Severity Of Myxomatous Mitral Valve Disease Research Articles

Retrospective evaluation of the utility of shock index to determine the presence of congestive heart failure in dogs with myxomatous mitral valve disease (2019-2021): 98 cases.

To calculate the shock index (SI) in dogs with myxomatous mitral valve disease (MMVD) and to evaluate its use to predict the presence of congestive heart failure (CHF). Retrospective study. Small animal university veterinary teaching hospital. Ninety-eight dogs with MMVD and 20 healthy dogs as part of a control group. Heart rate (HR) and systolic blood pressure (SBP) were recorded, and SI was calculated by dividing HR by SBP for each dog. The mean (SD) HR, SBP, and SI were 123/min (32.6), 147mmHg (21.5), and 0.86 (0.3), respectively, for dogs with MMVD and 98/min (20.9), 145mmHg (18.7), and 0.68 (0.13), respectively, for control dogs. Dogs with MMVD had a significantly higher HR compared with control dogs (P<0.01), and an elevation in HR was seen as the severity of MMVD increased. Dogs in stage B2 and C/D MMVD had a significantly higher SI value compared with control dogs (P=0.04 and P<0.01, respectively). SI was significantly higher in dogs in stage C/D MMVD compared with dogs in stage B2 MMVD (P<0.01). Ten of 98 (10%) dogs had an arrhythmia. HR, SBP, and SI were not significantly different between dogs with and without arrhythmias (P=0.13, P=0.57, and P=0.07, respectively), but significantly more dogs with CHF had an arrhythmia (P=0.01). SI (area under the curve [AUC]: 0.98) and HR (AUC: 0.95) were excellent indicators for the presence of CHF. An optimal SI cutoff value ≥1.1 had 92% sensitivity and 95% specificity for predicting the presence of CHF, and an optimal HR cutoff value of ≥157/min had 92% sensitivity and 93% specificity for the prediction of CHF. When there are compatible clinical signs, SI values ≥1.1 may suggest the presence of CHF in dogs with MMVD.

Platelet hyperresponsiveness and increased platelet-neutrophil aggregates in dogs with myxomatous mitral valve disease and pulmonary hypertension.

Pulmonary hypertension (PH) in dogs with myxomatous mitral valve disease (MMVD) is caused by increased pulmonary venous pressure. Thrombosis, vascular remodeling, and vasoconstriction mediated by platelets could exacerbate PH. Dogs with PH will exhibit a hypercoagulable state, characterized by increased platelet activation, platelet-leukocyte, and platelet-neutrophil aggregate formation. Eleven dogs (≥3.5 kg) diagnosed with MMVD and PH and 10 dogs with MMVD lacking PH. Prospective cohort ex vivo study. All dogs underwent echocardiographic examination, CBC, 3-view thoracic radiographs, and heartworm antigen testing. Severity of PH and MMVD were assessed by echocardiography. Viscoelastic monitoring of coagulation was assessed using thromboelastography (TEG). Platelet activation and platelet-leukocyte/platelet-neutrophil interactions were assessed using flow cytometry. Plasma serotonin concentrations were measured by ELISA. Unstimulated platelets from dogs with MMVD and PH expressed more surface P-selectin than MMVD controls (P = .03). Platelets from dogs with MMVD and PH had persistent activation in response to agonists. The number of platelet-leukocyte aggregates was higher in dogs with MMVD and PH compared with MMVD controls (P = .01). Ex vivo stimulation of whole blood resulted in higher numbers of platelet-neutrophil aggregates in dogs with MMVD and PH (P = .01). Assessment of hypercoagulability based on TEG or plasma serotonin concentrations did not differ between groups. Platelet hyperresponsiveness and increased platelet-neutrophil interaction occur in dogs with MMVD and PH, suggesting that platelets play a role of in the pathogenesis of PH. Clinical benefits of antiplatelet drugs in dogs with MMVD and PH require further investigation.

Iron parameters analysis in dogs with myxomatous mitral valve disease.

Myxomatous mitral valve disease (MMVD) is the most common acquired cardiovascular disease in small breed dogs. In contrast to human patients with heart failure (HF), iron deficiency (ID) prevalence in dogs with MMVD is weakly known. The study aimed to assess the usability of ID markers in serum and reticulocyte parameters from whole blood of dogs with MMVD to evaluate early ID symptoms. Sixty-eight dogs (43 male and 25 female) were included in the study. MMVD dogs were assigned according to the 2019 ACVIM guidelines for groups B1 (n = 9), B2 (n = 10), C (n = 27) and D (n = 10). Groups were also combined into B1 and B2 as non-symptomatic HF and C with D as symptomatic HF. Healthy controls were 12 dogs. Serum iron concentration below the reference range in dogs with MMVD was 12.5%. Other ID indices, such as %SAT, UIBC, and TIBC were similar in the MMVD groups and healthy controls (p > 0.05 for all parameters). Statistical comparison between control group and 4 groups of different stages of MMVD showed that significant differences occur only in serum transferrin. The assessment of ferritin and soluble transferrin receptors using Western Blotting did not show differences between control (n = 7) and MMVD (n = 33) dogs. Study has shown positive correlation between ID parameters and echocardiographic indices such as LA/Ao and LVIDdN, and some biochemical parameters. A significant increase in reticulocytes percentage, assessed manually, was observed in the HF group of animals (p = 0.027) compared to the control group. Studies have shown that ID parameters in serum are not significantly different in dogs with MMVD compared to healthy dogs. However, there is a clear correlation between atrial size and normalised left ventricular size to body size and some biochemical parameters, including ID parameters and therefore the severity of MMVD.

Myxomatous mitral valve disease and associated pulmonary hypertension might increase serum angiopoietin-2 in dogs.

To evaluate the relationships between the severity of myxomatous mitral valve disease (MMVD) and pulmonary hypertension (PH) and serum angiopoietin (Ang)-1 and Ang-2 concentrations in dogs with MMVD. 74 dogs (control, n = 12; MMVD, n = 62) were included. Serum Ang-1 and Ang-2 concentrations were estimated using the canine-specific ELISA kit. The concentrations were compared between dogs with MMVD and healthy dogs, and they were analyzed according to the severity of MMVD and PH. The median serum Ang-1 concentration did not differ among the study groups. The median serum Ang-2 concentration was higher in dogs with stage B2 MMVD (P = .041) and acute congestive heart failure (P = .002) than in control dogs. In addition, the median serum Ang-2 concentration was higher in MMVD dogs with PH than in those without PH (P = .031). Serum Ang-2 concentration was correlated with vertebral heart score (rs = 0.36, P = .004) and vertebral left atrial score (r = 0.50, P < .001) in dogs with MMVD, and correlated with vertebral heart score (r = 0.63, P = .01), maximum E wave amplitude of the diastolic transmitral flow (rs = 0.61, P = .018), ejection fraction (rs = -0.77, P < .001) and fractional shortening (rs = -0.56, P = .032) in dogs with acute congestive heart failure. Circulating Ang-2 levels increase in dogs with the severity of MMVD and the presence of PH.

Relationship between syringomyelia and myxomatous mitral valve disease in Cavalier King Charles spaniels.

Syringomyelia (SM) and myxomatous mitral valve disease (MMVD) are highly prevalent in Cavalier King Charles spaniels (CKCS). Cardiac status in CKCS with and without SM is currently unknown. To investigate the association between SM and MMVD severity in CKCS and CKCS with SM with and without clinical signs of SM. Fifty-five CKCS: 40 with SM (22 symptomatic and 18 asymptomatic) and 15 without SM. A combined retrospective and prospective study. MRI and echocardiography were used to diagnose SM and MMVD, respectively. The association between SM and MMVD severity (left ventricle internal diameter in diastole normalized to bodyweight [LVIDDN] and left atrium to aortic ratio [LA/Ao]) were tested using multivariable linear regression analysis adjusting for sex and age. Overall, no significant difference in LVIDDN and LA/Ao was found between CKCS with or without SM. However, CKCS with symptomatic SM had significantly smaller LVIDDN (1.45 [1.30-1.50]) (median [IQR]) and LA/Ao (1.20 [1.10-1.28]) compared to CKCS with asymptomatic SM (1.60 [1.50-1.90] and 1.40 [1.20-1.75]) as well as CKCS without SM (0.24 [0.03-0.45] and 0.30 [0.05-0.56]) (all P values <.03). An association between MMVD and SM was not confirmed in this cohort of CKCS, indicating that MMVD and SM do not co-segregate. However, CKCS with symptomatic SM had smaller left ventricle and atrial size compared to CKCS with asymptomatic SM and CKCS without SM.

No impact of polymorphism in the phosphodiesterase 5A gene in Cavalier King Charles Spaniels on pimobendan-induced inhibition of platelet aggregation response.

A variant in the canine phosphodiesterase (PDE) 5A gene (PDE5A:E90K) is associated with decreased concentrations of circulating cyclic guanosine monophosphate (cGMP) and response to PDE5 inhibitor treatment. Pimobendan is a PDE inhibitor recommended for medical treatment of certain stages of myxomatous mitral valve disease (MMVD) in dogs. PDE5A:E90K polymorphism attenuates the inhibitory effect of pimobendan on in vitro platelet aggregation and increases basal platelet aggregation in Cavalier King Charles Spaniels (CKCS). Selected clinical variables (MMVD severity, sex, age, hematocrit, platelet count in platelet-rich plasma [PRP], and echocardiographic left ventricular fractional shortening [LV FS]) will not show an association with results. Fifty-two privately owned CKCS with no or preclinical MMVD. Using blood samples, we prospectively assessed PDE5A genotype using Sanger sequencing and adenosine diphosphate-induced platelet aggregation response (area under the curve [AUC], maximal aggregation [MaxA], and velocity [Vel]) with and without pimobendan using light transmission aggregometry. Dogs also underwent echocardiography. Pimobendan inhibited platelet function as measured by AUC, MaxA, and Vel at a concentration of 10 μM (P < .0001) and Vel at 0.03 μM (P < .001). PDE5A:E90K polymorphism did not influence the inhibitory effect of pimobendan or basal platelet aggregation response. The PDE5A:E90K polymorphism did not influence in vitro basal platelet aggregation response or the inhibitory effect of pimobendan on platelet aggregation in CKCS. Dogs with the PDE5A:E90K polymorphism did not appear to have altered platelet function or response to pimobendan treatment.

Investigation of red blood cell and platelet indices in adult dogs suffered from myxomatous mitral valve disease with and without pulmonary hypertension.

Pulmonary hypertension (PH) is a common complication of cardiopulmonary disease. In dogs, PH commonly occurs secondary to myxomatous mitral valve disease (MMVD). Red blood cell and platelet indices including mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), mean platelet volume (MPV) and platelet distribution width (PDW), have previously been found to be indicators for predicting and prognosing PH in humans. Therefore, this study aimed to investigate whether these indices are associated with MMVD and/or PH in dogs. Two hundred and forty-six dogs were retrospectively recruited for the study and classified into 4 groups: normal (n = 49), MMVD (n =102), PH (n =17), MMVD+PH (n =78). A sub-analysis was performed in dogs with MMVD without evidence of PH according to stage B1 (n =20), stage B2 (n =15), stage C (n =67). The data are expressed as median (interquartile range). No significant differences (p < 0.05) were found in MCV, RDW and MPV among all groups (normal, MMVD, PH and MMVD+PH). However, decreases in MCH and MCHC were found in MMVD [22.40 (20.90-23.50) pg and 35.25 (33.08-36.90) g/dL], MMVD+PH [22.25 (20.85-23.98) pg and 35.65 (33.30-37.33) g/dL] and PH groups [21.20 (20.60-22.20) pg and 33.80 (32.75-35.70) g/dL] compared to the normal dogs [24.29 (23.55-24.90) pg and 38.20 (37.50-39.05) g/dL] (p < 0.001). Decreases in PDW were found in dogs in the MMVD+PH [15.10 (14.98-15.30) %] groups compared to dogs in the normal group [15.30 (15.10-15.50) %] (p = 0.004). Sub-analysis of MMVD dogs without PH showed a decrease in MCH in dogs with stage B2 MMVD [21.00 (20.50-22.90) pg] and stage C MMVD [22.40 (20.90-23.20) pg] compared to normal dogs [24.29 (23.55-24.90) pg] (p < 0.001). MCHC of dogs with stage B1 [36.55 (33.53-37.78) g/dL] (p = 0.004), B2 [32.90 (32.00-35.00) g/dL] (p < 0.001) and C MMVD [35.30 (33.30-36.80) g/dL] (p < 0.001) were lower than those of normal dogs [38.20 (37.50-39.05) g/dL]. PDW in the stage C MMVD group [15.10 (15.00-15.30) %] was reduced compared to the normal group [15.30 (15.10-15.50) %] (p = 0.042) and the stage B1 MMVD group [15.35 (15.23-15.68) %] (p = 0.002). MCH, MCHC and PDW were negatively correlated with the left atrial and left ventricular size. Decreases in MCH and MCHC are related to MMVD, precapillary PH and postcapillary PH while PDW are associated with MMVD severity but not with the presence of PH.

Prognostic Efficacy of Complete Blood Count Indices for Assessing the Presence and the Progression of Myxomatous Mitral Valve Disease in Dogs.

This study investigated the complete blood count (CBC) indices, including neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) in dogs with myxomatous mitral valve disease (MMVD) and analyzed their correlation with conventional biomarkers, as well as the effect of CBC indices on survival time in dogs with MMVD. Medical records of 75 healthy controls and 249 dogs with MMVD from March 2015 to October 2022 were analyzed. The NLR, MLR, and PLR were calculated by dividing the absolute counts of the CBC parameters. Dogs with MMVD had significantly higher NLR, MLR, and PLR than healthy dogs (all p < 0.0001), especially those in the symptomatic MMVD group with pulmonary edema (p < 0.0001, p = 0.0002, and p = 0.0387, respectively). The NLR and MLR were significantly correlated with N-terminal pro-B type natriuretic peptide levels (both p < 0.0001). The CBC indices showed potential as biomarkers for detecting the presence of MMVD (all p < 0.0001) and severity of MMVD (p < 0.0001, p < 0.0001, and p = 0.006, respectively) using receiver operating characteristic curve analysis. The negative effects of increased NLR, MLR, and PLR on survival were confirmed using Kaplan-Meier curve analysis. In conclusion, NLR, MLR, and PLR could be cost-effective and readily available potential diagnostic and prognostic biomarkers for MMVD in dogs.

Evaluation of progression of chronic kidney disease in dogs with myxomatous mitral valve disease.

Cardiovascular and renal diseases are known to affect each other in the cardiovascular renal axis disorder (CvRD). Although CvRD, which includes myxomatous mitral valve disease (MMVD) and chronic kidney disease (CKD), has been described in dogs, there are only a few reports on the progression of CKD in accordance with the severity of MMVD. The aim of this study was to evaluate whether the presence of MMVD is associated with the rate of progression of CKD in dogs. The time from the initial diagnosis to the worsening of the International Renal Interest Society (IRIS) stage and the time for the occurrence of hyperphosphatemia and isosthenuria were evaluated. In this retrospective study, CKD progression was determined as an increase in the IRIS stage by at least one level and the development of hyperphosphatemia or isosthenuria. The CKD progression was compared in dogs with and without comorbid MMVD. Dogs with CKD were divided into two groups: dogs with and without MMVD (n = 63, concurrent group; n = 52, CKD group, respectively). The concurrent group was further divided into two subgroups based on the American College of Veterinary Internal Medicine guidelines (B1 group, n = 24; B2 group, n = 39). The time for progression of CKD from IRIS stage 1 to IRIS stage 2 was significantly shorter in the concurrent group than in the CKD group (log-rank test, p < 0.001). MMVD was associated with an increased risk of progression from stage 1 to stage 2 (hazard ratio, 6.442; 95% confidence interval (CI), 2.354 to 18.850; p < 0.001). The timing of the onset of hyperphosphatemia or isosthenuria in the concurrent group and the CKD group was not significantly different. The results of this study suggest that MMVD could be a risk factor for the progression of CKD. Our findings may help predict the prognosis of dogs with both CKD and MMVD compared to CKD only.

Severity of myxomatous mitral valve disease in dogs may be predicted using neutrophil-to-lymphocyte and monocyte-to-lymphocyte ratio.

To investigate the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) in dogs with myxomatous mitral valve disease (MMVD). 106 dogs with MMVD and 22 healthy dogs were included in the study. CBC data were obtained retrospectively, and NLR, MLR, and PLR were compared between dogs with MMVD and healthy dogs. The ratios were also analyzed according to MMVD severity. NLR and MLR were significantly higher in dogs with MMVD C and D (NLR of 4.99 [3.69-7.27]; MLR of 0.56 [0.36-0.74]) than in healthy dogs (NLR: 3.05 [1.82-3.37], P < .001; MLR: 0.21 [0.14-0.32], P < .001), MMVD stage B1 (NLR: 3.15 [2.15-3.86], P < .001; MLR: 0.26 [0.20-0.36], P < .001), and MMVD stage B2 dogs (NLR: 3.22 [2.45-3.85], P < .001; MLR: 0.30 [0.19-0.37], P < .001). The area under the receiver operating characteristic curves of the NLR and MLR to distinguish dogs with MMVD C and D from those with MMVD B were 0.84 and 0.89, respectively. The optimal cutoff value for NLR was 4.296 (sensitivity, 68%; specificity, 83.95%), and the MLR value was 0.322 (sensitivity, 96%; specificity, 66.67%). NLR and MLR were significantly decreased after treatment in dogs with congestive heart failure (CHF). NLR and MLR can be used as adjunctive indicators of CHF in dogs.

Genetic Variants at the Nebulette Locus Are Associated with Myxomatous Mitral Valve Disease Severity in Cavalier King Charles Spaniels.

The most common cardiovascular disease in domestic dogs is myxomatous mitral valve disease (MMVD), accounting for 75% of all cardiac disease. An increase in age is generally associated with increased incidence of the disease, but Cavalier King Charles Spaniels (CKCS) exhibit an unusually high prevalence of early-onset MMVD, and thus, potentially greater cardiac morbidity and mortality compared to other breeds. Previous research has suggested that selected candidate risk alleles for MMVD are fixed in CKCSs, including six locations within the Nebulette (NEBL) gene on CFA2. The current study analysed genotypes of 180 Australian CKCSs at the identified risk loci. Of these, 178 were phenotyped for severity of disease by echocardiographic measurements of left atrium to aortic root ratio (LA:Ao) and weight normalised left ventricular end diastolic diameter (LVIDdN). Genotyping array markers correctly predicted the genotype at the risk-variant loci in the CKCS population, and the NEBL1, NEBL2 and NEBL3 variants were observed to be in perfect linkage disequilibrium in this cohort. The CKCS cohort included 6/178 dogs being heterozygous for the protective/wild-type alleles at the NEBL locus. The mean LA:Ao and LVIDdN scores of these dogs heterozygous at NEBL1-3 variants were significantly smaller, and with significantly lower variance compared to age-matched CKCSs that were homozygous for risk alleles. The lower cardiac measurements in the heterozygous dogs indicate a significantly reduced risk of severe MMVD disease. Our analysis suggests that despite relative fixation of the NEBL risk alleles, healthy reference alleles at NEBL1-3 exist in low frequency in the CKCS breed and can be used to reduce MMVD severity and mortality.

Hemodynamic Effects of Protamine Infusion in Dogs with Myxomatous Mitral Valve Disease Undergoing Mitral Valvuloplasty.

Protamine, an antagonizing agent to heparin, is indispensable for dogs undergoing cardiopulmonary bypass. Protamine-induced hypotension (PIH) during cardiac anesthesia has been reported in humans. The purpose of this study was to describe the hemodynamic effect of protamine administration in dogs during cardiac surgery in clinical cases. Study design: Retrospective, clinical, cohort study. A total of 14 client-owned dogs who suffered heart failure due to medically uncontrolled myxomatous mitral valve disease (MMVD) were included in this study. The severity of MMVD was classified according to American College of Veterinary Internal Medicine staging (ACVIM: stage B2, C, D) and dogs undergoing mitral valve surgery. Records with clinical data for dogs treated between July 2019 to August 2020 were examined for age, sex, breed, body weight, concurrent diseases, hospitalization, anesthetic record, and mortality within 3 months after the operation. PIH was defined as mean arterial pressure (MAP) lowered by 20% of that before protamine infusion. To evaluate the effect of protamine on hemodynamic variables, each of the other values was compared with values at the beginning of protamine infusion. MAP decreased by 41.0 and 45.7% in two dogs (14.3%) compared with pressure before protamine infusion. Others did not show obvious alteration in hemodynamic variables. Epinephrine treatment alleviated hypotension in one dog. Another dog with systemic hypotension concomitant with elevated central venous pressure did not respond to epinephrine treatment and a reboot of extracorporeal circulation was required. Reheparinization and reinstitution of cardiopulmonary bypass successfully resuscitate the second dog. In conclusion, clinicians should alert the incidence of severe hypotension even with slow protamine infusion following canine cardiac surgery. This study also provides two effective treatments for catastrophic hypotension during protamine infusion.

Polymorphisms in the serotonin transporter gene and circulating concentrations of neurotransmitters in Cavalier King Charles Spaniels with myxomatous mitral valve disease.

BackgroundThe neurotransmitter serotonin (5‐HT) affects valvular degeneration and dogs with myxomatous mitral valve disease (MMVD) exhibit alterations in 5‐HT signaling. In Maltese dogs, 3 single nucleotide polymorphisms (SNPs) in the 5‐HT transporter (SERT) gene are suggested to associate with MMVD.Hypothesis/ObjectivesDetermine the association of SERT polymorphisms on MMVD severity and serum 5‐HT concentration in Cavalier King Charles Spaniels (CKCS). Additionally, investigate the association between selected clinical and hematologic variables and serum 5‐HT and assess the correlation between HPLC and ELISA measurements of serum 5‐HT.AnimalsSeventy‐one CKCS (42 females and 29 males; 7.8 [4.7;9.9] years (median [Q1;Q3])) in different MMVD stages.MethodsThis prospective study used TaqMan genotyping assays to assess SERT gene polymorphisms. Neurotransmitter concentrations were assessed by HPLC and ELISA.ResultsTaqMan analyses identified none of the selected SERT polymorphisms in any of the CKCS examined. Serum 5‐HT was associated with platelet count (P < .001) but not MMVD severity, age or medical therapy and did not correlate with serum concentration of the 5‐HT metabolite, 5‐hydroxyindoleacetic acid. The ELISA serum 5‐HT correlated with HPLC measurements (ρ = .87; P < .0001) but was lower (mean difference = −22 ng/mL; P = .02) independent of serum 5‐HT concentration (P = .2).Conclusions and Clinical ImportanceSelected SERT SNPs associated with MMVD in Maltese dogs were not found in CKCS and only platelet count influenced serum 5‐HT concentration. These SNPs are unlikely to be associated with MMVD pathophysiology or serum 5‐HT concentration in CKCS. HPLC and ELISA serum 5‐HT demonstrated good correlation but ELISA systematically underestimated 5‐HT.

Genetics of canine myxomatous mitral valve disease.

Myxomatous mitral valve disease (MMVD) is the most common heart disease and cause of cardiac death in domestic dogs. MMVD is characterised by slow progressive myxomatous degeneration from the tips of the mitral valves onwards with subsequent mitral valve regurgitation, and left atrial and ventricular dilatation. Although the disease usually has a long asymptomatic period, in dogs with severe disease, mortality is typically secondary to left-sided congestive heart failure. Although it is not uncommon for dogs to survive long enough in the asymptomatic period to die from unrelated causes; a proportion of dogs rapidly advance into congestive heart failure. Heightened prevalence in certain breeds, such as the Cavalier King Charles Spaniel, has indicated that MMVD is under a genetic influence. The genetic characterisation of the factors that underlie the difference in progression of disease is of strong interest to those concerned with dog longevity and welfare. Advanced genomic technologies have the potential to provide information that may impact treatment, prevalence, or severity of MMVD through the elucidation of pathogenic mechanisms and the detection of predisposing genetic loci of major effect. Here we describe briefly the clinical nature of the disorder and consider the physiological mechanisms that might impact its occurrence in the domestic dog. Using results from comparative genomics we suggest possible genetic approaches for identifying genetic risk factors within breeds. The Cavalier King Charles Spaniel breed represents a robust resource for uncovering the genetic basis of MMVD.

The Mitral INsufficiency Echocardiographic score: A severity classification of myxomatous mitral valve disease in dogs.

BackgroundThere is no commonly shared severity score for myxomatous mitral valve disease (MMVD) based on routinely acquired echocardiographic variables.Hypothesis/ObjectivesTo propose an easy‐to‐use echocardiographic classification of severity of MMVD in dogs.AnimalsFive hundred and sixty dogs with MMVD.MethodsThis was a retrospective, multicenter, observational study. The proposed Mitral INsufficiency Echocardiographic (MINE) score was based on 4 echocardiographic variables: left atrium‐to‐aorta ratio, left ventricular end‐diastolic diameter normalized for body weight, fractional shortening, and E‐wave transmitral peak velocity. Specific echocardiographic cutoffs were defined based on previous prognostic studies on MMVD, and severity scores were assigned as follows: mild (score: 4‐5), moderate (score: 6‐7), severe (score: 8‐12), late stage (score: 13‐14).ResultsMedian survival time was significantly different (P < .05) between the proposed severity classes: mild (2344 days, 95% confidence interval [CI] 1877‐2810 days), moderate (1882 days, 95% CI 1341‐2434 days), severe (623 days, 95% CI 432‐710 days), and late stage (157 days, 95% CI 53‐257 days). A MINE score >8 was predictive of cardiac death (area under the curve = 0.85; P < .0001; sensitivity 87%, specificity 73%). In the multivariable analysis, all the echocardiographic variables of the MINE score were independent predictors of death because of heart disease (P < .001).Conclusions and Clinical ImportanceThe MINE score is a new easy‐to‐use echocardiographic classification of severity of MMVD, which has been proven to be clinically effective as it is associated with survival. This classification provides prognostic information and could be useful for an objective echocardiographic assessment of MMVD.

Radiographic quantification of left atrial size in dogs with myxomatous mitral valve disease.

BackgroundIn the absence of echocardiography, identification of cardiomegaly via thoracic radiography is a necessary criterion for classification of disease severity in dogs with myxomatous mitral valve disease (MMVD).ObjectiveModified‐vertebral left atrial size (M‐VLAS) facilitates objective radiographic assessment of the left atrium (LA) in 2 dimensions and identifies LA enlargement more accurately than existing methods.AnimalsSixty‐four dogs with various stages of MMVD and 6 control healthy dogs.MethodsRetrospective case–control study. Medical records were searched for dogs with varying severity of MMVD. Modified‐vertebral left atrial size, vertebral left atrial size (VLAS), vertebral heart size (VHS), and radiographic left atrial dimension (RLAD) were measured from thoracic radiographs and compared with echocardiographically derived measurements.ResultsPositive correlation to LA/Ao was identified for M‐VLAS (r = 0.77, P < .001), VLAS (r = 0.76, P < .001), RLAD (r = 0.75, P < .001), and VHS (r = 0.67, P < .001). Receiver operating characteristic analyzes provided an area under the curve of 0.97 (95% CI, 0.94‐1.00) for M‐VLAS, which was superior to VHS (0.90, 95% CI, 0.94‐1.00, P = .03) in identifying dogs with LA/Ao ≥1.6. A cut‐off value of ≥3.4 vertebrae using M‐VLAS provided 92.7% sensitivity and 93.1% specificity in predicting LA enlargement.Conclusions and clinical importanceM‐VLAS, which is superior to VHS, offers an accurate and repeatable way to radiographically identify LA enlargement in dogs with MMVD.

The effect of myxomatous mitral valve disease severity on packed cell volume in dogs.

The aim of this study was to examine whether associations between disease severity and packed cell volume exist in dogs with myxomatous mitral valve disease. Data were selected from 289 dogs that had been examined at a research clinic (2004-2017) on multiple occasions (n=1465). American College of Veterinary Internal Medicine stage and echocardiographic measurements were entered in separate multivariable linear mixed effects models with packed cell volume as the dependent variable. Age, breed, sex, weight and blood urea nitrogen concentrations were additionally tested in these analyses to control for patient characteristics. Packed cell volume (% whole blood) in stages B1 and B2 (B1: 42.62 ±0.27, P=0.001; B2: 41.77± 0.42, P< 0.001) was lower than stage A (44.57 ±0.53). In stage C, packed cell volume was greater than both preclinical stages (C: 43.84 ±0.46). When the administration of loop diuretics was included in statistical models, packed cell volume was inversely related to normalised left ventricular internal diameters (β: -2.37; 95% confidence intervals: -3.49, -1.25; P< 0.001). Dogs with myxomatous mitral valve disease may develop reductions in packed cell volume as their disease progresses. Although this finding was statistically significant at a population level, it should be noted that the differences described are relatively small. This, along with other causes of variation in packed cell volume, means that changes would be challenging to appreciate within individual patients. Plasma volume depletion following diuretic administration may explain why findings differed in stage C.

Pharmacokinetics of Repeated Oral Dosing with Coenzyme Q10 in Cavalier King Charles Spaniels with Myxomatous Mitral Valve Disease.

Coenzyme Q10 (Q10) is a mitochondrial cofactor and an antioxidant with the potential to combat oxidative stress in heart failure. This study aims to determine the pharmacokinetics of repeated oral dosing of Q10 in Cavalier King Charles Spaniels (CKCS) with spontaneous myxomatous mitral valve disease (MMVD) and to evaluate echocardiographic parameters, circulating cardiac biomarkers, and quality of life (QoL) after treatment. The study is a randomized, placebo-controlled, single-blinded crossover study. Nineteen CKCS with MMVD were randomized to receive 100 mg Q10 (ubiquinone) bi-daily for three weeks, then placebo (or in reverse order). Clinical examination, blood sampling, echocardiography, and QoL assessment were performed before and after each treatment phase. Q10 plasma concentrations were determined in plasma using a validated high-performance liquid chromatography method using electrochemical detection (HPLC-ECD). Eighteen CKCS were included in the analyses. Total plasma concentration of Q10 increased significantly (p < 0.0001) from baseline (median, 0.92 µg/mL; interquartile range (IQR), 0.70–1.26) to after treatment (median, 3.51 µg/mL; IQR, 2.30–6.88). Thirteen dogs reached the threshold of a total plasma Q10 concentration of ≥2.0 µg/mL. The average half-life (T1/2) of Q10 was 2.95 days (IQR, 1.75–4.02). No significant differences were observed in clinical MMVD severity, and the owner perceived QoL between Q10 and placebo treatment. The solubilized Q10 formulation was well-tolerated in the dogs. Individual variation in plasma concentrations was observed following oral treatment. A long-term placebo-controlled trial is warranted in dogs with MMVD to determine long-term efficacy on the clinical severity of MMVD.

Symmetric dimethylarginine in dogs with myxomatous mitral valve disease at various stages of disease severity

Symmetric dimethylarginine (SDMA) is a serum biomarker of renal damage in dogs. Moreover, SDMA concentration is an independent predictor of development of severe heart failure (HF) in humans with cardiac disease. This study evaluates whether the serum concentration of SDMA in dogs with myxomatous mitral valve disease (MMVD) is influenced by the severity of heart disease, pulmonary hypertension (PH) and treatment of HF. A total of 99 client-owned dogs were included in this retrospective case-control study; 78 dogs were affected by MMVD and classified according to the American College of Veterinary Internal Medicine (ACVIM) guidelines, and 21 were healthy controls. For each dog, history, physical examination, complete blood count, biochemical profile, thoracic radiography, 6-lead standard electrocardiogram and trans-thoracic echocardiography were available. Comparisons were performed between groups of dogs belonging to different ACVIM stages and between dogs with and without PH. The median SDMA concentration was neither significantly different among groups of dogs in different disease stages (overall P = 0.010), nor among dogs with MMVD, nor between those with [14.5 μg/dl (10.5–18.8)] and without PH [13 μg/dl (9–17.2)] (P = 0.295). The concentration of SDMA did not differ between dogs when considering the combined effect of the ACVIM group and cardiac treatment (overall P = 0.486). Furthermore, no correlation was found between SDMA concentration and radiographic and echocardiographic parameters associated with increased MMVD severity. In conclusion, this study failed to demonstrate the presence of renal impairment in dogs with MMVD, and the increase in renal parameters in some dogs in the more advanced stage of MMVD could be attributed to pre-renal azotemia.

The chromogranin A-derived peptides catestatin and vasostatin in dogs with myxomatous mitral valve disease

BackgroundThe protein chromogranin A (CgA) is stored and co-released with catecholamines from the stimulated adrenal glands. Increased plasma concentrations of CgA have been shown in people with heart disease. The aim of the study was to investigate whether plasma concentrations of the CgA-derived biologically active peptides catestatin and vasostatin were associated with the severity of myxomatous mitral valve disease (MMVD) in dogs and to assess potential associations between these blood variables and dog characteristics, echocardiographic variables, heart rate (HR), blood pressure (BP) and plasma N-terminal-proBNP (NT-proBNP) concentration. Sixty-seven privately owned dogs with or without MMVD were included. The dogs underwent physical examination, blood pressure measurement, blood sample collection, and echocardiographic examination. Plasma concentrations of catestatin and vasostatin were analyzed using radioimmunoassay.ResultsCatestatin concentration decreased with increasing left atrial and ventricular size (R2 ≤ 0.09, P ≤ 0.019), and increased with increasing systolic and diastolic blood pressures (R2 ≤ 0.08, P ≤ 0.038). Regression analyses showed no significant associations for vasostatin. No differences in plasma concentrations of catestatin or vasostatin were found between the disease severity groups used in the study.ConclusionsIn the present dog population, the catestatin concentration showed weak negative associations with left atrial and ventricular sizes, both of which are known to increase with increasing severity of MMVD. Furthermore, the catestatin concentration showed weak positive associations with blood pressure.