Melanie J. Hezzell

The Combined Prognostic Potential of Serum High-Sensitivity Cardiac Troponin I and N-Terminal pro-B-Type Natriuretic Peptide Concentrations in Dogs with Degenerative Mitral Valve Disease

BACKGROUND Identification of factors associated with decreased survival in dogs with degenerative mitral valve disease (DMVD) will allow more accurate prognosis. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is negatively associated with survival in dogs with DMVD. In human patients, multimarker strategies provide superior risk stratification compared with single markers. HYPOTHESIS High-sensitivity cardiac troponin I (hscTnI) and other clinical variables will be associated with survival time in dogs with DMVD. Measuring hscTnI and NT-proBNP in combination will be prognostically superior to measurement of either marker alone. The rate of change of these markers will vary according to cause of death. ANIMALS Client-owned dogs (n = 202) with DMVD of varying severity and age-matched healthy control dogs (n = 30) recruited from first opinion private practice. METHODS Prospective cohort study relating clinical variables at enrollment in dogs with DMVD to survival time (all-cause, cardiac, and noncardiac mortality). Multivariable Cox regression analysis was used to identify factors associated with survival. Measurements were obtained approximately every 6 months. Repeated measures models were constructed to assess changes over time. RESULTS hscTnI, LVEDDN, heart rate, and age were independently associated with decreased survival time (all-cause mortality). Survival times were shortest in dogs in which both serum hscTnI and NT-proBNP were increased. hscTnI and NT-proBNP increased more rapidly in dogs that died of cardiac disease. CONCLUSIONS AND CLINICAL IMPORTANCE Serum hscTnI has prognostic value in dogs with DMVD. Measurement of NT-proBNP and hscTnI is prognostically superior to measuring either alone. Serial measurement strategies provide additional prognostic information.

Selected echocardiographic variables change more rapidly in dogs that die from myxomatous mitral valve disease

OBJECTIVES To determine if echocardiographic measurements change at a greater rate in dogs with myxomatous mitral valve disease (MMVD) that die of cardiac mortality. ANIMALS Client-owned dogs (n = 242) with MMVD of varying severity were recruited from first opinion private practice. Only dogs which died during the study period (n = 102) were included in statistical analyses. METHODS Prospective cohort study comparing the rate of change of echocardiographic variables between dogs that experienced cardiac mortality and those that experienced non-cardiac mortality. Measurements were repeated approximately every 6 months and repeated measures linear models were constructed to estimate the rate of change of each variable over time. RESULTS Left ventricular (LV) end-diastolic diameter, normalized for body weight (LVEDDN) increased over time in both mortality groups. LV end-systolic diameter, normalized for body weight (LVESDN), LV end-diastolic diameter to LV free wall thickness in diastole (LVEDD/LVFWd) ratio, E wave velocity, E- to A-wave velocity ratio and left atrial to aortic root diameter ratio all increased over time in the cardiac mortality group, but did not change in the non-cardiac mortality group. MR velocity decreased over time in the cardiac mortality group but did not change in the non-cardiac mortality group. Tricuspid regurgitation jet velocity increased over time in both mortality groups. A wave velocity and fractional shortening did not change over time in either mortality group. CONCLUSIONS Serial echocardiographic examination every 6-12 months is useful to identify dogs with progressive MMVD that are at increased risk of cardiac mortality.

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.

Relationships between heart rate and age, bodyweight and breed in 10,849 dogs.

OBJECTIVES To evaluate relationships between heart rate and clinical variables in healthy dogs and dogs examined at a referral hospital. METHODS Clinical data were extracted from the electronic patient records of a first opinion group (5000 healthy dogs) and a referral hospital (5849 dogs). Univariable and multi-variable general linear models were used to assess associations between heart rate and clinical characteristics. Separate multi-variable models were constructed for first opinion and referral populations. RESULTS In healthy dogs, heart rate was negatively associated with bodyweight (P<0.001) but was higher in Chihuahuas. The mean difference in heart rate between a 5 and 55 kg dog was 10.5 beats per minute. In dogs presenting to a referral hospital, heart rate was negatively associated with bodyweight (P<0.001) and the following breeds; border collie, golden retriever, Labrador retriever, springer spaniel and West Highland white terrier and positively associated with age, admitting service (emergency and critical care, emergency first opinion and cardiology) and the following breeds; Cavalier King Charles spaniel, Staffordshire bull terrier and Yorkshire terrier. CLINICAL SIGNIFICANCE Bodyweight, age, breed and disease status all influence heart rate in dogs, although these factors account for a relatively small proportion of the overall variability in heart rate.

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.

Associations among serum N-terminal procollagen type III concentration, urinary aldosterone-to-creatinine ratio, and ventricular remodeling in dogs with myxomatous mitral valve disease

OBJECTIVE To assess relationships among serum N-terminal procollagen type III concentration, urinary aldosterone-to-creatinine concentration ratio (UAC), and clinical variables in dogs with myxomatous mitral valve disease (MMVD) and healthy dogs. ANIMALS 162 dogs with MMVD and 24 healthy control dogs of comparable age and body weight. PROCEDURES Blood and urine samples were collected from each dog. Dogs with MMVD underwent echocardiography and ECG. Ventricular diameter measurements were normalized for body weight. Serum N-terminal procollagen type III and urinary aldosterone concentrations were measured via radioimmunoassay. Each dog was examined on 1 to 3 occasions. Examinations were repeated at approximately 6-month intervals. RESULTS Serum N-terminal procollagen type III concentration decreased with increasing severity of MMVD and was negatively associated with age and left ventricular end-diastolic and end-systolic diameters. The UAC increased with prior percentage change in left ventricular end-diastolic diameter per month, subsequent percentage change in left ventricular end-systolic diameter per month, and treatment with diuretics and was negatively associated with age. Both UAC and serum N-terminal procollagen type III concentration were higher in Cavalier King Charles Spaniels than in other breeds when other measured variables were controlled for. CONCLUSIONS AND CLINICAL RELEVANCE In dogs with MMVD, echocardiographic indicators of left ventricular remodeling appeared to be associated with a decrease in serum concentration of a marker of collagen type III turnover and an increase in urinary aldosterone concentration.

Associations between N-terminal procollagen type III, fibrosis and echocardiographic indices in dogs that died due to myxomatous mitral valve disease

OBJECTIVES To evaluate associations between N-terminal procollagen type III (PIIINP), a serum biomarker of collagen biosynthesis, and myocardial fibrosis in dogs with naturally-occurring myxomatous mitral valve disease (MMVD). ANIMALS Twenty-two dogs with echocardiographically-confirmed MMVD were prospectively recruited from a hospital population. All died as a result of MMVD and their hearts were available for post mortem examination. METHODS Echocardiographic measurements and serum PIIINP concentrations were obtained from all dogs prior to death or euthanasia. Serum PIIINP concentrations (μg/mL) were measured using a validated commercially available radioimmunoassay. Myocardial tissue samples were collected post mortem and myocardial fibrosis was scored. The average fibrosis score for all cardiac sites in the heart was designated the global fibrosis score (GFS). The average fibrosis score for all papillary muscle sites was designated the papillary fibrosis score (PFS). Univariate and multivariate linear regression analyses were used separately to evaluate associations between GFS and PFS, respectively, and PIIINP and echocardiographic variables. RESULTS Left ventricular end-diastolic diameter normalized for body weight (LVEDDN) and PIIINP were weakly independently positively associated with both GFS and PFS. LVEDDN and PIIINP were weakly negatively correlated. CONCLUSIONS Both LVEDDN and serum PIIINP increase with increasing fibrosis score, although these relationships were not strong enough to be clinically useful. Although LVEDDN and PIIINP were positively correlated with fibrosis, PIIINP decreased with increasing LVEDDN, suggesting a complex interplay between fibrosis and remodeling in MMVD.

Effect of prespecified therapy escalation on plasma NT-proBNP concentrations in dogs with stable congestive heart failure due to myxomatous mitral valve disease

Background Treatment targeted to achieve reduction in N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) improves outcomes in human congestive heart failure (CHF) patients. Hypothesis A pre‐specified therapeutic algorithm that increased diuretic or pimobendan usage will reduce plasma NT‐proBNP concentrations in dogs with CHF secondary to myxomatous mitral valve disease (MMVD). Animals Twenty‐six dogs with clinically stable CHF secondary to MMVD. Methods Prospective, controlled before‐and‐after study. Dogs were examined up to 3 times over 21 days. Treatment was prescribed based on NT‐proBNP as follows: <1500 pmol/L at baseline, no treatment adjustment at any point during the study (group 1); ≥1500 pmol/L and creatinine ≤3.0 mg/dL at baseline or SC visits, treatment escalated according to the algorithm (group 2); ≥1500 pmol/L at baseline, no treatment adjustment (group 3). Results N‐terminal pro‐B‐type natriuretic peptide decreased significantly in group 2 (mean change = −1736 pmol/L (95% CI, −804 to −2668), P < .001) but not in groups 1 or 3 (623 pmol/L [–631 to 1877 pmol/L], P = .14 and 685 pmol/L [–304 to 1068 pmol/L], P = .46, respectively). Serum BUN and creatinine did not change significantly between visit 0 and visit 2 in group 1 (median = 23 mg/dL [range 13‐32] versus 19 mg/dL [12‐38], P = .72 and 1.15 mg/dL [0.70‐1.40] versus 0.95 mg/dL [0.70‐1.10], P = .10, respectively) or group 2 (28 mg/dL [18‐87] versus 43.5 mg/dL [21‐160], P = .092 and 1.10 mg/dL [0.90‐2.50] versus 1.55 mg/dL [0.90‐3.30], P = .062, respectively). Conclusions and Clinical Importance Use of this treatment escalation algorithm allows effective targeting of treatment for CHF in dogs against an objective criterion.