Comparison of N-terminal pro-atrial natriuretic peptide and three cardiac biomarkers for discriminatory ability of clinical stage in dogs with myxomatous mitral valve disease

Plasma N-terminal pro-atrial natriuretic peptide (NT-proANP) concentration increases with progression of myxomatous mitral valve disease (MMVD) in dogs. This multicentre, prospective study compared plasma NT-proANP, N-terminal pro-brain natriuretic peptide (NT-proBNP), ANP, and cardiac troponin I (cTnI) concentrations in dogs with MMVD for their characteristics and discriminatory ability to detect cardiac dilatation and congestive heart failure (CHF). Thirty-six healthy dogs and 69 dogs with MMVD were included. Clinical variables were obtained via physical examination, thoracic radiography, and echocardiography. The discriminatory ability of each cardiac biomarker (CB) to determine the presence or absence of cardiac dilatation (event 1) and CHF (event 2) was evaluated using the receiver operating characteristic curves. Plasma NT-proANP, NT-proBNP, and ANP concentrations showed a significant association with the left atrium/aorta ratio (P<0.01). The area under the curve of plasma NT-proANP and NT-proBNP concentrations were 0.72 and 0.75, respectively in event1 and 0.72 and 0.76, respectively in event2. Plasma NT-proANP and NT-proBNP concentrations showed sensitivity 80.0 and 80.0%; specificity 67.6 and 64.7% in event1 (cutoff value; 8,497.81 pg/ml and 1,453.00 pmol/l, respectively) and sensitivity 85.7 and 81.0%; specificity 60.4 and 64.6% in event2 (cutoff value; 8,684.33 pg/ml and 1,772.00 pmol/l, respectively). In dogs with MMVD, plasma NT-proANP, NT-proBNP, and ANP concentrations increase with left atrial enlargement. Particularly, plasma NT-proANP and NT-proBNP concentrations appeared to be equally useful in the discriminatory ability to detect cardiac dilatation and CHF.     

Tissue Doppler and Strain Imaging in Dogs with Myxomatous Mitral Valve Disease in Different Stages of Congestive Heart Failure

Background: Tissue Doppler imaging (TDI) including strain and strain rate (SR) assess systolic and diastolic myocardial function.
Hypothesis: TDI, strain, and SR variables of the left ventricle (LV) and the interventricular septum (IVS) differ significantly between dogs with myxomatous mitral valve disease (MMVD) with and without congestive heart failure (CHF).
Animals: Sixty-one dogs with MMVD with and without CHF. Ten healthy control dogs.
Methods: Prospective observational study.
Results: Radial motion : None of the systolic variables were altered and 3 of the diastolic velocities were significantly increased in dogs with CHF compared with dogs without CHF and control dogs. Longitudinal motion : 2 systolic velocities and 3 diastolic velocities were significantly increased in dogs with CHF compared with dogs without CHF and control dogs. Difference in systolic velocity time-to-peak between LV and IVS was significantly increased in dogs with MMVD with and without CHF compared with control dogs. In total, 11 (23%) of 48 TDI and strain variables differed significantly between groups. Left atrial to aortic ratio was positively correlated to early diastolic velocities, percentage increase in left ventricular internal diameter in systole was positively correlated to systolic and diastolic velocities, and mitral E wave to peak early diastolic velocity in the LV basal segment (E/Em) was positively correlated to radial strain and SR.
Conclusions and Clinical Importance: Few TDI and strain variables were changed in dogs with MMVD with and without CHF. Intraventricular dyssynchrony may be an early sign of MMVD or may be an age-related finding.     

Left atrial deformation and phasic function determined by two-dimensional speckle-tracking echocardiography in dogs with myxomatous mitral valve disease

Introduction

Left atrial (LA) function can provide useful information in dogs with myxomatous mitral valve disease (MMVD). Recently, we have demonstrated the feasibility of measuring LA longitudinal deformation using speckle-tracking echocardiography (STE) to estimate LA function in healthy dogs. Whether LA strain and strain rate variables provide additional information about LA function and clinical cardiac status in dogs with MMVD remains unexplored.

The diagnostic relevance of NT‐proBNP and proANP 31–67 measurements in staging of myxomatous mitral valve disease in dogs

Background

There is no agreement in current publications regarding the reliability of serum concentrations of natriuretic peptides (NPs) to detect dogs with subclinical myxomatous mitral valve disease (MMVD) and to differentiate between asymptomatic stages.

Objectives

We sought to compare N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and pro‐atrial natriuretic peptide 31‐67 (proANP) concentrations between various stages of canine MMVD and to investigate the influence of age, weight, and sex.

Methods

In this prospective study, dogs were classified in different disease stages using the modified Canine Heart failure International Expert Forum (CHIEF) system. Serum NP concentrations were compared between groups.

Results

A total of 559 samples from 116 healthy dogs and 236 dogs with MMVD were analyzed. Using cut‐off values (1207 pmol/L for NT‐proBNP, 1578 fmol/mL for proANP), dogs with MMVD with and without congestive heart failure (CHF) could be differentiated with a sensitivity of 83% for both and specificities of 85% and 86%, respectively. Dogs staged in CHIEF B1 and B2 could not be distinguished based on NP concentrations due to wide variation within the groups. Intact females (means 598 pmol/L and 1036 fmol/mL, respectively) had significantly higher values of both NPs than intact males (315 pmol/L and 836 fmol/mL).

Conclusions

NPs in canine MMVD are useful to discriminate between asymptomatic dogs and dogs with CHF. Due to a large overlap of NP‐concentrations between the groups, NPs do not seem to be useful to differentiate between dogs in stages B1 and B2. Interpretation of NT‐proBNP and proANP values should include consideration of sex‐specific differences.     

Change of Vertebral Left Atrial Size in Dogs With Preclinical Myxomatous Mitral Valve Disease Prior to the Onset of Congestive Heart Failure

Introduction/objectivesIt has been proposed that vertebral left atrial size (VLAS) on thoracic radiographs can be used to assess the left atrial enlargement in dogs with myxomatous mitral valve disease (MMVD). However, it remains unclear whether VLAS can be used to distinguish dogs between pre-clinical MMVD that are at a greater risk of developing congestive heart failure (CHF) from those at a lower risk. We investigated this possibility.Animals, materials and methodsForty-one dogs with MMVD were retrospectively classified into one of two groups, a group that developed CHF (group CHF, n = 17) or remained CHF-free (group no-CHF, n = 24). The value of vertebral heart scale (VHS) and VLAS at three time-points, change in VHS and VLAS at a specific time interval (ΔVHS, ΔVLAS) and rate of change in the values per month (ΔVHS/month, ΔVLAS/month) were compared.ResultsAt the first visit, there were no significant differences in VLAS between the groups. At the median of 105 (interquartile ranges 83–155) days prior to the onset of CHF (group CHF) or the last visit (group no-CHF), VLAS was significantly higher in group CHF (mean, 2.9; standard deviation ± 0.4) than in group no-CHF (2.6 ± 0.3) (p = 0.028). ΔVLAS/month (area under the curve, 0.91; p<0.001) showed high diagnostic accuracy in distinguishing which dogs would develop CHF within 180 days and which would not.ConclusionsVLAS and ΔVLAS/month in dogs with pre-clinical MMVD may be useful to identify dogs at risk of developing CHF within the next 180 days.     

Diagnostic and prognostic utility of surface electrocardiography in cats with left ventricular hypertrophy

Objectives

To assess the ability of electrocardiography (ECG) to predict left ventricular hypertrophy (LVH) in the cat and to investigate the prognostic value of selected ECG variables in cats with LVH.

Plasma adrenomedullin concentration in dogs with myxomatous mitral valvular disease

Adrenomedullin (AM), a peptide identified to have vasodilating and natriuretic effects, is involved in the regulation of the cardiovascular system. To evaluate plasma AM concentration in dogs with myxomatous mitral valvular disease (MMVD), and to investigate the associations between the concentrations of plasma AM and natriuretic peptides and the echocardiographic data, we evaluated plasma AM concentrations in 31 healthy control dogs and 57 dogs with MMVD. Plasma AM concentrations in dogs with MMVD were higher than that in the control subjects. The plasma AM concentration increased in conjunction with the severity of heart failure according to the International Small Animal Cardiac Health Council (ISACHC). The AM concentrations were 25.1 ± 5.0 fmol/ml (ISACHC class Ia), 29.9 ± 11.0 fmol/ml (ISACHC class Ib), 43.4 ± 19.8 fmol/ml (ISACHC class II) and 73.5 ± 21.7 fmol/ml (ISACHC class III) and 7.5 ± 5.1 fmol/ml (control group), respectively. The receiver operating characteristic curve indicated an area of 0.93 (95% CI, 0.8801-0.9889; <0.0001), a cutoff value of 30.5 fmol/ml, a sensitivity of 87.1%, and a specificity of 82.5% for the determination of congestive heart failure. Plasma AM concentrations correlated with atrial natriuretic peptide concentrations, LA/Ao ratio, and left ventricular diameter. In conclusion, AM may be a potential diagnostic marker for canine MMVD and possibly plays a pathophysiological role in collaboration with the other neurohumoral factors such as natriuretic peptides.     

Retrospective evaluation of notched and fragmented QRS complex in dogs with naturally occurring myxomatous mitral valve disease

Myxomatous mitral valve disease (MMVD) is the most common cardiac disease in dogs. The association of QRS notching (nQRS) or fragmentation (fQRS) with disease severity is currently unknown. The study objective was to assess the prevalence of nQRS and fQRS in dogs with MMVD and its severity according to ACVIM classification and to compare the results with a group of healthy dogs. This retrospective cross-sectional study included 34 healthy control dogs and 155 dogs with spontaneous MMVD (42% of dogs in class B1, 23% in class B2 and 35% in class C). fQRS was defined as nQRS complexes in two contiguous leads in the frontal plane (leads I and aVL) and (II, III or aVF). A one-way ANOVA with Bonferroni post-hoc test was used to assess the differences in continuous data between control and MMVD groups. Of the MMVD group, 58% showed nQRS in at least one lead and 27% presented fQRS. There was no difference between the number of leads with a nQRS and disease severity (p = 0.75) nor did the number of leads with a nQRS correlate with left atrial size (r = 0.48; p = 0.5). The number of dogs with fQRS did not differ among classes of MMVD (p = 0.21). nQRS and fQRS were more prevalent in dogs with MMVD compared to control dogs (p < 0.01). This study did not identify any relationship between the number of leads with a nQRS and disease severity. However, dogs with MMVD had a higher prevalence of nQRS and fQRS compared to control group.     

Two-dimensional echocardiographic estimates of left atrial function in healthy dogs and dogs with myxomatous mitral valve disease

Objectives

To provide reference intervals for 2-dimensional linear and area-based estimates of left atrial (LA) function in healthy dogs and to evaluate the ability of estimates of LA function to differentiate dogs with subclinical myxomatous mitral valve disease (MMVD) and similarly affected dogs with congestive heart failure (CHF).

Effect of atorvastatin on oxidative stress and inflammation markers in myxomatous mitral valve disease in dogs: A comparison of subclinical and clinical stages

Myxomatous mitral valve disease (MMVD) is the most common acquired cardiac disorder found in dogs. The disease process can lead to heart failure (HF) and has been found to be associated with oxidative stress and inflammation. Statins exert antioxidant and anti‐inflammatory effects in human HF patients. However, the beneficial effects of statins in MMVD dogs are still unclear. Thirty MMVD dogs were enrolled in the study and were divided into two groups: MMVD without HF dogs (n = 15) and MMVD with HF dogs (n = 15). Atorvastatin (8 mg kg^?1 day^?1) was administered orally to all dogs for 4 weeks. All dogs underwent physical examination and cardiac examination at the beginning and end of the experiment, including baseline values for hematology, blood chemistry profile, lipid profile, N‐terminal pro B‐type natriuretic peptide, oxidative stress marker (8‐isoprostane), and inflammatory marker (tumor necrosis factor alpha). The results showed that atorvastatin reduced plasma cholesterol levels in both groups. In addition, plasma concentrations of 8‐isoprostane, tumor necrosis factor alpha, and N‐terminal pro B‐type natriuretic peptide were significantly lower after atorvastatin administration, but only in MMVD dogs in the HF group. Atorvastatin found to be associated with possible antioxidant and inflammatory effects in dogs with HF secondary to MMVD. The potential benefits of statins in dogs with HF merits further investigation in larger, placebo‐controlled studies.     

Comparison of different radiographic scores with associated echocardiographic measurements and prediction of heart enlargement in dogs with and without myxomatous mitral valve disease

IntroductionStaging of myxomatous mitral valve disease (MMVD) requires an echocardiographic examination along with thoracic radiographs. The aims of this study were to calculate mean values for radiographic scores vertebral heart size (VHS), left atrial width (LA_Width), radiographic left atrial dimension (RLAD), and vertebral left atrial size (VLAS) in conventional and grayscale inverted images in healthy dogs and dogs with different stages of MMVD, and to find cutoff values for a stage assignment.AnimalsOne hundred fifty dogs in different stages of MMVD and 50 unaffected dogs were evaluated.MethodsRadiographic scores, echocardiographic left atrium-to-aorta ratio and normalized left ventricular internal dimension at end-diastole, and results of a clinical examination were obtained. Analyses were performed to evaluate the correlation between radiographic scores and echocardiographic values, to determine cutoff values for a radiographic stage assignment, and to compare measurements in conventional and inverted radiographs.ResultsAfter excluding breed-specific higher VHS, the means of VHS, LA_Width, RLAD, and VLAS were similar in the control group and stage B1. All radiographic scores increased in stages B2 and C. The cutoff values identifying heart enlargement, and therefore differentiating stages B1 and B2, were 11.0 for VHS, 1.8 for LA_Width, 2.0 for RLAD, and 2.3 for VLAS. Besides RLAD, scores were similar in conventional and inverted radiographs.ConclusionCutoff values for the different radiographic scores for stage assignment were calculated. Radiographic cardiac scores using either conventional or inverted grayscale could be a tool to differentiate between different stages of MMVD when echocardiography is unavailable.     

Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST study

Background: Myxomatous mitral valve disease (MMVD) continues to be an important cause of morbidity and mortality in geriatric dogs despite conventional therapy. Hypothesis: Pimobendan in addition to conventional therapy will extend time to sudden cardiac death, euthanasia for cardiac reasons, or treatment failure when compared with conventional therapy plus benazepril in dogs with congestive heart failure (CHF) attributable to MMVD. Animals: Two hundred and sixty client‐owned dogs in CHF caused by MMVD were recruited from 28 centers in Europe, Canada, and Australia. Methods: A prospective single‐blinded study with dogs randomized to PO receive pimobendan (0.4–0.6 mg/kg/d) or benazepril hydrochloride (0.25–1.0 mg/kg/d). The primary endpoint was a composite of cardiac death, euthanized for heart failure, or treatment failure. Results: Eight dogs were excluded from analysis. One hundred and twenty‐four dogs were randomized to pimobendan and 128 to benazepril. One hundred and ninety dogs reached the primary endpoint; the median time was 188 days (267 days for pimobendan, 140 days for benazepril hazard ratio = 0.688, 95% confidence limits [CL] = 0.516–0.916, P= .0099). The benefit of pimobendan persisted after adjusting for all baseline variables. A longer time to reach the endpoint was also associated with being a Cavalier King Charles Spaniel, requiring a lower furosemide dose, and having a higher creatinine concentration. Increases in several indicators of cardiac enlargement (left atrial to aortic root ratio, vertebral heart scale, and percentage increase in left ventricular internal diameter in systole) were associated with a shorter time to endpoint, as was a worse tolerance for exercise. Conclusions and Clinical Importance: Pimobendan plus conventional therapy prolongs time to sudden death, euthanasia for cardiac reasons, or treatment failure in dogs with CHF caused by MMVD compared with benazepril plus conventional therapy.     

QT instability,an indicator of augmented arrhythmogenesis,increases with the progression of myxomatous mitral valve disease in dogs

Objectives

To investigate QT instability in dogs with myxomatous mitral valve disease (MMVD) and to determine if this is associated with arrhythmogenesis.

Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease

Objective

Myxomatous mitral valve disease (MMVD) induces progressive left atrial (LA) enlargement. The LA modulates left ventricular filling and performance through its reservoir, conduit, and contractile function. Assessment of LA size and function may provide valuable information on the level of cardiac compensation. Left atrial function in dogs with naturally occurring MMVD remains largely unexplored. The objective of this study was to evaluate LA volume and function in dogs with naturally occurring MMVD.

Circulating cytokine concentrations in dogs with different degrees of myxomatous mitral valve disease

Cytokines have been associated with the progression of congestive heart failure (CHF) in humans and may be implicated in the pathophysiology of myxomatous mitral valve disease (MMVD) in dogs. The aim of this study was to determine the serum concentrations of cytokines in dogs with MMVD. The study included 16 Cairn terriers with no or minimal mitral regurgitation (MR), 41 Cavalier King Charles Spaniels (CKCS) with different degrees of MR and 11 dogs of different breeds with CHF due to MMVD. Granulocyte-macrophage colony-stimulating factor, interferon-γ, interleukin (IL)-2, IL-6, IL-7, IL-8, IL-10, IL-15, IL-18, keratinocyte-derived chemokine, interferon-γ-induced protein and monocyte chemoattractant protein-1 (MCP-1) were measured using a canine-specific multiplex immunoassay. CHF dogs had significantly higher MCP-1 concentrations than dogs with no or minimal MR. Among the CKCS, IL-2 and IL-7 decreased with increasing left atrial size and IL-7 also decreased with increasing MR. IL-8 decreased with increasing left ventricular end-systolic internal dimensions. MCP-1 was increased in CHF dogs compared to healthy control dogs and IL-2, IL-7 and IL-8 decreased with increasing indices of disease severity. The results suggest a role for these cytokines in canine MMVD and CHF.     

Heart rate variability parameters of myxomatous mitral valve disease in dogs with and without heart failure obtained using 24-hour Holter electrocardiography

Time-domain heart rate variability (HRV) parameters and the correlation between echocardiography and Holter examinations in dogs with myxomatous mitral valve disease (MMVD) were determined. Holter examination was also performed at different time frames: an entire 24-hour period, a four-hour period during sleep, and a four-hour period while awake. Ten healthy (control group) and 28 MMVD dogs, 15 with and 13 without heart failure, were evaluated. The SDANN (sd of the mean normal RR intervals for all five-minute segments during 24-hour Holter) and pNN(50) (percentage of differences between adjacent normal RR intervals that are >50 ms computed over 24-hour Holter) variables were significantly lower in the dogs with MMVD heart failure. The differences in HRV between the groups were only detected during the 24-hour evaluation period (P<0.05). There were high correlations (canonical analysis) between Holter and echocardiography examinations when considering pNN(50), SDANN, and LA/AO (left atrial to aortic root ratio) (r=0.92; P<0.05), indicating that both are important in evaluating MMVD dogs. SDANN and pNN(50) are measures of parasympathetic control of the heart, and thus, it is possible to infer that the MMVD dogs exhibit parasympathetic withdrawal during the development of heart failure.     

Risk Factors for Coughing in Dogs with Naturally Acquired Myxomatous Mitral Valve Disease

Background

Cough often is reported as the primary clinical sign of congestive heart failure (CHF) in dogs with chronic degenerative myxomatous mitral valve disease (MMVD). Concurrent airway disease and compression of the left mainstem bronchus by a large left atrium also have been proposed as potential causes of coughing in these patients.

Objectives

To investigate the association between the presence of coughing and different potential causes of cough, including CHF, abnormal radiographic airway pattern, and cardiomegaly in dogs affected by naturally acquired MMVD.

Animals

Two hundred six client‐owned dogs.

Methods

Retrospective analysis performed on medical records of dogs affected by MMVD that underwent full cardiac evaluation, including echocardiographic examination and thoracic radiography.

Results

Univariate analyses showed that CHF is not a predictor of coughing (OR = 1.369; 0.723, 2.594), whereas abnormal radiographic airway pattern (OR = 3.650; 2.051, 6.496) and increased left atrial size observed radiographically (OR = 3.637; 1.904, 6.950) or echocardiographically (OR = 2.553; 1.436, 4.539) were significantly associated with coughing in dogs with MMVD. The same risk factors were significant in multivariate analyses.

Conclusions and Clinical Importance

This study indicates that CHF is not significantly associated with coughing in dogs with MMVD. Instead, abnormal radiographic airway pattern and left atrial enlargement are associated with coughing in these patients. This important finding should be taken into account when considering diagnosis and clinical management of CHF in these dogs.     

Holter monitoring in 36 dogs with myxomatous mitral valve disease

Objective Describe the presence of arrhythmias in dogs with myxomatous mitral valve disease (MMVD) and the potential association with class of heart failure and left atrial enlargement. Compare the standard electrocardiogram (ECG) with Holter monitoring for assessing heart rate (HR). Experimental procedure The study group of 36 dogs weighing less than 20 kg was divided into MMVD and no clinical signs (preclinical) or MMVD and clinical signs (clinical). A standard echocardiogram, ECG and 24-h Holter recording were obtained in all dogs. Results Minimum and mean Holter HRs were higher in the clinical group than in the preclinical group. Clinical dogs had more ventricular arrhythmias than preclinical dogs. An enlarged left atrium was associated with the presence of more supraventricular arrhythmias. Conclusions Arrhythmias are a common finding in dogs with MMVD and Holter monitoring is a reliable tool for both HR monitoring and diagnosis.     

Long QT syndrome in dogs with tick toxicity (Ixodes holocyclus)

OBJECTIVE: To evaluate cardiac electrical function in dogs with tick toxicity. DESIGN: A prospective clinical investigation of 39 client-owned dogs treated for naturally occurring tick toxicity. PROCEDURE: An ECG was performed on each dog on several occasions; at admission to hospital with tick toxicity, 24 h later, at discharge from hospital when clinically normal and approximately 12 months later. RESULTS: The mean QT interval corrected for heart rate (QTc) was prolonged at admission, 24 h and at discharge compared to the QTc measured 12 months later. T wave morphology was altered in dogs at admission. All other parameters were within normal limits. CONCLUSIONS: The prolonged QTc interval and altered T wave morphology of dogs with tick toxicity reflects delayed cardiac repolarisation and is comparable with long QT syndrome (LQTS) in people who are predisposed to polymorphic ventricular tachycardia and sudden death. Resolution of ECG changes lagged behind clinical recovery.     

Evaluation of the bromosulfophthalein 30-minute retention test for the diagnosis of hepatic disease in dogs

The purpose of this study was to evaluate efficacy of bromosulfophthalein (BSP) retention testing in dogs with and without histopathologically confirmed hepatobiliary disease. Medical records of 150 dogs with hepatobiliary disease having both a BSP test and hepatic biopsy were retrieved. Histopathologic slides of liver tissue were reviewed, and dogs were classified according to 1 of 11 histopathologic categories. Twenty-five clinically normal random-source dogs were used as controls for hepatic biopsy and BSP testing. No dogs suffered adverse effects due to BSP administration. BSP retention was significantly (P < .05) higher in hospitalized (13.9%) than control (3.2%) dogs, but the test could not distinguish between hospitalized dogs with different types of hepatobiliary disease. Sensitivity, specificity, and predictive values of BSP retention as a test for hepatic disease were calculated. Using 5.0% as a cutoff for normal BSP retention resulted in a specificity of 88% and a sensitivity of 76%. Using 6.0% as a cutoff for normal BSP retention resulted in a specificity of 100% and a sensitivity of 70%. Dogs of this study having BSP retention of >6% had at least an 86% chance of having an abnormal liver. We concluded that continued use of BSP retention testing is warranted as a noninvasive diagnostic test for liver disease in dogs.