for body surface
area to obtain the EDV-I and the ESV-I. The LA/Ao was obtained
from the 2-D short-axis view.17
Clinical Progress and Survival
The clinical progress of each dog was ascertained by telephone in-
terview with the owner. The interviews were conducted by specifically
trained senior students, and the results were recorded in an electronic
questionnaire. The questionnaire consisted of questions with a definite
number of possible answers, most commonly yes/no. The interviewer
was not blinded to the clinical status of the dog at the initial examin-
ation. The owner was asked if the dog was dead or alive. If the dog
was dead, the owner was asked if the dog had been euthanized or died
spontaneously, reasons for euthanasia, and, in case of spontaneous
death, the possible causes, including cardiac-related sudden death,
presence of syncope, or progression of HF were probed. Cardiac-re-
lated death was defined as death occurring because of progression of
clinical signs of HF. Dogs that were euthanized because of refractory
HF were scored as cardiac-related deaths. In this study, sudden death
was defined as death occurring during sleep or activity such as run-
ning, or within 2 hours after the dog showed sudden signs of HF
(dyspnea). Sudden death was regarded as cardiac-related if no other
cause of death was obvious. A survival analysis was performed on all
causes of deaths and on cardiac-related deaths separately.
Statistical Analysis
Statistical analysis was performed by a freeware statis-
tical software package (R 2.3.0).c
Normal distribution
of data was assessed by the Shapiro Wilk normality test.
Descriptive statistics were used for gender, age, body
weight, heart rate, the presence and intensity of heart
murmur, presence of dyspnea, syncope, class of HF and
presence of arrhythmia, and all 2-D, M-mode, and
Doppler-derived variables. Numerical variables were re-
ported as the mean standard deviation (SD). Effects on
survival of the 16 clinical, ECG, echocardiographic,
and Doppler variables were evaluated, which included
gender, dyspnea, syncope, age48 years, weight420 kg,
HR4140 bpm, murmur4II/VI, SBP4140 mmHg, class
of HF according to ISACHC classification, furosemide
treatment (yes/no), affected leaflet (anterior, posterior,
or both), EDV-I4100 mL/m2
, ESV-I430 mL/m2
, LA/
Ao41.7, Emax41.2 m/s, and Edto80 ms.
Univariate Cox survival analysis was used in survival
analysis to evaluate the hazard ratio of an adverse event.
Survival curves, median survival times, and 95% CIs
were obtained by the Kaplan-Meier method. Survival
time was counted from the day of diagnosis of CMVI at
the referral center to either the day of death or closing
time of the study. End-point of the study was death (all
causes). A subanalysis was performed including only
deaths that were considered cardiac-related. Dogs avail-
able to follow up but for which the time point of death
was not available or were still alive were censored. Univ-
ariate Cox survival model was used to define significant
121
Mitral Valve Disease in Dogs

3. variables (Po.05) for subsequent analysis. Multivariate
analysis was performed by Cox proportional hazard re-
gression. Results of multivariate analysis were
considered significant when P values were o.05 with a
hazard ratio confidence interval of 95%, excluding 1.
Results
Baseline Characteristics
Five hundred and fifty-eight dogs from 36 breeds were
included in the analysis; 157 dogs had been excluded
from the analysis, and of these, 143 (91.1%) were not in-
cluded because it was not possible to contact the owner
(ie change of address) and 14 (8.9%) because echocar-
diographic data were missing. The dogs not available for
followup had different classes of HF: 76 were in class 1
(48.4%), 48 in class 2 (30.6%), and 19 (12.1%) were in
class 3 ISACHC, whereas the ISACHC class in dogs with
echocardiographic data missing could not be established.
The majority of dogs included in the study were small
(o 20 kg) mixed breed dogs (n 5 176; 31%) followed by
Yorkshire Terrier (n 5 58; 10.4%) and Miniature Poodle
(n 5 50; 9.0%). There were 180 females and 378 males;
the mean age was 10.6 2.62 years (range 3–18 years),
and the mean weight was 11.6 9.3 kg (range 2–67 kg).
Four hundred and seventy-six dogs weighed 20 kg and
77420 kg. At baseline examination, 67 dogs (12%) had
dyspnea, 115 (20.6%) had a case history of syncope, and
17 dogs (3.0%) presente an arrhythmia on the ECG re-
cording. The mean HR (n 5 171) was 121 28 bpm. All
dogs presented with a systolic murmur that was charac-
terized as a soft midsystolic murmur (1–2/6) in 46 dogs
(8.2%) and as a moderate to loud holosystolic murmur
(3–5/6) in 347 dogs (62.2%). The intensity of the murmur
was not characterized in 165 dogs (29.6%). Three hun-
dred and two dogs (54.1%) had asymptomatic disease
(class I ISACHC), 157 (28.1%) were in class II ISACHC,
and 99 (17.8%) were in class III ISACHC. The mean
EDV-I and ESV-I (n 5 555) were 107.1 67.04 and
58.75 59.3 mL/m2
, respectively. The mean LA/Ao
(n 5 526) was 1.8 0.7. The mean Emax (n 5 377) was
0.94 0.45 and the mean Edt (n 5 298) was 93 28 ms.
Tables 1a and 1b report clinical and echocardiographic
variables for each ISACHC HF class.
By 2-D-echocardiogram, all dogs presented MVP and
thickening of mitral valve leaflets. Description of which
leaflet was affected was available for 189 dogs. In this
subgroup bilateral mitral valve leaflet involvement was
identified in 105 animals (55.5%), 80 (42.3%) had only
the anterior leaflet affected, and 4 dogs (2.2%) had only
the posterior leaflet affected. At baseline, 339 (60.7%)
dogs were receiving medical therapy for HF. Of these
dogs, 272 dogs received furosemide alone or in combina-
tion with other drugs. The baseline treatments are
summarized in Table 2.
Univariate Survival Analysis
The mean followup time of this study was 22.7 13.6
months. Altogether 252 dogs (45.2%) had died or were
euthanized during the observation period; 174 deaths
were considered as cardiac related. Ninety-one dogs
(36.1%) had been euthanized, 71 (28.2%) of which had
been requested because of refractory HF. Twenty-two
dogs (8.7%) had sudden death. Of these, 5 were in class I,
8 were in class II, and 9 in class 3 ISACHC class at
initial examination. The median survival time, regard-
less cause of death, was 19.5 13.2 months (range
0.03–72 months). Of the 16 variables that were used as
Table 1b. ISACHC class distribution for the discrete studied
variables.
ISACHC 1 ISACHC 2 ISACHC 3
TOT
No. % No. % No. %
Sex
Males 190 62.9 116 73.9 72 72.7
Females 112 37.1 41 26.1 27 27.3
TOT 302 157 99 558
Murmur
I—II 19 11.5 25 19.4 8 8.1
III—V 146 88.5 104 80.6 91 91.9
TOT 165 129 99 393
Syncope
Yes 24 9.3 43 28.3 48 48.5
No 235 90.7 109 71.7 51 51.5
TOT 259 152 99 510
Dyspnea
Yes 24 38.1 22 100.00 21 100.00
No 39 61.9 0 0.00 0 0.00
TOT 63 22 21 106
Arrhythmia
Yes 2 0.9 9 8.0 6 12.0
No 229 99.1 104 92.0 44 88.0
TOT 231 113 50 394
MVL
Anterior 47 46.5 21 39.6 12 38.7
Both 54 53.5 32 60.4 19 61.3
TOT 101 53 31 185
MVL, mitral valve leaflet; ISACHC, International Small Animal
Cardiac Health Council.
Table 1a. Report on mean SD variable for each ISACHC heart
failure class.
ISACHC 1 ISACHC 2 ISACHC 3
Mean SD Mean SD Mean SD
Age (years) 10.24 2.78 11.16 2.49 10.91 2.13
Weight (kg) 11.89 10.01 11.25 8.46 11.12 8.51
ESV-I (mL/m2
) 34.29 29.67 65.59 53.5 40.18 26.91
EDV-I (mL/m2
) 93.94 46.65 131.64 75.9 188.39 57.77
LA/Ao 1.45 0.47 2.04 0.52 2.49 0.79
Edt (ms) 95.03 29.23 90.85 31.04 73.76 20.55
E peak (m/s) 0.78 0.34 1.08 0.43 1.41 0.54
HR (beat/min) 121.47 26.65 122.63 29.36 141.72 17.15
SBP (mmHg) 161.30 27.34 150.89 32.08 142.50 23.88
ESV-I, end systolic volume index; EDV-I, end diastolic volume
index; LA/Ao, left atrium aortic root ratio; Edt, E wave decelera-
tion time; E peak, peak velocity of E wave; HR, heart rate; SD,
standard deviation; SBP, systolic blood pressure; ISACHC, Inter-
national Small Animal Cardiac Health Council.
122 Borgarelli et al

4. predictors in Kaplan-Meier analysis, age, syncope, HR
4140 bpm, dyspnea, arrhythmias, class of HF, treat-
ment with furosemide, ESV-I430 mL/m2
, LA/Ao41.7,
Emax41.2 m/s, and bilateral mitral valve leaflet involve-
ment were significantly associated with overall survival
time (Fig 1; Table 3). For the cardiac-related deaths, all
the previous significant variables, except dyspnea, had a
significant relationship with survival. Moreover, EDV-I
4100 mL/m2
had a significant effect on survival (Fig 2,
Table 4). Syncope was not associated with an increased
risk of sudden death.
Multivariate Survival Analysis
In multivariate analysis, syncope (hazard ratio 3.3,
95% CI 5 1.30–7.74, Po.05), LA/Ao41.7 (hazard
ratio 5 3.70, 95% CI 5 1.79–7.63, Po.01), Emax41.2
(hazard ratio 5 3.10, 95% CI 5 1.48–6.25, Po.01)
were independent predictors of all-cause mortality.
When only dogs with cardiac-related death were includ-
ed in the analysis, only LA/Ao41.7 (hazard ratio 5 2.1,
95% CI 5 1.31–3.91, Po.0001) had a significant effect
on survival time, although Emax41.2 m/s (P 5 .054) was
very close to the chosen 5% level of significance. Mitral
valve leaflet engagement and HR were excluded from
multivariate analysis because of the relatively low num-
ber of dogs for which these data were available.
Furthermore, furosemide treatment (yes/no) was also ex-
cluded from this analysis because it was highly covariate
with class of HF.
Discussion
Many studies have reported survival time and prognos-
tic indicators in dogs with CMVI. However, these studies
were focused mainly on specific breeds and did not include
large breed dogs,8–11,18–20
or focused on specific aspects of
the disease, such as influence on survival after chordal
rupture21
or effect of therapy on survival time.22–24
Ac-
cordingly, the importance of the present study is that it
documents the long-term outcome and influence of certain
clinical and echocardiographic variables on survival in a
large series of dogs of different breeds and weight affected
with CMVI. In this large study, 384 of 558 dogs survived
or died for causes unrelated to CMVI during the observa-
tion period. This finding may indicate that CMVI is a
comparably benign condition as previously reported in
both humans and dogs.1,22,25–28
This is particularly appar-
ent for dogs in ISACHC class 1 HF. More than 60% of
the dogs in this group were still alive after 70 months after
initial diagnosis. This finding is in agreement with previ-
ous reports.21,22
The mean interval time to develop HF in
113 asymptomatic Cavalier King Charles Spaniels with-
out any medical treatment was reported to be 27.2 13.5
months.22
A recent study reporting survival data in a
group of dogs with CMVI and chordae tendineae rupture
reported a survival rate of 75% at 24 months for 28 dogs
in class I ISACHC.21
However, in dogs CMVI has been
linked to serious complications, including progressive HF,
acute exacerbation of pulmonary congestion and edema,
severe arrhythmias, right-side HF caused by pulmonary
hypertension, and left atrial rupture and cardiac tampon-
ade. Identification of animals that are at high risk for
complications might allow targeting individuals in need of
therapy for progression of HF. For low-risk patients, un-
warranted owner concerns of HF might also be avoided.
The most significant clinical and echocardiographic in-
dependent predictors in our study for survival when all
causes of deaths were included were syncope, LA/Ao ratio,
and Emax. However, when only cardiac-related deaths
were included only the LA/Ao ratio maintained statistical
significance. Left atrial enlargement reflects the degree of
severity and chronic nature of mitral valve regurgitation,
Table 2. Distribution of medical treatments at inclusion.
Therapy regimen N %
ACE-I 1 furo 175 51.2
ACE-I 65 19.2
ACE-I 1 furo 1 dig 28 8.2
ACE-I 1 furo 1 b-blocker 19 5.6
ACE-I 1 furo 1 pimo 18 5.3
ACE-I 1 furo 1 spiro 7 2.1
Furo 5 1.5
ACE-I 1 furo 1 dig 1 spiro 4 1.2
ACE-I 1 furo 1 CCB 3 0.9
ACE-I 1 furo 1 spiro 1 b-blocker 2 0.6
ACE-I 1 b-blocker 2 0.6
ACE-I 1 furo 1 nitrates 2 0.6
Furo 1 nitrates 2 0.6
Dig 1 spiro 1 0.3
Dig 1 spiro 1 0.3
ACE-I 1 furo 1 dig 1 nitrates 1 0.3
ACE-I 1 furo 1 dig 1 pimo 1 0.3
ACE-I 1 furo 1 CCB 1 spiro 1 0.3
ACE-I 1 furo 1 CCB ant 1 dig 1 0.3
Furo 1 dig 1 CCB ant 1 nitro 1 0.3
ACE-I, angiotensin converting enzyme inhibitor; furo, furose-
mide; dig, digoxin; pimo, pimobendan; spiro, spironolacton; CCB,
calcium channel blocker; nitro, nitroglycerin.
0
1.0
0.8
0.6
0.4
0.2
0.0
10 20 30 40 50 60 70
Time after Diagnosis (Months)
Proportion
Alive
(%)
ISACHC1
ISACHC2
ISACHC3
Fig 1. Survival according to the International Small Animal Cardi-
ac Health Council (ISACHC) class of HF 1, 2, and 3 when all causes
of death were included in the dataset. As more than 50% of dogs
with class ISACHC 1 survived during the observation period, me-
dian survival time was not determinable (lower 95% confidence
limit 38 months), class ISACHC 2 median survival time 28 months
(lower 95% 24 months), class ISACHC 3 median survival time 9
months (95% confidence intervals 8–15 months).
123
Mitral Valve Disease in Dogs

5. whereas peak velocity of early transmitral filling is depen-
dent on atrial volume and pressure.29
Consequently,
increased LA/Ao ratio and Emax can be considered as in-
dicators of left atrium volume overload and increased left
atrial pressure. Therefore, the data from this study indi-
rectly agree with reports from other studies in both
humans and dogs, which suggest that severity of mitral
valve regurgitation is a predictor of poor prognosis.9,28,30
Syncope was related to mortality when all causes of
death were considered. Tussive fainting that may occur
in conjunction with paroxysm of coughing is common in
dogs with chronic pulmonary, bronchial disease, or both.
In the latter case, the frequency and severity of episodes
are often associated with severity of mitral regurgitation
because the left atrium compresses the left mainstem
bronchus. In dogs with severe CMVI, syncope may be
induced by strenuous exercise, by cardiac tamponade
caused by left atrial rupture, or by pulmonary hyper-
tension.1,31
However, syncope can also be the conse-
quence of tachyarrhythmias, which are associated with
Table 3. Probability of adverse effect of each of 15 studied variables in the univariate analysis when all causes of death were included in the
dataset.
Variable Death (%) HRa 95% CI P Value
n 5 58 0.99 0.76–1.30 NS
Male 68% 44 (168/378)
Female 32% 46 (84/180)
n 5 553 1.16 0.59–1.26 NS
Weighto20 kg 86% 45 (215/476)
Weight420 kg 14% 45 (35/77)
n 5 549 1.94 1.36–2.77 o.01
Age48 years 81% 49 (217/443)
Age o 8 years 19% 33 (35/106)
n 5 172 2.4 1.55–3.71 o.001
HRo140 bpm 67% 39.1 (45/115)
HR4140 bpm 33% 68.4 (39/57)
n 5 393 0.73 0.48–1.12 NS
Murmur I–II 12% 56 (26/46)
Murmur III–V 88% 52 (181/347)
n 5 510 1.70 1.29–2.24 o.001
Syncope Y 23% 67 (77/115)
Syncope N 77% 38 (150/395)
n 5 106 2.27 1.10–4.74 o.05
Dyspnea Y 63% 49 (33/67)
Dyspnea N 37% 31 (12/39)
n 5 394 1.98 1.07–3.66 o.05
Arrhythmias Y 4% 64 (11/17)
Arrhythmias N 96% 34 (129/377)
n 5 117 1.31 0.69–2.49 NS
Pressure4140 mmHg 64% 41 (31/75)
36% 33 (14/42)
Pressure140 mmHg
n 5 526 2.64 2.02–3.45 o.0001
LA/Aoo1.7 49% 31 (80/258)
LA/Ao41.7 51% 60 (161/268)
n 5 185 2.01 1.29–3.40 o.001
Ant MVL 43% 29 (23/80)
Both MVL 57% 56 (59/105)
n 5 555 1.0 0.87–1.39 NS
EDVo100 mL/m2
41% 45 (104/230)
EDV4100 mL/m2
59% 45 (145/325)
n 5 555 2.94 2.21–3.90 o.0001
ESV430 mL/m2
51% 55 (155/284)
ESVo30 mL/m2
49% 35 (94/271)
n 5 377 2.37 1.66–3.39 o.001
E peako1.2 m/s 74% 30 (84/279)
E peak41.2 m/s 26% 50 (49/98)
n 5 298 0.64 0.44–0.93 NS
Edt480 ms 68% 34 (69/202)
Edto80 ms 32% 49 (47/96)
HR, heart rate; LA/Ao, left atrium aortic root ratio; ant MVL, anterior mitral valve leaflet; post-MVL, posterior mitral valve leaflet;
EDV-I, end-diastolic volume index; ESV-I, end-systolic volume index; E peak, peak velocity of E wave; Edt, E wave deceleration time;
CI, confidence interval; HRa, hazard ratio; NS, not significant.
124 Borgarelli et al

6. disease severity, the most common being atrial fibrillation
or intermittent supraventricular tachycardia.1
Except in
cases with primary lung disease, syncope is associated with
the severity of mitral regurgitation, and it is therefore like-
ly that the cases with syncope in our study had more severe
mitral regurgitation. Consequently, it is not surprising it
was associated with an increased risk of death.1
Chronic mitral valve disease has been reported to more
commonly affect male dogs,1
which was confirmed in this
study. However, gender did not influence survival. This
study found that age more than 8 years was associated
with a reduced survival time, both when all and only car-
diac causes of death were included. This is in agreement
with previous studies.1,32
However, age was not an inde-
pendent prognostic variable in multivariate analysis,
presumably because this variable was highly covariate
with severity of MR.
In contrast to previous studies,8,22,32,33
we found no
significant effect of heart murmur intensity on survival
time. This finding can partly be explained by the fact that
the present study included a greater diversity of breeds
with different body sizes and chest conformations. Fur-
thermore, the present study grouped only intensity of
murmurs in 2 groups: those with a low intensity and
those with moderate to high intensity murmurs. The out-
come of this grouping was that a relatively low number of
dogs were included in the low-intensity group, whereas
the majority of dogs were included in the moderate- to
high-intensity group. Presumably, the imbalance in num-
ber and the greater diversity of severity of MR in the
moderate to high intensity group may contribute to the
lack of significance of this variable in survival analysis.
Although other studies included dogs in HF, the present
study also included dogs with atrial fibrillation. This con-
dition may cause a more pronounced reduction in the
pressure gradient between the left atrium and ventricle
and thereby a reduced murmur intensity.
Although the presence of dyspnea was significantly as-
sociated with an increased risk of death when all causes
of death were included in the analysis, it was not signifi-
cant when only cardiac deaths were included. This
finding is surprising, but it could be caused by the high
prevalence of primary respiratory disease in geriatric
dogs. In these cases it is more likely that dyspnea is
caused by the primary respiratory disease, and that this
could determine shorter survival. On the other hand, the
lack of statistical significance for dyspnea in dogs that
died of HF might also be caused by the relatively low
numbers of dogs in which the presence of this sign was
reported in the clinical records.
The finding of sudden death in 8.9% is noteworthy. To
the authors’ knowledge, this is the first time sudden death
has been reported in asymptomatic dogs with CMVI.
Humans with MVP have twice the risk of the general
population for sudden death.34,35
Ventricular arrhythmias,
substantial mitral regurgitation, redundant tendinous
chords, and depressed left ventricular function have been
associated with an increased risk of sudden death in hu-
mans.5
In dogs, sudden death in animals with CMVI is a
comparably uncommon event and has been associated
with nonatherogenic dysplasia of the intramural coro-
nary arteries.d
Preliminary data from Holter recording in
dogs with CMVI indicate that ventricular arrhythmias
may be more common than previously thought.
In humans, systolic dysfunction has been associated
with an increased risk of adverse events.35,36
In this re-
gard, we recently reported that dogs with moderate HF
caused by CMVI have reduced systolic function.37
How-
ever, increased ESV-I was associated with a reduction in
survival time in univariate analysis, but was not an
independent risk factor as it was associated with class of
HF. Although not included in the multivariate analysis,
the finding that bilateral mitral valve involvement repre-
sents a risk factor is noteworthy, and is in agreement with
previous reports in both humans and dogs.8,36,38
It is also
interesting to observe that only 4 of the 189 dogs for
which this information was available presented isolated
lesions of the posterior mitral valve leaflet. Similarly, the
recent paper by Serres et al 21
also reported that only 4 of
114 dogs had a rupture of posterior mitral valve leaflet.
This could reflect a different anatomy of the mitral valve
leaflets, where the posterior leaflet appears to be smaller
than the anterior.39
However, it is also possible that iso-
lated posterior MVP is more difficult to identify using a
right parastenal view because of its smaller extension,
and this finding could represent an echocardiographic
artifact for less severe cases.
A heart rate 4140 bpm was associated with decreased
survival time in univariate analysis. We did not include
this data in multivariate analysis because of the low num-
ber of dogs for which this parameter was available.
However, this is not an unexpected finding as increased
HR is the consequence of increased sympathetic drive
and neurohormonal activation, and thus reflects more
severe disease.
Although this study was not designed to evaluate the
effects of therapy on survival, it should be pointed that
only 5.6% of the population received pimobendan. As
1.0
0.8
0.6
0.4
0.2
0.0
0 20 40 60 80
Time after Diagnosis (months)
Proportion
Alive
(%)
ISACHC1
ISACHC2
ISACHC3
Fig 2. Survival times for the International Small Animal Cardiac
Health Council (ISACHC) classes of HF 1, 2, and 3 when only car-
diac-related deaths were included in the dataset. As more than 70%
of dogs with class ISACHC 1 survived during the observation
period, median survival time and 95% confidence intervals could
not be determined; class ISACHC 2 median survival time 33 months
(lower 95% 26 months); class ISACHC 3 median survival time
9 months (95% confidence intervals 8–15 months).
125
Mitral Valve Disease in Dogs

7. pimobendan has become a more common treatment in
Europe, it could be possible that our study could be used
in the future as a historical control when more data on
this drug are available.
Limitations of the Study
This study has some limitations. First, our population
was not intentionally selected and consisted of a series
of dogs visiting 4 animal clinics. This means that it may
not represent the general canine population. In fact, the
referral hospital population is more likely to represent a
more advanced disease state compared with the general
one, because some of these dogs were referred for the
presence of clinical signs of heart disease. It is also pos-
sible that some dogs may have been referred when
conventional treatment failed and this may have influ-
enced the estimates of survival times. However, most of
the dogs were referred for cardiological consultation at
the time they were asymptomatic or mildly symptomatic;
this is reflected by the fact that 82.2% of dogs were in
class I or II ISACHC. Second, although the question-
Table 4. Probability of adverse effects of each of 15 studied variables in the univariate analysis of the survival time when only cardiac related
death was included in the dataset.
Variable Proportion (%) HRa 95% CI P Value
n 5 463 1.21 0.86–1.69 NS
Male 70% 39 (126/324)
Female 30% 34 (48/139)
n 5 460 0.8 0.49–1.32 NS
Weight420 kg 13% 40 (17/59)
Weighto20 kg 87% 29 (160/401)
n 5 455 2.01 1.35–3.01 o.05
Age48 years 79% 41 (148/361)
Ageo8 years 81% 28 (26/94)
n 5 141 3.48 2.04–5.94 o.001
HRo140 bpm 67% 27.7 (26/94)
HR4140 bpm 33% 61.7 (29/47)
n 5 301 1.11 0.6–1.77 NS
Murmur I–II 10% 43 (13/30)
Murmur III–V 90% 45 (127/271)
n 5 408 2.85 2.12–3.84 o.0001
Syncope Y 22% 77 (70/91)
Syncope N 78% 32 (104/317)
n 5 90 2.30 1.16–4.56 o.05
Dyspnea Y 64% 17 (10/58)
Dyspnea N 36% 50 (16/32)
n 5 330 2.18 1.17–4.05 o.01
Arrhythmias Y 5% 62 (10/16)
Arrhythmias N 95% 27 (85/314)
n 5 96 1.42 0.66–3.01 NS
Pressure4140 mmHg 61% 36 (21/59)
Pressure140 mmHg 39% 27 (10/37)
n 5 436 3.76 2.69–5.23 o.0001
LA/Ao41.7 52% 55 (125/227)
LA/Ao1.7 48% 20 (42/209)
n 5 158 1.77 1.06–2.69 o.0001
Ant MVL 42% 9 (6/67)
Both MVL 58% 42 (38/91)
n 5 459 3.12 1.96–5.03 o.0001
EDVo100 mL/m2
38% 17 (31/174)
EDV4100 mL/m2
62% 49 (140/285)
n 5 459 4.11 2.90–5.82 o.0001
ESVo30 mL/m2
50% 24 (55/230)
ESV430 mL/m2
50% 51 (117/229)
n 5 158 3.17 2.18–4-06 o.001
E peako1.2 m/s 78% 24 (30/124)
E peak41.2 m/s 22% 59 (20/34)
n 5 246 0.5 0.33–0.77 NS
Edt480 ms 66% 24 (39/163)
Edto80 ms 34% 46 (38/83)
HR, heart rate; LA/Ao, left atrium aortic root ratio; ant MVL, anterior mitral valve leaflet; post-MVL, posterior mitral valve leaflet; EDV-
I, end-diastolic volume index; ESV-I, end-systolic volume index; E peak, peak velocity of E wave; Edt, E wave deceleration time; HRa, hazard
ratio; CI, confidence interval; NS, not significant.
126 Borgarelli et al

8. naire was carefully designed, it is not possible to exclude
that some deaths considered as cardiac related were
because of other causes. However, there were small
differences in the estimates of the studied risk factors be-
tween the 2 data sets used in univariate and multivariate
analyses. Third, it is possible that therapy influenced out-
come. We analyzed only differences between dogs treated
with and without furosemide. However, because ongoing
furosemide treatment was strictly a covariate with class
of HF, we decided not to include it in multivariate anal-
ysis. Because this was a retrospective study and many
combinations of drugs had been used, it was not possible
to perform an appropriate analysis of effect of therapy
on survival. Finally, the present study comprised a retro-
spective case series of dogs, which potentially makes it
vulnerable for confounding factors. Although obvious
confounding factors such as age and sex were controlled
for in the present study, it is possible that the results
could have been systematically influenced by other un-
known factors.
This study shows that although a low degree CMVI
can be considered a relatively benign condition in dogs,
there are some echocardiographic variables that can
identify dogs at higher risk of death. Specifically, synco-
pe, a left-atrial aortic root ratio41.7 and an Emax4
1.2 m/s were shown to have the greatest potential to pre-
dict outcome in multivariate analysis. Univariate
analysis also suggests that other clinical and echocardio-
graphic variables, such as age, heart rate, and class of
HF also have the potential to identify dogs at higher risk
of death.
Footnotes
a
Ultrasonic Doppler Flow detector model 811-B, Parks Medical
Electronics, Alhoa, OR USA
b
MEGAS, ESAOTE Biomedica, Florence, Italy
c
The R Foundation for statistical computing version 2.3.0 (2006-04-
24) ISBN 2-900051-07-0
d
Falk T, Jonsson L, Olsen LH, Pedersen HD. Arteriosclerotic
changes in myocardium, lung and kidney in dogs with chronic con-
gestive heart failure and myxomatous mitral valve disease. J Vet Int
Med 2005;19:932 (abstract)
e
Crosara S, Perego E, Santilli RAS, et al. Holter monitoring in
dogs with mitral regurgitation and different classes of heart failure.
J Vet Int Med 2006;20:1535 (abstract)
Acknowledgments
This study has been granted by ‘‘Fondo Regione Pie-
monte Ricerca Scientifica Applicata 2004.’’
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