key: cord-0861470-inxkiaql authors: Freeman, Lisa; Rush, John; Adin, Darcy; Weeks, Kelsey; Antoon, Kristen; Brethel, Sara; Cunningham, Suzanne; Santos, Luis Dos; Girens, Renee; Goldberg, Robert; Karlin, Emily; Lessard, Darleen; Lopez, Katherine; Rouben, Camden; Vereb, Michelle; Yang, Vicky title: Prospective study of dilated cardiomyopathy in dogs eating nontraditional or traditional diets and in dogs with subclinical cardiac abnormalities date: 2022-03-17 journal: J Vet Intern Med DOI: 10.1111/jvim.16397 sha: c0b3bbb5bf40143a4a4958563cfb59572e671ef3 doc_id: 861470 cord_uid: inxkiaql BACKGROUND: Recent studies have investigated dogs with presumed diet‐associated dilated cardiomyopathy (daDCM), but prospective studies of multiple breeds are needed. HYPOTHESIS/OBJECTIVES: To evaluate baseline features and serial changes in echocardiography and cardiac biomarkers in dogs with DCM eating nontraditional diets (NTDs) or traditional diets (TDs), and in dogs with subclinical cardiac abnormalities (SCA) eating NTD. ANIMALS: Sixty dogs with DCM (NTD, n = 51; TDs, n = 9) and 16 dogs with SCA eating NTDs. METHODS: Echocardiography, electrocardiography, and measurement of taurine, cardiac troponin I, and N‐terminal pro‐B‐type natriuretic peptide were performed in dogs with DCM or SCA. Diets were changed for all dogs, taurine was supplemented in most, and echocardiography and cardiac biomarkers were reassessed (3, 6, and 9 months). RESULTS: At enrollment, there were few differences between dogs with DCM eating NTDs or TDs; none had low plasma or whole blood taurine concentrations. Improvement in fractional shortening over time was significantly associated with previous consumption of a NTD, even after adjustment for other variables (P = .005). Median 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 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. 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. arrhythmia, congestive heart failure, grain-free, heart disease, nutrition, pulses Most cases of dilated cardiomyopathy (DCM) in dogs are thought to have a familial or genetic basis, affecting large and giant breeds. 1 However, secondary forms of DCM also can occur as a result of drugs, infectious agents, and nutritional causes. 2 Taurine deficiency is a form of secondary DCM in cats 3 and dogs, [4] [5] [6] [7] [8] [9] [10] [11] but deficiencies of other nutrients such as thiamine or copper also can cause secondary DCM. 2 Other causes of secondary nutritional DCM include diet-related toxins, such as heavy metals or monensin-contaminated feed. 2 In 2018, the United States Food and Drug Administration (FDA) issued an alert regarding a possible connection between diet and DCM. 12 Since that time, there have been 2 FDA updates 13, 14 and several peerreviewed research studies describing dogs with presumed diet-associated DCM (daDCM). [15] [16] [17] [18] Nontraditional diets (NTDs) eaten by dogs with daDCM have typically been grain-free or rich in pulses (eg, peas, lentils, and chickpeas) or potatoes/sweet potatoes. [14] [15] [16] [17] [18] Breeds typically affected by primary DCM (eg, Doberman Pinschers) and breeds that do not commonly develop DCM (eg, Miniature Schnauzers) have been affected by daDCM. [14] [15] [16] [17] [18] This secondary form of DCM is unique because of the improvement in various echocardiographic variables and longer survival times after diet change, [14] [15] [16] [17] [18] [19] whereas dogs with primary DCM typically have limited echocardiographic improvement and shorter survival times. [20] [21] [22] [23] [24] Published research studies on daDCM thus far have been retrospective [16] [17] [18] or conducted in a single breed, 15 (or breed-specific criteria for Doberman Pinschers or Boxers). 16, 17, 25, 26 Eligible dogs had to be eating a commercial nontraditional or traditional extruded (kibble) diet as their main source of calories for at least 6 months. Baseline diets were categorized as NT if they were grainfree or included pulses or potatoes/sweet potatoes in the top 10 ingredients and T if they were grain-inclusive and had no pulses or potatoes/sweet potatoes in the top 10 ingredients. 14, 17, 18 Ingredients were determined based on the ingredient list of the diet providing the majority of calories to each dog. Grain-free diets were defined as those not containing grains or grain-derived ingredients. 14, 17, 27 Oils (eg, corn oil) were not classified as a grain product. Dogs with SCA were identified during evaluation of dogs as potential healthy controls for the current study, screening of housemates of dogs diagnosed with DCM, or routine evaluation of dogs by the Cardiology Service. Dogs were eligible for enrollment in the SCA group if they were eating NTDs for at least 6 months and met 1 of the following 2 criteria: 1. M-mode FS ≤25% plus either increased N-terminal pro-B-type natriuretic peptide (NT-proBNP) >900 pmol/L (>735 pmol/L in Doberman Pinschers) or increased high-sensitivity cardiac troponin I (hs-cTnI) >0.06 ng/mL (>0.12 in older dogs) concentrations. 2. M-mode FS <35% plus increased NT-proBNP and increased hs-cTnI concentrations. Dogs with >1+ (mild) mitral regurgitation or obvious thickening of the mitral valve were excluded from this group. Required testing (ie, laboratory testing, echocardiogram, electrocardiogram, and genetic testing) and an initial supply of taurine supplement and dog food (to ensure early use and good compliance) were paid for by the study. Owners signed informed consent and completed diet history forms. Diet pulse and diet pulse/potato scores were calculated for each dog's diet at enrollment (Table S1 ). Dogs had a diagnostic electrocardiogram and echocardiogram performed using standard techniques at baseline. 28 Echocardiograms were performed by board-certified veterinary cardiologists or a supervised cardiology resident, with the same person performing serial measurements on an individual dog. Blood and buccal swabs were collected for the following variables at baseline: CBC; serum biochemistry profile; concentrations of NT-proBNP, hs- 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 reference ranges (Table S2) . Selected nutritional variables also were analyzed in small subgroups of the 60 dogs with DCM and compared to small subgroups of 18 control dogs determined to be healthy based on history, physical examination, CBC, serum biochemistry profile, and echocardiography (Table S3 ). Medical treatment of DCM was at the discretion of each dog's primary clinician. In most dogs, taurine supplementation was initiated at the baseline visit. Owners were instructed to administer taurine supplementation until laboratory results were available 2 to 4 weeks later and to continue supplementation if plasma or whole blood taurine concentrations were low or borderline. Owners were given the choice to continue or discontinue taurine supplementation if plasma and whole blood taurine concentrations were found to be normal or high (Table S4) . Owners of dogs with DCM in both diet groups and of dogs with SCA were instructed to change to 1 of 6 commercial extruded diets that were lower in sodium, grain-inclusive, did not contain pulses or potatoes/sweet potatoes in the top 10 ingredients, and were made by manufacturers that met the World Small Animal Veterinary Association Global Nutrition Committee's guidelines. 29 Diet options had variable caloric densities, manufacturers, and costs to address different dog and owner needs. In some dogs with concurrent medical conditions, a diet different from the main 6 intervention diets (but meeting the same criteria) was selected to tailor the diet to the individual dog's needs (eg, higher fiber and lower fat). All dogs ate primarily an extruded diet as their main source of calories, but 3 canned options were available to supplement the extruded diet if desired by the owner or if dogs would not eat extruded food alone. Dogs with congestive heart failure (CHF) were re-evaluated 1 to 2 weeks after diagnosis to assess their overall status, serum biochemical profile variables, and, if indicated, an electrocardiogram. Dogs were classified as having CHF based on a combination of clinical signs and echocardiographic findings, along with either radiographic evidence of cardiogenic pulmonary edema or presence of ascites or pleural effusion judged to be cardiogenic in origin. Dogs were re-evaluated 3, 6, and 9 months after the diet changes, at which time an echocardiogram was performed and blood was collected for NT-proBNP and hs-cTnI analysis. Dogs with arrhythmias also had a 6-lead electrocardiogram performed, and dogs with CHF had a serum biochemistry profile performed at each visit. Thoracic radiographs were performed as clinically indicated. Differences in selected characteristics between dogs in the NTD and TD groups were compared at baseline using Fisher's exact tests (categorical variables) or Mann-Whitney U tests (continuous variables). Dogs that were still alive or that died from noncardiac causes were right-censored. Kaplan Figure 1 ). Dogs in the nontraditional group weighed significantly less than dogs in the traditional group (P = .04; Table 1 ). Overall, breed was not significantly different between the 2 diet groups but breeds not typically affected by DCM were only found in the nontraditional group (eg, Chihuahua, Jack Russell Terrier, and Pit Bull). Congestive heart failure (NTD: 77%, TD: 78%; P = 1.00) and arrhythmias (NTD: 49%, TD: 67%; P = .47) were common in both diet groups but not significantly different between groups (Table 1 ). There was no difference in duration eating NTDs or TDs (Table 1 ). The only significant difference in CBC and serum biochemistry profile variables was a higher serum magnesium concentration in the NTD group (Table 1 ; P = .01; other variables not shown), although no dog had a serum magnesium concentration above the reference range. Plasma and whole blood taurine concentrations were not significantly 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 concentrations. Seven dogs (including 2 Golden Retrievers) had borderline low plasma or whole blood taurine concentrations, but no dog had both a borderline plasma and borderline whole blood concentration. Weak positive correlations were found for all 60 dogs at baseline between plasma taurine and hs-cTnI (r = 0.33, P = .02) concentrations and between whole blood taurine and hs-cTnI (r = 0.35, P = .01) concentrations. No measured vitamin or mineral concentrations were significantly different between dogs in the NTD group and healthy controls (Table S3) Previous diet had no pulses/potatoes in the top 10 ingredients (n = 3) Home-cooked diet (n = 1) • 6-month re-evaluation not possible because of COVID-19 restrictions, so only had 0, 3, and 9-month visits (n = 1). • All other dogs that were still alive attended all 3-, 6-, and 9-month re-evaluations Previous nontraditional diet (n = 55) • All dogs that were still alive attended all 3-, 6-, and 9-month re-evaluations Previous traditional diet (n = 11) Analyzed (n = 9) • Excluded from analysis (n = 2) Previous diet had peas in top 10 ingredients (n = 1) Home-cooked diet (n = 1) Changed diet (n = 66) Dogs with DCM in both diet groups received many cardiac medications throughout the study, without any between-group differences (Table S4 ). Fifty-one of the 58 discharged dogs (88%) received taurine 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, 6.5 months; range, 0.4-9.0 months; TD group: median, 4.9 months; range, 0.1-9.0 months; P = .99). Twenty-nine of 51 dogs (57%) in the NTD group and 3/9 dogs (33%) in the TD group survived until the 9-month re-evaluation (P = .28). In the NTD group, a significant decrease was found in hs-cTnI concentrations between 0 and 9 months (P = .03), but the change in NT-proBNP was not significant ( Table 2 ). Among dogs in the TD group, the change from baseline to 9 months was not significant for hs-cTnI or NT-proBNP concentrations ( Table 2) . The final mixed model for serial changes in hs-cTnI concentrations showed that the interaction between diet group and time was not 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 NT-proBNP. For the echocardiographic endpoints, the 29 dogs that completed the study in the NTD group had a significant within-group increase from 0 to 9 months in FS (P < .001) and significant decreases in LVIDdN (P = .005), LVIDsN (P < .001), and LA : Ao (P = .004; Table 2 ). Within-group changes for the 3 dogs in the TD group that completed the study were not significant for any of the echocardiographic variables examined ( Table 2) . Mixed models analysis incorporating all time points (0, 3, 6, and 9 months) for dogs in both diet groups showed that the interaction between diet group and time was significantly associated with improvements in FS (P = .005), with greater improvement in the NTD group after adjustment for age, sex, weight, intervention diet, arrhythmia, and CHF ( The cause of death was not significantly different between dogs in the NTD vs TD groups (P = .47). For dogs with DCM that were discharged after their initial visit (n = 58), median survival time was 611 days (range, 2-940 days) for the NTD group and 161 days (range, 12-669 days) for the TD group (P = .21; Figure 2 ). After adjusting for age, CHF, arrhythmia, intervention diet, hs-cTnI, and LA : Ao, diet group still was not significantly associated with survival time (Figure 2 ). Sixteen dogs comprised the SCA group ( (Table 3) . Over the course of the study, 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 variables 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. Figure 2 ). This result is in contrast to findings from 2 retrospective studies, 17, 18 which showed longer survival times in dogs with DCM eating NTDs after diet change. In 1 of these studies, eating a NTD was associated with a longer survival time after diet was changed, even after adjustment for the presence of CHF and cardiac arrhythmias. 17 In the second recent retrospective study of dogs with DCM and CHF, prior NTD was associated with longer survival, after adjustment for breed, atrial fibrillation, and age of diagnosis. 18 However, both studies used all-cause mortality and Cox proportional hazards analysis, which does not account for competing risks, whereas we analyzed for cardiac mortality and adjusted for competing risks. In addition, 1 study had some different inclusion criteria (eg, smaller LVIDdN, required presence of CHF) that could account for the different results. 18 Finally, as previously noted, an important limitation of our study is sample size. It is likely that the relatively small number of dogs (especially in the TD group [n = 9]) might have contributed to the lack of significant differences in survival times between the 2 diet groups. The most common cause of death in the dogs with DCM in both diet groups was sudden death, accounting for 54% of deaths overall, and cause of death was not different between diet groups. This finding suggests that dogs with DCM (whether primary or diet-associated) are at high risk for sudden death. Arrhythmias were present in many dogs at the time of enrollment or over the course of the study in both diet groups, which may limit the time for cardiac improvement to be observed given the propensity for sudden cardiac death for those dogs with arrhythmias. The percentage of dogs in our study that died suddenly appeared relatively high compared to studies of dogs with primary DCM where sudden death was reported to account for 10% to 15% of deaths for dogs of multiple breeds and 29% to 42% for Doberman Pinschers. [20] [21] [22] [23] [24] [33] [34] [35] The limited number of baseline differences between dogs in the different diet groups emphasizes the similar clinical findings of dogs with primary or secondary forms of DCM, which is consistent with previous studies. 16 The SCA group size in our study was small and did not include a control group, but findings from this group might be helpful for under- [16] [17] [18] 46 Nonetheless, the small numbers in the TD group made analysis of the data more challenging, especially for within-group comparisons. The total number of dogs (n = 60) also limited the number of adjustments that could be considered in the mixed models and survival analyses. Other limitations are related to the definitions used for diet groups and classification of dogs into diet groups. Definitions for NTDs have varied among studies and have been refined over time as additional data on this disease have accumulated. [14] [15] [16] [17] [18] [43] [44] [45] The definition of NTDs used in our study focused on the presence or absence of ingredients, rather than subjective criteria. This definition still might not be optimal because, until the exact cause is known, it is impossible to specifically target ingredients or certain compounds that are lacking or in excess in the food. Therefore, definitions might need to be further refined over time. Diet pulse and potato/pulse scores were calculated to assess dogs' "dose" of pulses and potatoes, but these scores may not accurately reflect the exact amount of these ingredients in the diet, may not be related to clinical outcome, and have not been validated. Another limitation is that dogs were not all changed to the same diet for the 9-month study. Although a single diet would have been 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 was available so that diets could be individualized or account for preexisting concurrent disease. In addition, the study's goal was not to determine if dogs might have a better response with a specific diet over another, but rather to evaluate changes after NTDs had been discontinued. Statistical adjustment for the intervention diet (and other variables) did not change the findings in the mixed models and survival Authors declare human ethics approval was not needed for this study. 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