Received: 6 October 2021 Accepted: 15 February 2022

DOI: 10.1111/jvim.16397

STANDARD ARTICLE

Prospective study of dilated cardiomyopathy in dogs eating

nontraditional or traditional diets and in dogs with subclinical
cardiac abnormalities

Lisa Freeman1 | John Rush1 | Darcy Adin2 | Kelsey Weeks1 |

Kristen Antoon1 | Sara Brethel2 | Suzanne Cunningham1 | Luis Dos Santos1 |
Renee Girens2 | Robert Goldberg3 | Emily Karlin1 | Darleen Lessard3 |
Katherine Lopez1 | Camden Rouben2 | Michelle Vereb2 | Vicky Yang1

1
Cummings School of Veterinary Medicine,
Tufts University, North Grafton, Abstract
Massachusetts, USA Background: Recent studies have investigated dogs with presumed diet-associated
2
College of Veterinary Medicine, University of
dilated cardiomyopathy (daDCM), but prospective studies of multiple breeds are
Florida, Gainesville, Florida, USA
3
Department of Population and Quantitative needed.
Health Sciences, University of Massachusetts Hypothesis/Objectives: To evaluate baseline features and serial changes in echocar-
Medical School, Worcester,
Massachusetts, USA diography and cardiac biomarkers in dogs with DCM eating nontraditional diets
(NTDs) or traditional diets (TDs), and in dogs with subclinical cardiac abnormalities
Correspondence
Lisa Freeman, Cummings School of Veterinary (SCA) eating NTD.
Medicine, Tufts University, 200 Westboro Animals: Sixty dogs with DCM (NTD, n = 51; TDs, n = 9) and 16 dogs with SCA
Road, North Grafton, MA 01536, USA.
Email: [email protected] eating NTDs.
Methods: Echocardiography, electrocardiography, and measurement of taurine, car-
Present address
Sara Brethel and Camden Rouben, Charlotte diac troponin I, and N-terminal pro-B-type natriuretic peptide were performed in
Animal Referral and Emergency, Charlotte, dogs with DCM or SCA. Diets were changed for all dogs, taurine was supplemented
North Carolina, USA
in most, and echocardiography and cardiac biomarkers were reassessed (3, 6, and
Luis Dos Santos, Purdue University College of
Veterinary Medicine, West Lafayette, 9 months).
Indiana, USA Results: At enrollment, there were few differences between dogs with DCM eating
Michelle Vereb, Iowa State University College NTDs or TDs; none had low plasma or whole blood taurine concentrations. Improve-
of Veterinary Medicine, Ames, Iowa, USA
ment in fractional shortening over time was significantly associated with previous
Funding information consumption of a NTD, even after adjustment for other variables (P = .005). Median
Nestlé Purina PetCare; The Barkley Fund
survival time for dogs with DCM was 611 days (range, 2-940 days) for the NTD
group and 161 days (range, 12-669 days) for the TD group (P = .21). Sudden death

Abbreviations: 2D, 2-dimensional; CHF, congestive heart failure; daDCM, presumed diet-associated dilated cardiomyopathy; DCM, dilated cardiomyopathy; FDA, United States Food and Drug
Administration; FS, fractional shortening; hs-cTnI, high-sensitivity cardiac troponin I; LA : Ao, ratio of the left atrial to aortic diameters (2D); LVIDdN, normalized left ventricular internal diameter
in diastole; LVIDsN, left ventricular internal diameter in systolc; NTD, nontraditional diet; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SCA, subclinical cardiac abnormalities; TD,
traditional diet.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2022 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.

J Vet Intern Med. 2022;36:451–463. wileyonlinelibrary.com/journal/jvim 451

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452 FREEMAN ET AL.

was the most common cause of death in both diet groups. Dogs with SCA also had
significant echocardiographic improvements over time.
Conclusions and Clinical Importance: Dogs with DCM or SCA previously eating
NTDs had small, yet significant improvements in echocardiographic parameters after
diet changes.

KEYWORDS
arrhythmia, congestive heart failure, grain-free, heart disease, nutrition, pulses

1 | I N T RO DU CT I O N University and University of Florida). The study's definition of DCM

consisted of M-mode fractional shortening (FS) ≤25%, normalized left
Most cases of dilated cardiomyopathy (DCM) in dogs are thought to ventricular internal diameter in diastole (LVIDdN) ≥1.8, and normal-
have a familial or genetic basis, affecting large and giant breeds. 1
ized left ventricular internal diameter in systole (LVIDsN) ≥1.2
However, secondary forms of DCM also can occur as a result of drugs, (or breed-specific criteria for Doberman Pinschers or Boxers).16,17,25,26
2
infectious agents, and nutritional causes. Taurine deficiency is a form Eligible dogs had to be eating a commercial nontraditional or tradi-
of secondary DCM in cats3 and dogs,4-11 but deficiencies of other tional extruded (kibble) diet as their main source of calories for at least
nutrients such as thiamine or copper also can cause secondary DCM.2 6 months. Baseline diets were categorized as NT if they were grain-
Other causes of secondary nutritional DCM include diet-related free or included pulses or potatoes/sweet potatoes in the top
toxins, such as heavy metals or monensin-contaminated feed.2 10 ingredients and T if they were grain-inclusive and had no pulses or
In 2018, the United States Food and Drug Administration (FDA) potatoes/sweet potatoes in the top 10 ingredients.14,17,18 Ingredients
12
issued an alert regarding a possible connection between diet and DCM. were determined based on the ingredient list of the diet providing the
Since that time, there have been 2 FDA updates13,14 and several peer- majority of calories to each dog. Grain-free diets were defined as
reviewed research studies describing dogs with presumed diet-associated those not containing grains or grain-derived ingredients.14,17,27 Oils
DCM (daDCM).15-18 Nontraditional diets (NTDs) eaten by dogs with (eg, corn oil) were not classified as a grain product.
daDCM have typically been grain-free or rich in pulses (eg, peas, lentils, Dogs with SCA were identified during evaluation of dogs as
and chickpeas) or potatoes/sweet potatoes.14-18 Breeds typically affected potential healthy controls for the current study, screening of house-
by primary DCM (eg, Doberman Pinschers) and breeds that do not com- mates of dogs diagnosed with DCM, or routine evaluation of dogs by
monly develop DCM (eg, Miniature Schnauzers) have been affected by the Cardiology Service. Dogs were eligible for enrollment in the SCA
14-18
daDCM. This secondary form of DCM is unique because of the group if they were eating NTDs for at least 6 months and met 1 of
improvement in various echocardiographic variables and longer survival the following 2 criteria:
times after diet change,14-19 whereas dogs with primary DCM typically
have limited echocardiographic improvement and shorter survival 1. M-mode FS ≤25% plus either increased N-terminal pro-B-type
20-24
times. Published research studies on daDCM thus far have been retro- natriuretic peptide (NT-proBNP) >900 pmol/L (>735 pmol/L in
spective16-18 or conducted in a single breed,15 and many questions remain. Doberman Pinschers) or increased high-sensitivity cardiac troponin
The objectives of our prospective study were to: (a) compare the I (hs-cTnI) >0.06 ng/mL (>0.12 in older dogs) concentrations.
baseline characteristics of dogs with DCM eating NTDs versus tradi- 2. M-mode FS <35% plus increased NT-proBNP and increased hs-
tional diets (TDs), (b) evaluate serial changes in echocardiographic cTnI concentrations.
measurements and cardiac biomarkers after medical treatment and
change in diet, and (c) measure survival times in dogs with DCM eat- Dogs with >1+ (mild) mitral regurgitation or obvious thickening of the
ing NTD compared to TDs. In addition, dogs eating NTDs that had mitral valve were excluded from this group.
subclinical cardiac abnormalities (SCA) not meeting the definition of Required testing (ie, laboratory testing, echocardiogram, electro-
DCM were enrolled to evaluate serial echocardiographic and bio- cardiogram, and genetic testing) and an initial supply of taurine sup-
marker changes after dietary changes. plement and dog food (to ensure early use and good compliance)
were paid for by the study.

2 | MATERIALS AND METHODS

2.2 | Baseline analyses
2.1 | Subjects
Owners signed informed consent and completed diet history forms.
Dogs diagnosed with DCM were continuously enrolled between Diet pulse and diet pulse/potato scores were calculated for each dog's
September 2018 and March 2020 from 2 universities (Tufts diet at enrollment (Table S1). Dogs had a diagnostic electrocardiogram
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FREEMAN ET AL. 453

and echocardiogram performed using standard techniques at base- and 9 months after the diet changes, at which time an echocardiogram
line.28 Echocardiograms were performed by board-certified veterinary was performed and blood was collected for NT-proBNP and hs-cTnI
cardiologists or a supervised cardiology resident, with the same per- analysis. Dogs with arrhythmias also had a 6-lead electrocardiogram
son performing serial measurements on an individual dog. Blood and performed, and dogs with CHF had a serum biochemistry profile per-
buccal swabs were collected for the following variables at baseline: formed at each visit. Thoracic radiographs were performed as clinically
CBC; serum biochemistry profile; concentrations of NT-proBNP, hs- indicated.
cTnI, plasma, and whole blood taurine; and, for Doberman Pinschers
or Boxers, genetic mutation testing (Table S2). Taurine status was
defined as low, borderline, normal, or high based on the laboratory's 2.5 | Statistical analysis
reference ranges (Table S2). Selected nutritional variables also were
analyzed in small subgroups of the 60 dogs with DCM and compared Differences in selected characteristics between dogs in the NTD and
to small subgroups of 18 control dogs determined to be healthy based TD groups were compared at baseline using Fisher's exact tests (cate-
on history, physical examination, CBC, serum biochemistry profile, gorical variables) or Mann-Whitney U tests (continuous variables).
and echocardiography (Table S3). Spearman correlation tests were used to compare taurine and hs-cTnI
concentrations at the time of enrollment. In examining serial changes
in various variables over time, the primary outcomes were FS,
2.3 | Interventions LVIDdN, LVIDsN, ratio of the left atrial-to-aortic diameters (LA : Ao),
and hs-cTnI and NT-proBNP concentrations. Paired t tests (normally
Medical treatment of DCM was at the discretion of each dog's pri- distributed data) or Wilcoxon signed-rank tests (skewed data) were
mary clinician. In most dogs, taurine supplementation was initiated at used to compare baseline and 9-month variables for dogs that lived
the baseline visit. Owners were instructed to administer taurine sup- until the 9-month time point. In addition, serial changes for all dogs
plementation until laboratory results were available 2 to 4 weeks later (excluding 2 dogs that died or were euthanized during their initial hos-
and to continue supplementation if plasma or whole blood taurine pitalization) were analyzed using mixed linear models adjusted for sev-
concentrations were low or borderline. Owners were given the choice eral possible confounding variables. Initially, a model was constructed
to continue or discontinue taurine supplementation if plasma and that adjusted for key characteristics that were significantly different
whole blood taurine concentrations were found to be normal or high between the 2 diet groups at baseline (ie, age, sex, and body weight
(Table S4). for most outcome variables; age and sex only for LVIDdN and
Owners of dogs with DCM in both diet groups and of dogs LVIDsN). The second regression model added key clinical confounders
with SCA were instructed to change to 1 of 6 commercial (ie, presence of CHF, presence of any supraventricular or ventricular
extruded diets that were lower in sodium, grain-inclusive, did not arrhythmia, and the intervention diet that dogs were changed to after
contain pulses or potatoes/sweet potatoes in the top 10 ingredi- enrollment [classified into the 4 most commonly fed diets and a 5th
ents, and were made by manufacturers that met the World Small “other diet” category]).
Animal Veterinary Association Global Nutrition Committee's guide- For dogs that were no longer alive at the time of analysis (1 May
lines.29 Diet options had variable caloric densities, manufacturers, 2021), the date and cause of death were recorded as either worsen-
and costs to address different dog and owner needs. In some dogs ing CHF, sudden cardiac death, or noncardiac in origin. Cause of
with concurrent medical conditions, a diet different from the main death in dogs with sudden cardiac arrest that underwent successful
6 intervention diets (but meeting the same criteria) was selected to cardiopulmonary resuscitation and subsequently were euthanized
tailor the diet to the individual dog's needs (eg, higher fiber and within 1 hour of resuscitation were classified as sudden cardiac
lower fat). All dogs ate primarily an extruded diet as their main death (n = 2). Survival times were calculated from the time of diag-
source of calories, but 3 canned options were available to supple- nosis of DCM until the time of death or euthanasia (excluding 2 dogs
ment the extruded diet if desired by the owner or if dogs would that died or were euthanized during their initial hospitalization).
not eat extruded food alone. Dogs that were still alive or that died from noncardiac causes were
right-censored. Kaplan-Meier curves were constructed and the Fine
and Gray proportional hazards models were utilized to examine dif-
2.4 | Serial assessment ferences in survival between the 2 diet groups after adjustment for
several important, potentially confounding clinical and demographic
Dogs with congestive heart failure (CHF) were re-evaluated 1 to factors, including age, presence of CHF or cardiac arrhythmia, inter-
2 weeks after diagnosis to assess their overall status, serum biochemi- vention diet, serum hs-cTnI concentration, and LA : Ao. Competing
cal profile variables, and, if indicated, an electrocardiogram. Dogs were risk from noncardiac death was accounted for by calculating cause-
classified as having CHF based on a combination of clinical signs and specific hazard ratios.
echocardiographic findings, along with either radiographic evidence of Commercial statistical software (SAS version 9.4, SAS Institute,
cardiogenic pulmonary edema or presence of ascites or pleural effu- Cary, NC; SPSS version 26.0, IBM Corp., Armonk, NY) was used for all
sion judged to be cardiogenic in origin. Dogs were re-evaluated 3, 6, analyses. P values ≤.05 were considered significant.
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454 FREEMAN ET AL.

3 | RESULTS biochemistry profile variables was a higher serum magnesium con-

centration in the NTD group (Table 1; P = .01; other variables not
3.1 | Dilated cardiomyopathy group shown), although no dog had a serum magnesium concentration
above the reference range.
Between September 2018 and March 2020, 60 dogs with DCM were Plasma and whole blood taurine concentrations were not signifi-
enrolled (51 [85%] eating NTDs, 9 [15%] eating TDs; Figure 1). cantly different between diet groups, nor were the percentages of dogs
in categories of plasma or whole blood taurine status (Table 1). No dogs
had low plasma (<40 nmol/mL) or whole blood (<150 nmol/mL) taurine
3.1.1 | Baseline comparisons concentrations. Seven dogs (including 2 Golden Retrievers) had border-
line low plasma or whole blood taurine concentrations, but no dog had
Dogs in the nontraditional group weighed significantly less than both a borderline plasma and borderline whole blood concentration.
dogs in the traditional group (P = .04; Table 1). Overall, breed was Weak positive correlations were found for all 60 dogs at baseline
not significantly different between the 2 diet groups but breeds between plasma taurine and hs-cTnI (r = 0.33, P = .02) concentrations
not typically affected by DCM were only found in the non- and between whole blood taurine and hs-cTnI (r = 0.35, P = .01) con-
traditional group (eg, Chihuahua, Jack Russell Terrier, and Pit Bull). centrations. No measured vitamin or mineral concentrations were sig-
Congestive heart failure (NTD: 77%, TD: 78%; P = 1.00) and nificantly different between dogs in the NTD group and healthy
arrhythmias (NTD: 49%, TD: 67%; P = .47) were common in both controls (Table S3). All dogs in the NTD group in which iron indices
diet groups but not significantly different between groups were measured had normal hematocrits, but 1 dog had low serum iron
(Table 1). There was no difference in duration eating NTDs or TDs concentration and high ferritin concentration and 2 dogs had increased
(Table 1). The only significant difference in CBC and serum serum ferritin concentrations. At baseline, the only echocardiographic

Enrollment Eligible DCM cases (n = 69)

Excluded (n = 3)
• Declined to participate (n = 3)

Changed diet (n = 66)

Previous nontraditional diet (n = 55) Previous traditional diet (n = 11)

Follow-Up
• 6-month re-evaluation not possible because • All dogs that were still alive attended all 3-,
of COVID-19 restrictions, so only had 0, 3, 6-, and 9-month re-evaluations
and 9-month visits (n = 1).
• All other dogs that were still alive attended all
3-, 6-, and 9-month re-evaluations

Analysis
Analyzed (n = 51) Analyzed (n = 9)
• Excluded from analysis (n = 4) • Excluded from analysis (n = 2)
Previous diet had no pulses/potatoes Previous diet had peas in top 10
in the top 10 ingredients (n = 3) ingredients (n = 1)
Home-cooked diet (n = 1) Home-cooked diet (n = 1)

F I G U R E 1 Flow diagram illustrating the enrollment of dogs with dilated cardiomyopathy (DCM), reasons for exclusion, missed re-evaluations,
and number of statistically evaluable cases
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FREEMAN ET AL. 455

T A B L E 1 Baseline comparison of signalment, clinical, laboratory, and echocardiographic variables for dogs with dilated cardiomyopathy eating
nontraditional or traditional diets. Data are presented as number, mean ± SD, median (range), or number (percentage). P values are for comparison
of nontraditional vs traditional groups, with significant P values in bold

Variable Nontraditional diet (n = 51) Traditional diet (n = 9) P value

Age (years) 7.0 ± 2.7 8.9 ± 2.4 .06
Sex .07
Male 27 (20 castrated) 8 (5 castrated)
Female 24 (22 spayed) 1 (1 spayed)
Female (% of total) 47% 11%
Breed .98
Doberman Pinscher 11 (22%) 2 (22%)
Pit Bull 6 (12%) 0 (0%)
Boxer 5 (10%) 1 (11%)
Golden Retriever 5 (10%) 1 (11%)
Great Dane 4 (8%) 1 (11%)
Mixed breed 4 (8%) 0 (0%)
Other 16 (31%) 4 (44%)
DNA positive 8/15 (53%)a 2/3 (67%) 1.00
Body weight (kg) 33.8 ± 14.6 44.8 ± 15.6 .04
Body condition score 5.1 ± 1.3 4.9 ± 1.8 .74
Muscle condition score .11
Normal 30 (59%) 4 (44%)
Mild muscle loss 16 (31%) 2 (22%)
Moderate muscle loss 4 (8%) 1 (11%)
Severe muscle loss 1 (2%) 2 (22%)
Cardiac murmur intensity 2 (0-5) 2 (0-5) .68
Cardiac arrhythmia
Any arrhythmia 25 (49%) 6 (67%) .47
Supraventricular 8 (16%) 4 (44%) .07
Ventricular 20 (39%) 3 (33%) 1.00
Congestive heart failure 39 (77%) 7 (78%) 1.00
NT-proBNP (pmol/L) 4778 (461-10 000) 7997 (2811-10 000) .14
hs-cTnI (ng/mL) 0.670 (0.024-5.950) 0.892 (0.167-11.299) .16
Magnesium (mEq/L) 2.0 ± 0.2 1.8 ± 0.3 .01
Duration eating diet (months) 48 (6-156) 72 (12-132) .09
Diet pulse score 66 (0-125) 0 (0-12) <.001
Diet pulse/potato score 84 (23-125) 0 (0-12) <.001
Plasma taurine (nmol/mL) 145 (45-411) 115 (53-202) .07
Plasma taurine categories .28
Low (<40 nmol/mL) 0 (0%) 0 (0%)
Borderline (40-59 nmol/mL) 3 (6%) 1 (11%)
Normal (60-120 nmol/mL) 14 (28%) 5 (56%)
High (>120 nmol/mL) 28 (55%) 3 (33%)
Whole blood taurine (nmol/mL) 336 (192-618) 347 (240-460) .87
Whole blood taurine categories 1.00
Low (<150 nmol/mL) 0 (0%) 0 (0%)
Borderline (150-199 nmol/mL) 3 (6%) 0 (0%)
Normal (200-350 nmol/mL) 26 (51%) 5 (56%)
High (>350 nmol/mL) 21 (41%) 4 (44%)

(Continues)
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456 FREEMAN ET AL.

TABLE 1 (Continued)

Variable Nontraditional diet (n = 51) Traditional diet (n = 9) P value

Echocardiography
M-mode
Fractional shortening (%) 14.12 ± 5.22 17.85 ± 6.82 .06
LVIDdN 2.25 ± 0.39 2.05 ± 0.19 .03
LVIDsN 1.80 ± 0.34 1.56 ± 0.21 .04
2D
Left atrium : aorta 2.17 ± 0.57 2.21 ± 0.58 .83
Sphericity index 1.34 ± 0.21 1.30 ± 0.16 .56

Abbreviations: 2D, 2-dimensional; FS, fractional shortening; hs-cTnI, high-sensitivity cardiac troponin I; LA : Ao, ratio of the left atrial to aortic diameters
(2-dimensional); LVIDdN, normalized left ventricular internal diameter in diastole; LVIDsN, normalized left ventricular internal diameter in systole; NT-
proBNP, N-terminal pro-B-type natriuretic peptide.
a
DNA tested only in Doberman Pinschers and Boxers. DNA was not tested in 1 Doberman Pinscher in the nontraditional group.

differences were a significantly larger LVIDdN (P = .03) and LVIDsN Within-group changes for the 3 dogs in the TD group that completed
(P = .04) in the NTD group (Table 1). the study were not significant for any of the echocardiographic vari-
ables examined (Table 2). Mixed models analysis incorporating all time
points (0, 3, 6, and 9 months) for dogs in both diet groups showed that
3.1.2 | Medications and supplements the interaction between diet group and time was significantly associ-
ated with improvements in FS (P = .005), with greater improvement
Dogs with DCM in both diet groups received many cardiac medica- in the NTD group after adjustment for age, sex, weight, intervention
tions throughout the study, without any between-group differences diet, arrhythmia, and CHF (Table 2). No diet group x time interaction
(Table S4). Fifty-one of the 58 discharged dogs (88%) received taurine was found for LVIDdN, LVIDsN, or LA : Ao after adjustment (Table 2).
supplementation after enrollment (NTD group: n = 44/49; TD group:
n = 7/9). The median duration of taurine supplementation was not
significantly different between diet groups (NTD group: median, 3.1.4 | Survival
6.5 months; range, 0.4-9.0 months; TD group: median, 4.9 months;
range, 0.1-9.0 months; P = .99). At the time of analysis (1 May 2021), 19 dogs in the NTD group (37%)
and 2 dogs in the TD group (22%) were still alive (P = .47). The most
common cause of death was sudden death (16/32 [50%] in the NTD
3.1.3 | Serial changes in cardiac biomarkers and group and 5/7 [72%] in the TD group). Euthanasia for worsening CHF
echocardiographic measurements occurred in 12/32 dogs in the NTD group [38%] and in 1/7 dogs in
the TD group [14%]. Four of 32 dogs in the NTD group (13%) and 1/7
Twenty-nine of 51 dogs (57%) in the NTD group and 3/9 dogs dogs in the TD group (14%) were euthanized for noncardiac causes.
(33%) in the TD group survived until the 9-month re-evaluation The cause of death was not significantly different between dogs in
(P = .28). In the NTD group, a significant decrease was found in hs- the NTD vs TD groups (P = .47).
cTnI concentrations between 0 and 9 months (P = .03), but the For dogs with DCM that were discharged after their initial visit
change in NT-proBNP was not significant (Table 2). Among dogs in (n = 58), median survival time was 611 days (range, 2-940 days) for
the TD group, the change from baseline to 9 months was not sig- the NTD group and 161 days (range, 12-669 days) for the TD group
nificant for hs-cTnI or NT-proBNP concentrations (Table 2). The (P = .21; Figure 2). After adjusting for age, CHF, arrhythmia, interven-
final mixed model for serial changes in hs-cTnI concentrations tion diet, hs-cTnI, and LA : Ao, diet group still was not significantly
showed that the interaction between diet group and time was not associated with survival time (Figure 2).
significant after adjusting for age, sex, weight, CHF, intervention
diet, and arrhythmia (P = .06 for diet group  time interaction;
Table 2). No significant diet group  time interaction was found for 3.2 | Subclinical cardiac abnormalities group
NT-proBNP.
For the echocardiographic endpoints, the 29 dogs that completed Sixteen dogs comprised the SCA group (Table 3). The median duration
the study in the NTD group had a significant within-group increase eating NTDs was significantly shorter in dogs with SCA compared to
from 0 to 9 months in FS (P < .001) and significant decreases in dogs with DCM eating NTDs (P < .001), but median diet pulse
LVIDdN (P = .005), LVIDsN (P < .001), and LA : Ao (P = .004; Table 2). (P = 1.00) and diet pulse/potato (P = .62) scores for NTDs were not
 FREEMAN ET AL.

T A B L E 2 Serial changes in key outcome variables in dogs with dilated cardiomyopathy (DCM) eating nontraditional or traditional diets. Data are presented as mean ± SD or median (range).
Significant P values are in bold

Nontraditional diet group Traditional diet group

P value
P value (within-
P value (diet (within-group group
Variable group  time)a 0 month 3 months 6 months 9 months change)b 0 month 3 months 6 months 9 months change)b
n — 51 37 30 29 — 9 5 5 3 —
Biomarkers
hs-cTnI .06 0.670 0.306 0.394 0.374 .03 0.892 0.642 0.650 0.178 .59
(ng/mL) (0.024-5.95) (0.025-2.411) (0.025-3.270) (0.016-3.296) (0.167-11.299) (0.122-0.695) (0.090-1.514) (0.090-0.757)
NT-proBNP .13 4778 3015 3607 4061 .28 7997 3868 4536 4012 .18
(pmol/L) (461-10 000 (370-10 000) (363-10 000) (336-10 000) (2811-10 000) (1177-8031) (674-10 000) (666-10 000)
Echocardiographic variables
FS (%) .005 14.12 ± 5.22 16.26 ± 6.51 16.60 ± 6.54 18.70 ± 7.53 <.001 17.85 ± 6.82 20.98 ± 8.42 14.95 ± 3.88 18.02 ± 4.51 .58
LVIDdN .70 2.25 ± 0.39 2.11 ± 0.36 2.07 ± 0.35 2.04 ± 0.41 .005 2.05 ± 0.19 1.98 ± 0.18 1.88 ± 0.14 1.79 ± 0.33 .31
LVIDsN .60 1.80 ± 0.34 1.65 ± 0.35 1.63 ± 0.38 1.56 ± 0.39 <.001 1.56 ± 0.21 1.44 ± 0.17 1.47 ± 0.12 1.36 ± 0.31 .17
LA : Ao .23 2.17 ± 0.57 1.89 ± 0.55 1.74 ± 0.47 1.72 ± 0.52 .004 2.21 ± 0.58 1.67 ± 0.60 1.86 ± 0.51 1.98 ± 1.17 .86

Abbreviations: 2D, 2-dimensional; FS, fractional shortening; hs-cTnI, high-sensitivity cardiac troponin I; LA : Ao, ratio of the left atrial to aortic diameters (2-dimensional); LVIDdN, normalized left ventricular
internal diameter in diastole; LVIDsN, normalized left ventricular internal diameter in systole; NT-proBNP, N-terminal pro-B-type natriuretic peptide.
a
Mixed models analysis of diet x time interaction for all 58 dogs (both non-traditional and traditional diets) discharged from the hospital after adjustment for age, sex, body weight, intervention diet, congestive
heart failure, and arrhythmia.
b
Comparing 0 to 9 months for the 29 dogs in the non-traditional group and 3 dogs in the traditional group that completed the study.
457

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458 FREEMAN ET AL.

4 | DI SCU SSION

The main finding of our prospective study was that FS, an indicator of
systolic function, significantly improved over a 9-month period in dogs
with DCM eating NTDs that underwent diet change in addition to
standard medical treatment. This finding was consistent when vari-
ables were measured as within-group changes for the 29 dogs that
completed the 9-month study or using mixed models analysis that
included all dogs and time points for both diet groups.
Some echocardiographic improvements have been identified in
each of the 4 published studies on this disease, but significant
improvement in FS was only seen in a prospective study of Golden
Retrievers with daDCM.15-18 The lack of significant changes in FS in
other previous studies might be related to their retrospective design
or limited sample size. The 4 earlier studies also showed significant
F I G U R E 2 Kaplan-Meier survival curves comparing survival time
improvements in left ventricular and left atrial size, although not all of
in 60 dogs with dilated cardiomyopathy (DCM) after diet change.
Median survival time of the 51 dogs originally eating a nontraditional the studies found significant changes in all of these echocardiographic
diet (611 days, range, 2-940 days; solid line) was not significantly measurements.15-18 In our study, LVIDdN, LVIDsN, and LA : Ao all
longer than that of the 9 dogs originally eating a traditional diet showed significant within-group improvements in the NTD group, but
(161 days, range, 12-669 days; dashed line; P = .21) the mixed models diet group  time interaction for these echocardio-
graphic variables was not significant. The small sample size of our
study limited statistical power to detect serial differences in cardiac
significantly different between dogs with SCA and dogs with DCM size or biomarkers after adjusting for other important potentially con-
(Tables 1 and 3). None of the 16 dogs with SCA had observable clini- founding variables. The findings from this relatively small study can be
cal signs of heart disease at the time of enrollment. Cardiac arrhyth- used to design more optimal studies in the future. Statistical adjust-
mias were present in 4/16 (25%) of SCA dogs (known before ment for various confounding variables was not performed in previous
arrhythmia [1 dog] or detected at enrollment [3 dogs]). studies. Cardiac medications, especially pimobendan and furosemide,
No dogs in the SCA group had both low plasma and low whole can be associated with a decrease in cardiac size, and these medica-
blood taurine concentrations, but 1 dog had low plasma taurine tions also could have influenced the changes in cardiac size in the cur-
concentration (19 nmol/mL) with borderline whole blood taurine rent and previous studies. However, in our study, no differences in
concentration (168 nmol/mL). Another dog had borderline plasma cardiac medications received by dogs were found between the 2 diet
taurine concentration (42 nmol/mL) and normal whole blood tau- groups. More detailed echocardiographic assessment, such as volume
rine concentration (304 nmol/mL). All others had normal or high indices, 3D measurements, and global longitudinal strain would be
taurine concentrations (Table 3). Over the course of the study, valuable to include in future studies of this disease. In addition,
5 dogs in the SCA group received ≥1 cardiac medications: because echocardiograms were not blinded, there is the potential for
pimobendan (n = 3), carvedilol (n = 2), and sotalol (n = 1). Fifteen bias in performing echocardiographic measurements. This possibility is
dogs received taurine supplementation for a median of 3 months an important limitation of the study that must be considered in inter-
(range, 1-9 months). preting the results.
Two dogs in the SCA group could not be evaluated at the In our study, dogs in the TD group did not have significant
6-month visit because of COVID-19 restrictions, and were evaluated within-group improvement in any echocardiographic measurement,
at 0, 3, and 9 months. One dog died suddenly 95 days after the start but the within-group analysis was markedly limited by the fact that
of the study; all 15 other dogs survived the full 9 months of the study. only 3 of 9 dogs in the traditional group survived until the final study
At the time of analysis, 2 dogs had been euthanized for noncardiac visit for the within-group analysis. Nevertheless, the mixed models
reasons (osteosarcoma, n = 1; pneumonia, n = 1). The range of sur- analysis also showed improved FS only in the NTD group. Cardiac tro-
vival times for all dogs was 95 to 906 days. ponin I concentrations decreased significantly in the NTD group when
A significant within-group increase in FS (24.06 ± 4.65% vs comparing 0 to 9-month results, but analysis over time using mixed
30.11 ± 5.81%; P = .005) and significant decreases in LVIDdN models analysis did not reach statistical significance. Although not sig-
(P = .02), LVIDsN (P = .005), and LA : Ao (P = .04) were observed in nificant, hs-cTnI concentrations also decreased in the TD group, and
these 15 SCA dogs between 0 and 9 months (Table 4). No signifi- thus some of these changes may be associated with medical treat-
cant association was found between changes in any of the echocar- ment and require further study. Concentrations of NT-proBNP did
diographic measurements and either diet score or duration eating not decrease significantly in either group, but serial changes in this
the NTD. Within-group changes in NT-proBNP and hs-cTnI biomarker may be limited by differences among breeds and week-to-
(Table 4) were not significant. week variability.30-32
 19391676, 2022, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jvim.16397 by Purdue University (West Lafayette), Wiley Online Library on [31/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
FREEMAN ET AL. 459

T A B L E 3 Baseline characteristics for signalment, clinical, TABLE 3 (Continued)

laboratory, and echocardiographic variables for dogs with subclinical
Variable Nontraditional diet (n = 16)
cardiac abnormalities eating a nontraditional diet. Data are presented
as number, mean ± SD, or median (range) Echocardiography
M-mode
Variable Nontraditional diet (n = 16)
Fractional shortening (%) 23.78 ± 4.62
Age (years) 5.2 ± 2.2
LVIDdN 1.58 ± 0.13
Sex
LVIDsN 1.11 ± 0.11
Male 7 (3 castrated)
2D
Female 9 (5 spayed)
Left atrium: aorta 1.74 ± 0.38
Female (% of total) 56%
Sphericity 1.67 ± 0.30
Breed
Boxer 3 Abbreviations: 2D, 2-dimensional; hs-cTnI, high-sensitivity cardiac
troponin I; LVIDdN, normalized left ventricular internal diameter in
Irish Wolfhound 3
diastole; LVIDsN, normalized left ventricular internal diameter in systole;
Doberman Pinscher 2 NT-proBNP, N-terminal pro-B-type natriuretic peptide.
a
English Bulldog 2 DNA tested only in Doberman Pinschers and Boxers.

Golden Retriever 2
Other 4 In our study, survival time in the dogs with DCM eating a NTD
DNA positive 3/5a (611 days; range, 2-940 days) was not significantly different from that
Weight (kg) 29.7 (6.2-82.7) of dogs in the TD group (161 days; range, 12-669 days; Figure 2). This
Body condition score 5.8 ± 1.1 result is in contrast to findings from 2 retrospective studies,17,18
Muscle condition score which showed longer survival times in dogs with DCM eating NTDs
Normal 14 after diet change. In 1 of these studies, eating a NTD was associated

Mild 2 with a longer survival time after diet was changed, even after adjust-
ment for the presence of CHF and cardiac arrhythmias.17 In the sec-
Moderate 0
ond recent retrospective study of dogs with DCM and CHF, prior
Severe 0
NTD was associated with longer survival, after adjustment for breed,
Cardiac murmur intensity 0 (0-5)
atrial fibrillation, and age of diagnosis.18 However, both studies used
Arrhythmia
all-cause mortality and Cox proportional hazards analysis, which does
Any arrhythmia 3
not account for competing risks, whereas we analyzed for cardiac
Supraventricular 2
mortality and adjusted for competing risks. In addition, 1 study had
Ventricular 2 some different inclusion criteria (eg, smaller LVIDdN, required pres-
Congestive heart failure 0 ence of CHF) that could account for the different results.18 Finally, as
NT-proBNP (pmol/L) 1367 (302-3706) previously noted, an important limitation of our study is sample size. It
hs-cTnI (ng/mL) 0.135 (0.017-0.504) is likely that the relatively small number of dogs (especially in the TD
Magnesium (mEq/L) 2.1 ± 0.2 group [n = 9]) might have contributed to the lack of significant differ-
Diet pulse score 65 (16-121) ences in survival times between the 2 diet groups.

Diet pulse/potato score 81 (16-121) The most common cause of death in the dogs with DCM in both
diet groups was sudden death, accounting for 54% of deaths overall,
Duration eating diet (months) 30 (7-36)
and cause of death was not different between diet groups. This find-
Plasma taurine (nmol/mL) 112 (19-237)
ing suggests that dogs with DCM (whether primary or diet-associated)
Plasma taurine categories
are at high risk for sudden death. Arrhythmias were present in many
Low (<40 nmol/mL) 1
dogs at the time of enrollment or over the course of the study in both
Borderline (40-59 nmol/mL) 1
diet groups, which may limit the time for cardiac improvement to be
Normal (60-120 nmol/mL) 8
observed given the propensity for sudden cardiac death for those
High (>120 nmol/mL) 4 dogs with arrhythmias. The percentage of dogs in our study that died
Whole blood taurine (nmol/mL) 290 (168-564) suddenly appeared relatively high compared to studies of dogs with
Whole blood taurine categories primary DCM where sudden death was reported to account for 10%
Low (<150 nmol/mL) 0 to 15% of deaths for dogs of multiple breeds and 29% to 42% for
Borderline (150-199 nmol/mL) 1 Doberman Pinschers.20-24,33-35
Normal (200-350 nmol/mL) 11 The limited number of baseline differences between dogs in the

High (>350 nmol/mL) 3 different diet groups emphasizes the similar clinical findings of dogs
with primary or secondary forms of DCM, which is consistent with
(Continues)
 19391676, 2022, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jvim.16397 by Purdue University (West Lafayette), Wiley Online Library on [31/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
460 FREEMAN ET AL.

T A B L E 4 Changes in cardiac biomarkers and key echocardiographic variables after diet change in dogs with subclinical cardiac abnormalities
that had been eating nontraditional diets. Values [presented as mean ± SD or median (range)] are for 15 of 16 dogs at baseline (0 months) and
9 months. One dog died suddenly 95 days after starting the study and is not included in the analysis. P-values are for comparison of variables
from 0 to 9 months, with significant P values in bold

Variable 0 months 9 months P value

Biomarkers
hs-cTnI (ng/mL) 0.126 (0.017-0.504) 0.121 (0.024-0.363) .49
NT-proBNP (pmol/L) 1346 (302-3706) 1275 (250-5533) .87
Echocardiographic variables
Fractional shortening (%) 24.06 ± 4.65 30.11 ± 5.81 .005
LVIDdN 1.59 ± 0.13 1.51 ± 0.19 .02
LVIDsN 1.11 ± 0.12 0.99 ± 0.18 .005
LA : Ao 1.70 ± 0.34 1.55 ± 0.18 .04

Abbreviations: hs-cTnI, high-sensitivity cardiac troponin I; LA : Ao, ratio of the left atrial to aortic diameters (2-dimensional); LVIDdN, normalized left
ventricular internal diameter in diastole; LVIDsN, normalized left ventricular internal diameter in systole; NT-proBNP, N-terminal pro-B-type natriuretic
peptide.

previous studies.16-18 However, it is important to acknowledge that a availability of plasma and whole blood taurine concentration results
larger sample size might have provided additional statistical power to and our desire to optimize dogs' chances for clinical improvement
identify other differences in our study. Moreover, there was a wide while awaiting results, especially because, at the time the study was
range of breeds in the NTD group that included both atypical and typ- initiated, taurine deficiency was a popular hypothesis for the cause of
ical breeds. Although some dogs of breeds typically associated with daDCM. We elected to give owners the choice of continuing or dis-
primary DCM in the NTD group had clinical and echocardiographic continuing taurine supplementation once deficiency was ruled out.
improvements and were therefore likely to have had daDCM, others Nonetheless, no difference was identified between diet groups in the
in this group might have had primary DCM instead of daDCM, proportion of dogs that received taurine or the duration of taurine
skewing the study's results. supplementation, making the differences in FS between groups more
Although the study numbers were small and provide only prelimi- likely associated with diet than with taurine supplementation. Taurine,
nary insights, no significant differences were found between dogs in however, might exert some positive effects on myocardial function,
the NTD group and healthy controls in concentrations of any mea- even in the absence of deficiency, including mitochondrial tRNA mod-
sured vitamin, mineral, or other nutrients. In addition to the small ification for normal mitochondrial tRNA translation.41,42 Therefore,
numbers of dogs, only a limited number of nutrients were measured. further evaluation of taurine in primary and secondary forms of DCM
These nutrients were selected for analysis based on their potential is warranted.
association with DCM, but a direct or indirect role for other nutrients The SCA group size in our study was small and did not include a
in daDCM cannot be ruled out. Therefore, analysis of more nutrients control group, but findings from this group might be helpful for under-
in larger numbers of dogs is warranted. standing daDCM because it could represent an earlier form of the dis-
Taurine deficiency is a possible cause of daDCM. However, no ease. Dogs in the SCA group all were eating NTDs with diet pulse and
dogs with DCM in our study had low plasma or whole blood taurine pulse/potato scores similar to the diets fed to dogs with DCM eating
concentrations; few had borderline taurine concentrations, and no dif- NTDs. However, dogs in the SCA group had been eating the diets for
ferences in plasma or whole blood taurine concentrations were found a shorter time (30 months) compared to the DCM group (48 months),
between diet groups. In fact, many dogs with DCM in both the NTD suggesting that exposure time to the diet might be associated with
and TD groups (and dogs in the SCA group) had high plasma or whole disease severity. This hypothesis is supported by findings from a ret-
blood taurine concentrations. Taurine concentrations were weakly rospective study of dogs with daDCM that showed a longer duration
correlated with cTnI concentrations, suggesting that the high taurine on a grain-free diet was associated with shorter survival time.18 Tau-
concentrations might reflect myocardial damage. Some studies in rine concentrations in the SCA group were similar to those in the
rodents and humans have shown that myocardial ischemia is associ- DCM group, with no dogs having low plasma and whole blood taurine
ated with decreased myocardial taurine concentrations and increased concentrations, and few having borderline taurine concentrations.
whole blood taurine concentrations.36-40 Although the FDA's data did This less severely affected SCA group had serial echocardiographic
not show a difference in dietary taurine concentrations of grain-free improvements that were similar to those seen in the DCM group, with
and grain-containing diets, we did not analyze dietary taurine or tau- significant increases in FS and significant decreases in LVIDdN,
13
rine bioavailability. LVIDsN, and LA : Ao, although no dogs received diuretics and only
The decision to initiate taurine supplementation at the time of 3 received pimobendan, suggesting dogs with SCA represent an ear-
study enrollment was caused by the delay between diagnosis and lier stage in the spectrum of disease. Three studies in apparently
 19391676, 2022, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jvim.16397 by Purdue University (West Lafayette), Wiley Online Library on [31/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
FREEMAN ET AL. 461

healthy dogs now have provided some evidence that NTDs are associ- analysis, but further investigation into the role of diet in improvement
ated with negative cardiac effects (larger left ventricular diameter, from daDCM is warranted. Based on a perceived change in attitudes
lower left ventricular systolic function, higher hs-cTnI concentrations, among dog owners and enhanced knowledge about this disease, a
more arrhythmias) even in apparently healthy dogs.43-45 more consistent approach to the intervention diet likely could be used
Our study had some additional limitations. Although most dogs for future studies.
in both DCM diet groups had CHF, others had no clinical signs and, Despite the limitations, our results indicate that dogs with
even in dogs with CHF, severity varied. Arrhythmias were common DCM eating NTDs have small but significant improvements in
in both diet groups and impacted survival time, especially because echocardiographic measurements during a 9-month study period,
sudden death was the most common cause of death in both and had a median survival time of 611 days. Nonetheless, they had
groups. Some dogs with daDCM could have had disease that was a high risk of sudden death similar to that in dogs with primary
too severe to allow for significant echocardiographic improvement. DCM. Dogs with SCA likely represent an earlier form of the dis-
However, because primary DCM typically is a progressive disease, ease, and improvement of echocardiographic abnormalities
even stable echocardiographic measurements might be noteworthy occurred after diet change.
for daDCM. Although the improvements in FS were significantly
associated with diet, studying a more homogeneous population ACKNOWLEDG MENT
could have made it easier to identify differences in survival, cardiac The study was supported by Nestlé Purina PetCare and the Barkley
biomarkers, and other echocardiographic variables as the result of Fund. Presented, in part, in abstract form at the 2020 ACVIM Forum
diet. Another limitation is that 9 months might not have been long On Demand. We gratefully acknowledge technical support from Mel-
enough to detect echocardiographic changes in all dogs. Additional anie Borglund, Lana Fagman, Courtney Hanner, Viviana Heinekin,
investigation of long-term echocardiographic changes in dogs with Michelle Maillet, and Melissa Pisaroglo de Carvalho; clinical manage-
daDCM, SCA, and in apparently healthy dogs eating NTDs after ment by Dr Amelie Beaumier; and analysis of DNA samples by Dr
diet change would be valuable. Kate Meurs. We also thank the owners of the dogs that participated
Eighty-five percent of dogs with DCM enrolled in our study were in the study.
eating NTDs, with only 15% eating TDs. This low percentage eating
TDs is not surprising because so many dogs with DCM in recent years CONFLICT OF INTEREST DIS CLOSURE
are eating NTDs (between 64% and 95% in 4 recent studies).16-18,46 In the last 3 years, Dr Freeman has received research or residency
Nonetheless, the small numbers in the TD group made analysis of the funding from, given sponsored lectures for, or provided professional
data more challenging, especially for within-group comparisons. The services for Aratana Therapeutics, Elanco, Guiding Stars Licensing Co,
total number of dogs (n = 60) also limited the number of adjustments LLC, Hill's Pet Nutrition, Nestlé Purina PetCare, P&G Petcare (now
that could be considered in the mixed models and survival analyses. Mars), and Royal Canin. In the past 3 years, Dr Rush has received
Other limitations are related to the definitions used for diet groups research funding from, given sponsored lectures for, or provided pro-
and classification of dogs into diet groups. Definitions for NTDs have fessional services for Aratana Therapeutics, Boehringer Ingelheim,
varied among studies and have been refined over time as additional Elanco, IDEXX, Nestlé Purina PetCare, and Royal Canin. Dr Adin
data on this disease have accumulated.14-18,43-45 The definition of acknowledges research support from Nestle Purina PetCare and is a
NTDs used in our study focused on the presence or absence of ingredi- consultant and sponsored lecturer for Ceva Animal Health and
ents, rather than subjective criteria. This definition still might not be Boehringer Ingelheim.
optimal because, until the exact cause is known, it is impossible to spe-
cifically target ingredients or certain compounds that are lacking or in OF F-LABEL ANTIMI CROBIAL DECLARATION
excess in the food. Therefore, definitions might need to be further Authors declare no off-label use of antimicrobials.
refined over time. Diet pulse and potato/pulse scores were calculated
to assess dogs' “dose” of pulses and potatoes, but these scores may INSTITU TIONAL ANIMAL C AR E AND USE COMMITTEE
not accurately reflect the exact amount of these ingredients in the diet, (IACUC) OR OTHER APPROVAL DECLARATION
may not be related to clinical outcome, and have not been validated. This study was approved by the Cummings School of Veterinary Med-
Another limitation is that dogs were not all changed to the same icine Clinical Studies Review Committee (006.18) and the University
diet for the 9-month study. Although a single diet would have been of Florida IACUC (201810504).
ideal in terms of study design, it was not medically optimal for the
dogs or practical in this clinical study, and thus a range of diet options HUMAN E THICS APPROVAL DECLARATION
was available so that diets could be individualized or account for pre- Authors declare human ethics approval was not needed for this study.
existing concurrent disease. In addition, the study's goal was not to
determine if dogs might have a better response with a specific diet OR CID
over another, but rather to evaluate changes after NTDs had been dis- Lisa Freeman https://orcid.org/0000-0002-0569-9557
continued. Statistical adjustment for the intervention diet (and other John Rush https://orcid.org/0000-0002-8277-8996
variables) did not change the findings in the mixed models and survival Darcy Adin https://orcid.org/0000-0003-0972-0365
 19391676, 2022, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jvim.16397 by Purdue University (West Lafayette), Wiley Online Library on [31/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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