Serum Serotonin Concentrations in Dogs with Degenerative Mitral Valve Disease

Background: Increased serotonin (5HT) signaling has been implicated in valvular disease of humans and animals, including canine degenerative mitral valve disease (DMVD). High circulating 5HT concentration is a potential source of increased signaling, and serum 5HT concentrations have not been previously reported in dogs with DMVD.
Hypothesis: Dogs with DMVD and small breed dogs predisposed to DMVD have higher serum 5HT concentrations than large breed controls.
Animals: Fifty dogs affected with DMVD, 34 dogs predisposed to DMVD but without cardiac murmur or echocardiographic evidence of DMVD, and 36 healthy large breed control dogs.
Methods: Prospective analysis. Serum 5HT concentration was measured by an ELISA test.
Results: Median serum 5HT concentration was significantly higher in dogs with DMVD and in dogs predisposed to DMVD as compared with controls (DMVD, 765.5 ng/mL [interquartile range, 561.3–944.4]; predisposed, 774.9 ng/mL [528.3–1,026]; control, 509.8 ng/mL [320.8–708.8]; P = .0001). Subgroup analysis of predisposed dogs indicated significantly higher serum 5HT concentrations in Cavalier King Charles Spaniel (CKCS) dogs than in other breeds (CKCS, 855.0 ng/mL [635.8–1,088]; non-CKCS, 554.2 ng/mL [380.6–648.4]; P = .0023). Age, platelet count, and platelet morphology were not correlated with 5HT concentration in any group.
Conclusions and Clinical Importance: Dogs with DMVD had significantly higher serum 5HT concentrations when compared with large breed control dogs. Healthy CKCS dogs had significantly higher serum 5HT concentrations than other healthy dogs predisposed to DMVD. Additional investigation into a possible role of 5HT in the pathogenesis of DMVD is warranted.     

Noninvasive Clinical Assessment of Systolic Torsional Motions by Two‐Dimensional Speckle‐Tracking Echocardiography in Dogs with Myxomatous Mitral Valve Disease

Background

Left ventricular torsional motion plays an important role for effective pump function. However, noninvasive clinical assessment of torsional deformations by two‐dimensional speckle‐tracking echocardiography (2D‐STE) in dogs with myxomatous mitral valve disease (MMVD) has not been reported.

Hypothesis

Left ventricular torsion is determined by the native orientation of the helical myocardial fibers, such that it might provide better assessment of myocardial function than conventional methods.

Animals

Sixty‐seven client‐owned dogs with MMVD were classified into 3 classes based on the International Small Animal Cardiac Health Council classification and 16 weight‐ and age‐matched healthy dogs.

Methods

Dogs were examined for myocardial deformations by 2D‐STE and were evaluated for peak systolic rotation and rotation rate at each basal and apical view. Dogs also were evaluated for peak systolic torsion and torsion rate.

Results

Peak systolic torsion was higher in class II than in class I (P < .001) dogs. Peak systolic torsion was lower in class III than in class II (P = .001) dogs and controls (P = .003).

Conclusions and Clinical Importance

Torsional deformations assessed by 2D‐STE differed among clinical classes of MMVD. Myocardial torsional deformations by 2D‐STE may provide more detailed assessment of contractile function in dogs with MMVD.     

Longitudinal Electrocardiographic Evaluation of Dogs with Degenerative Mitral Valve Disease

Background

Increased heart rate (HR) and decreased heart rate variability (HRV) are evident in some dogs with degenerative mitral valve disease (DMVD).

Objectives

Evaluation of the factors influencing HR and HRV (assessed by the vasovagal tonus index; VVTI) and their change over time in dogs with DMVD.

Animals

Client‐owned dogs (n = 257) with DMVD recruited from first opinion practice.

Methods

Prospective longitudinal follow‐up at six‐monthly intervals of dogs with DMVD. Dogs followed up for at least 18 months (n = 102) were grouped according to their outcome as dogs dying/euthanized because of cardiac disease (n = 28; Group 1), noncardiac disease (n = 40; Group 2) and dogs alive (n = 34; Group 3). HR and VVTI were measured on 1‐minute ECG recordings. Repeated measures linear models were constructed to investigate the factors that influence HR and VVTI and their changes over time.

Results

Heart rate and VVTI were affected by disease severity and were different in Cavaliers compared to other breeds. Group 1 and Group 2 dogs underwent an increase in HR and decrease in VVTI, evident at least 18 months before death. Group 1 had a further decrease in VVTI followed by an increase in HR approximately 1 year and 6 months before death, respectively.

Conclusions and Clinical Importance

Dogs with DMVD have an increase in HR and decrease in HRV over a year before death, with greater changes in those dogs dying/euthanized because of cardiac disease. Both HR and VVTI can potentially be regarded as biomarkers for all‐cause mortality.     

Biopterin Status in Dogs with Myxomatous Mitral Valve Disease is Associated with Disease Severity and Cardiovascular Risk Factors

Background

Endothelial dysfunction (ED) has been suggested to be associated with myxomatous mitral valve disease (MMVD) in dogs. Tetrahydrobiopterin (BH4) is an important cofactor for production of the endothelium‐derived vasodilator nitric oxide (NO). Under conditions of oxidative stress, BH4 is oxidized to the biologically inactive form dihydrobiopterin (BH2). Thus, plasma concentrations of BH2 and BH4 may reflect ED and oxidative stress.

Objective

To determine plasma concentrations of BH2 and BH4 in dogs with different degrees of MMVD.

Animals

Eighty‐four privately owned dogs grouped according to ACVIM guidelines (37 healthy control dogs including 13 Beagles and 24 Cavalier King Charles Spaniels [CKCSs], 33 CKCSs with MMVD of differing severity including 18 CKCSs [group B1] and 15 CKCSs [group B2], and 14 dogs of different breeds with clinical signs of congestive heart failure [CHF] because of MMVD [group C]).

Methods

Dogs underwent clinical examination including echocardiography. Plasma concentrations of BH2 and BH4 were measured using high‐performance liquid chromatography with fluorescence detection.

Results

Higher plasma BH4 and BH2 concentrations were found with dogs in CHF compared with all other groups (control, B1 and B2; P ≤ .001). Females had higher concentrations of BH4 and BH4/BH2 (P ≤ .0003). BH4/BH2 was found to decrease with age (P < .0001). Cardiovascular risk factors in humans such as passive smoking (P ≤ .01) and increased body weight (P ≤ .009) were associated with lower BH4 concentrations.

Conclusions and Clinical Importance

Age, sex, body weight, passive smoking, and cardiac status are associated with plasma biopterin concentration in dogs. Additional studies should clarify the clinical implications of the findings.     

Clinical Severity Score System in Dogs with Degenerative Mitral Valve Disease

Background

Several risk factors already have been determined for dogs with degenerative mitral valve disease (DMVD). Risk factors often have been considered in isolation and have not always taken into account additional information provided by the history and physical examination (PE).

Hypothesis/Objectives

Data obtained from history and PE of dogs with DMVD provide prognostic information and can be used for risk stratification.

Animals

Client‐owned dogs (n = 244) with DMVD recruited from first opinion practice.

Methods

Prospective longitudinal follow‐up of dogs with DMVD. History and PE data were obtained at 6‐month intervals and analyzed with time‐dependent Cox models to derive relative risk of cardiac death. Independent hazard ratios were used to derive a clinical severity score (CSS), the prognostic value of which was evaluated by analyzing the median survival times for different risk groups and ROC analysis. Analysis of the progression of CSS over time also was undertaken.

Results

History of cough, exercise intolerance, decreased appetite, breathlessness (difficulty breathing) and syncope with PE findings of heart murmur intensity louder than III/VI and absence of respiratory sinus arrhythmia were independently associated with outcome and allowed development of the CSS. Clinical severity score distinguished groups of dogs with significantly different outcomes.

Conclusions and Clinical Importance

Routinely obtained clinical findings allow risk stratification of dogs with DMVD. Results of ancillary diagnostic tests may be complementary to history and PE findings and always should be interpreted in conjunction with these findings.     

Longitudinal Analysis of Quality of Life,Clinical, Radiographic,Echocardiographic, and Laboratory Variables in Dogs with Preclinical Myxomatous Mitral Valve Disease Receiving Pimobendan or Placebo: The EPIC Study

Background

Changes in clinical variables associated with the administration of pimobendan to dogs with preclinical myxomatous mitral valve disease (MMVD ) and cardiomegaly have not been described.

Objectives

To investigate the effect of pimobendan on clinical variables and the relationship between a change in heart size and the time to congestive heart failure (CHF ) or cardiac‐related death (CRD ) in dogs with MMVD and cardiomegaly. To determine whether pimobendan‐treated dogs differ from dogs receiving placebo at onset of CHF .

Animals

Three hundred and fifty‐four dogs with MMVD and cardiomegaly.

Materials and Methods

Prospective, blinded study with dogs randomized (ratio 1:1) to pimobendan (0.4–0.6 mg/kg/d) or placebo. Clinical, laboratory, and heart‐size variables in both groups were measured and compared at different time points (day 35 and onset of CHF ) and over the study duration. Relationships between short‐term changes in echocardiographic variables and time to CHF or CRD were explored.

Results

At day 35, heart size had reduced in the pimobendan group: median change in (Δ) LVIDDN ?0.06 (IQR : ?0.15 to +0.02), P  < 0.0001, and LA :Ao ?0.08 (IQR : ?0.23 to +0.03), P  < 0.0001. Reduction in heart size was associated with increased time to CHF or CRD . Hazard ratio for a 0.1 increase in ΔLVIDDN was 1.26, P  = 0.0003. Hazard ratio for a 0.1 increase in ΔLA :Ao was 1.14, P  = 0.0002. At onset of CHF , groups were similar.

Conclusions and Clinical Importance

Pimobendan treatment reduces heart size. Reduced heart size is associated with improved outcome. At the onset of CHF , dogs treated with pimobendan were indistinguishable from those receiving placebo.

     

Prevalence and Prognostic Importance of Pulmonary Hypertension in Dogs with Myxomatous Mitral Valve Disease

Background

Pulmonary hypertension (PH) is common in dogs with myxomatous mitral valve disease (MMVD) but its effect on clinical outcome has not been investigated.

Hypothesis/objectives

The presence of PH worsens the outcome in dogs with MMVD. To compare survival times of dogs with MMVD and PH to those without PH.

Animals

Two hundred and twelve client‐owned dogs.

Methods

Case review study. Medical records of dogs diagnosed with ACVIM stage B2 and C MMVD between January 2010 and December 2011 were retrospectively reviewed. Long‐term outcome was determined by telephone interview or from the medical record. End of the observation period was March 2013. PH was identified if tricuspid regurgitation peak velocity was >3 m/s.

Results

Two hundred and twelve were identified. Eighty‐three dogs (39%) had PH. PH was more commonly identified in stage C compared to B2 (P < .0001). One hundred and five (49.5%) dogs died during the observation period. Median survival time for the entire study population was 567 days (95% CI 512–743). Stage C (P = .003), the presence of PH (P = .009), left atrial to aortic root ratio (LA/Ao) >1.7 (P = .0002), normalized left‐ventricular end‐diastolic diameter (LVEDn) >1.73 (P = .048), and tricuspid regurgitation pressure gradient (TRPG) >55 mmHg (P = .009) were associated with worse outcomes in the univariate analyses. The presence of TRPG >55 mmHg (HR 1.8 95% CI 1–2.9; P = .05) and LA/Ao > 1.7 (HR 2 95% CI 1.2–3.4; P = .01) remained significant predictors of worse outcome in the multivariate analysis.

Conclusions and Clinical Importance

In dogs with MMVD, moderate to severe PH worsens outcome.     

Evaluation of Pimobendan and N-Terminal Probrain Natriuretic Peptide in the Treatment of Pulmonary Hypertension Secondary to Degenerative Mitral Valve Disease in Dogs

Background: Pimobendan is a positive inotrope and vasodilator that may be useful in the treatment of pulmonary hypertension (PHT) secondary to degenerative mitral valve disease.
Hypothesis: Pimobendan decreases the severity of PHT measured echocardiographically and improves quality-of-life scores. Changes in N-terminal probrain natriuretic peptide (NT-proBNP) concentrations will reflect improvement in severity of PHT.
Animals: Ten client-owned dogs with peak tricuspid regurgitant flow velocity (TRFV) ≥3.5 m/s.
Methods: Prospective short-term, double-blinded, crossover design, with a long-term, open-label component. Short term, dogs were randomly allocated to receive either placebo or pimobendan (0.18–0.3 mg/kg PO q12 h) for 14 days. After a 1-week washout, they received the alternative treatment for 14 days, followed by pimobendan open-label for 8 weeks.
Results: Short-term comparison: peak TRFV decreased in all dogs on pimobendan compared with placebo from a median of 4.40 (range, 3.2–5.6) to 3.75 (range, 2.4–4.8) m/s ( P < .0001). NT-proBNP concentration decreased after treatment with pimobendan from a median of 2,143 (range, 450–3,981) to 1,329 (range, 123–2,411) pmol/L ( P = .0009). All dogs improved their quality-of-life score ( P = .006). In the long-term comparisons, peak TRFV decreased in all dogs from a median of 4.28 (range, 3.5–5.7) to 3.52 (range, 2.4–5.0) m/s ( P < .0001). No significant changes in NT-proBNP or quality-of-life scores were detected.
Conclusions and Clinical Importance: Pimobendan lowered severity of measurable PHT, improved quality-of-life scores, and decreased NT-proBNP concentrations short-term. Long term, only the reduction in TRFV was maintained.     

Efficacy of Spironolactone on Survival in Dogs with Naturally Occurring Mitral Regurgitation Caused by Myxomatous Mitral Valve Disease

Background: Spironolactone, an aldosterone antagonist, has been demonstrated to decrease mortality in human patients when added to other cardiac therapies. Hypothesis: Spironolactone in addition to conventional therapy increases survival compared with conventional therapy in dogs with naturally occurring myxomatous mitral valve disease (MMVD). Animals: Between February 2003 and March 2005, 221 dogs were recruited in Europe. Nine dogs were excluded from analysis, leaving 212 dogs with moderate to severe mitral regurgitation (MR) caused by MMVD (International Small Animal Cardiac Health Council classification classes II [n = 190] and III [n = 21]). Methods: Double‐blinded, field study conducted with dogs randomized to receive either spironolactone (2 mg/kg once a day) or placebo in addition to conventional therapy (angiotensin converting enzyme inhibitor, plus furosemide and digoxin if needed). Primary endpoint was a composite of cardiac‐related death, euthanasia, or severe worsening of MR. Results: Primary endpoint reached by 11/102 dogs (10.8%) in the spironolactone group (6 deaths, 5 worsening) versus 28/110 (25.5%) in control group (14 deaths, 8 euthanasia, 6 worsening). Risk of reaching the composite endpoint significantly decreased by 55% (hazard ratio [HR] = 0.45; 95% confidence limits [CL], 0.22–0.90; log rank test, P= .017). Risk of cardiac‐ related death or euthanasia significantly reduced by 69% (HR = 0.31; 95% CL, 0.13–0.76; P= .0071). Number of dogs not completing the study for cardiac and other miscellaneous reasons similar in spironolactone (67/102) and control groups (66/110). Conclusion and Clinical Importance: Spironolactone added to conventional cardiac therapy decreases the risk of reaching the primary endpoint (ie, cardiac‐related death, euthanasia, or severe worsening) in dogs with moderate to severe MR caused by MMVD.     

Epidemiology and Inheritance of Mitral Valve Prolapse in Dachshunds

One hundred ninety consecutive Dachshunds >2 years of age, including 18 families consisting of both parents and 4 or more offspring, were examined clinically and echocardiographically to study the epidemiology and inheritance of mitral valve prolapse (MVP) and other signs of myxomatous mitral valve disease in the dog. From video-recorded echocardiograms, MVP severity, jet size (color Doppler), and leaflet thickness were assessed. With regard to murmur intensity and each of these 3 echocardiographic measurements. the inheritance and the influence of age, gender, coat type, body weight, degree of obesity, heart rate, and thorax dimensions were evaluated. MVP severity correlated positively with age (P < .0001) and heart rate (P = .002), negatively with thorax circumference (P = .0005), and was related to coat type (P = .006). MVP severity progressed faster in males than in females (P = .0002). The other measures of disease severity (jet size, leaflet thickness, and murmur intensity) also correlated positively with age (all P < .0001). When compared in pairs, all 4 measures of disease severity correlated significantly with one other. Pedigree analyses did not disclose agreement with simple Mendelian models, but high disease prevalence made interpretation difficult. Mean parental MVP severity correlated significantly with MVP severity in the offspring (P = .03). The epidemiology of MVP in Dachshunds resembles that of MVP in humans, MVP severity correlates significantly with other measures of the degree of myxomatous mitral valve disease, and MVP is an inherited condition in Dachshunds. A polygenic mode of inheritance is suggested.     

Size and Shape of Right Heart Chambers in Mitral Valve Regurgitation in Small-Breed Dogs

Background: The contribution of right heart (RH) chamber enlargement to general heart enlargement seen on thoracic radiographs in mitral regurgitation (MR) is not known.
Objectives: To determine the size and shape of the RH chambers in normal dogs and dogs with varying degrees of MR.
Animals: Fifty-four privately owned dogs: 13 normal, 41 with varying degrees of MR including 25 with congestive heart failure (CHF).
Methods: Archived first pass radionuclide angiocardiograms were used to produce static images of the RH and left heart (LH) chambers. Indexes of size and shape of the RH and LH chambers were related to severity of MR determined by heart rate-normalized pulmonary transit time (nPTT), vertebral heart scale (VHS), and clinical status. RH shape was measured by a circularity index of RH short axis/long axis.
Results: A 2nd degree polynomial fit best described the ratios; RH/LH dimension to nPTT ( R ²= 0.62) and to VHS ( R ²= 0.43), RH/LH area to nPTT ( R ²= 0.64) and to VHS ( R ²= 0.58), all P < .001. RH circularity was decreased in CHF, P < .001. In CHF, the RH chambers of 16 dogs were both flattened and enlarged, whereas 9 had convex septal borders.
Conclusions: RH chambers are not significantly dilated in dogs with mild to moderate MR without CHF. In CHF, RH chambers enlarge and also may be compressed by the LH chambers. Pulmonary hypertension probably is present in some dogs with CHF. Increased sternal contact is not a useful sign of right-sided heart dilatation in MR.