Temporal Variability of Ventricular Arrhythmias in Boxer Dogs with Arrhythmogenic Right Ventricular Cardiomyopathy

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is prevalent in the Boxer. There is little information on the temporal variability of ventricular arrhythmias within affected dogs.
Objective: To evaluate ambulatory electrocardiograms (AECG) from Boxers with ARVC for hourly variation in premature ventricular complexes (PVC) and heart rate (HR).
Animals: One hundred and sixty-two Boxer dogs with ARVC.
Methods: Retrospective, observational study of 1,181 AECGs collected from Boxer dogs at The Ohio State University from 1997 to 2004 was evaluated. The proportion of depolarizations that were PVCs was compared across each hour of the day, during six 4-hour periods of day, to the time after AECG application, and to the maximum and minimum HR.
Results: A lower proportion of PVCs was noted during early morning (midnight to 0400 hours) as compared with the morning (0800–1200 hours) and late (1600–2000 hours) afternoon ( P = .012). There was no increase in PVC proportion in the 1st hour after AECG application as compared with all other hours of the day ( P = .06). There was poor correlation between maximum (ρ= 0.19) and minimum (ρ= 0.12) HR and PVC proportion.
Conclusions and Clinical Importance: The likelihood of PVC occurrence in Boxer dogs with ARVC was relatively constant throughout the day, although slightly greater during the hours of 0800–1200 and 1600–2000. A biologically important correlation with HR was not apparent. The role of autonomic activity in the modulation of electrical instability in the Boxer with ARVC requires further study.     

Arrhythmogenic right ventricular cardiomyopathy in dogs

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease seen in dogs, cats, and humans. A common entity in Boxers and the related English bulldog, the disease is characterized by fatty or fibrofatty replacement of the myocardium, ventricular arrhythmias, and the potential for syncope or sudden death. In some individuals, concomitant left ventricular involvement results in systolic dysfunction and a progression to congestive heart failure. The clinical and pathological characteristics of ARVC share many similarities in dogs and humans, and Boxers serve as an important spontaneous model of the disease.Although multiple mechanisms have been implicated in the pathogenesis of ARVC, the disease is ultimately considered to be a disorder of the desmosome. Multiple causal genetic mutations have been identified in people, and over 50% of affected humans have an identifiable mutation in desmosomal proteins. To date, only a single genetic mutation has been associated with ARVC in Boxer dogs. Other as-yet-undiscovered genetic mutations and epigenetic modifiers of the disease are likely. Treatment of ARVC in dogs is focused on controlling ventricular arrhythmias and associated clinical signs. This article will review the pathophysiology, clinical diagnosis, treatment, and prognosis of ARVC in the dog.     

Pathological features of arrhythmogenic right ventricular cardiomyopathy in middle-aged dogs

The hearts of four dogs (a 4-year-old Shetland sheepdog, a 4-year-old Labrador retriever, a 5-year-old English Bulldog, and a 6-year-old Dalmatian; three males and one female), that had died suddenly and had been clinically diagnosed as having arrhythmogenic right ventricular cardiomyopathy (ARVC), were studied post mortem. At the cut surface, all four hearts showed mild to moderate hypertrophy of the left and right ventricular free walls and ventricular septum, with grayish-white tissue replacement of the myocardium to various degrees. Histologically, all had typical right ventricular features of ARVC and morphological evidence of left ventricular and ventricular septal involvement. Two main histological patterns were identified: a fatty type (two cases) and a fibrofatty type (two cases). With either type, myocardial replacement by fatty or fibrofatty tissue were detected in both ventricles, but were more severe in the right ventricle, where they usually became transmural. Furthermore, this myocardial replacement was more severely seen in the epimyocardium and midmyocardium; the endomyocardium was less severely affected. On the basis of the present observation, it is evident that, in dogs, the disease process of ARVC affects both the right and left ventricles, although the striking pathological feature is right ventricular involvement. The pathological evidence of biventricular involvement in these canine cases of ARVC may represent a wider spectrum of the disease than has previously been recognized, suggesting that, in dogs, this disease should no longer be considered as limited to the right ventricle.     

Right Ventricular Outflow Obstruction Caused by Primary Cardiac Neoplasia

Obstruction to pulmonary blood flow as a result of neoplasia in the right ventricular outflow tract is described in two dogs. Whereas one dog had exertional syncope and a systolic ejection murmur, the other had signs of congestive failure and hypoxia. In both animals the mass was detected in the right ventricle with two-dimensional echocardiography and confirmed angiographically. Although rare, primary right ventricular neoplasia represents a potentially treatable form of cardiac disease and should be considered as a cause of acquired outflow tract obstruction.     

An index of myocardial performance applied to the right ventricle of Boxers with arrhythmogenic right ventricular cardiomyopathy

OBJECTIVE: To use an index of myocardial performance (IMP) to assess right ventricular function in Boxers with arrhythmogenic right ventricular cardiomyopathy (ARVC). ANIMALS: 22 Boxers (12 Boxers with ARVC diagnosed by the detection of > or = 1,000 ventricular premature complexes (VPCs)/24 h and 10 Boxers with < or = 5 VPCs/24 h (control dogs). Procedures-Pulsed-wave Doppler recordings of tricuspid inflow and pulmonic outflow were acquired. Preejection period (PEP), ejection time (ET), PEP/ET, and IMP were determined for the right ventricle by use of data from separate cardiac cycles. RESULTS: A significant difference was not identified between groups for right ventricular PEP, right ventricular ET, right ventricular PEP/ET, or right ventricular IMP. Right ventricular IMP was not significantly correlated with VPC number (r = 0.21) or VPC grade (r = -0.3) in Boxers with ARVC. CONCLUSIONS AND CLINICAL RELEVANCE: Boxers with ARVC did not have significant differences in right ventricular IMP, compared with results for control Boxers. This would suggest that right ventricular dysfunction does not develop in Boxers with ARVC or that a more severe phenotype of the disease may be necessary for detection of dysfunction. Additional studies that use more sensitive techniques to evaluate myocardial function may be warranted.     

Echocardiographic assessment of right ventricular systolic function in Boxers with arrhythmogenic right ventricular cardiomyopathy

Objectives

To determine whether there are differences in measures of longitudinal right ventricular (RV) systolic function among Boxers with arrhythmogenic right ventricular cardiomyopathy (ARVC) compared with healthy control Boxer dogs. To explore relationships between markers of RV systolic function and age, body weight, gender, arrhythmia frequency, and markers of left ventricular (LV) systolic function in Boxer dogs.

Arrhythmogenic right ventricular cardiomyopathy in Boxer dogs is associated with calstabin2 deficiency

ObjectiveTo examine the presence and effect of calstabin2-deficiency in Boxer dogs with arrhythmogenic right ventricular cardiomyopathy (ARVC).AnimalsThirteen Boxer dogs with ARVC.Materials and methodsTissue samples were collected for histopathology, oligonucleotide microarray, PCR, immunoelectrophoresis, ryanodine channel immunoprecipitation and single-channel recordings, and calstabin2 DNA sequencing.ResultsIn cardiomyopathic Boxer dogs, myocardial calstabin2 mRNA and protein were significantly decreased as compared to healthy control dogs (calstabin2 protein normalized to tetrameric cardiac ryanodine receptor (RyR2) complex: affected, 0.51 ± 0.04; control, 3.81 ± 0.22; P < 0.0001). Calstabin2 deficiency in diseased dog hearts was associated with a significantly increased open probability of single RyR2 channels indicating intracellular Ca²⁺ leak. PCR-based sequencing of the promoter, exonic and splice site regions of the canine calstabin2 gene did not identify any causative mutations.ConclusionsCalstabin2 deficiency is a potential mechanism of Ca²⁺ leak-induced ventricular arrhythmias and heart disease in Boxer dogs with ARVC.     

Right ventricular systolic and diastolic function assessed by two-dimensional speckle tracking echocardiography in dogs with myxomatous mitral valve disease

Pulmonary hypertension (PH) is a common comorbidity in dogs with myxomatous mitral valve disease (MMVD), and can induce various changes in the right heart, such as right ventricular (RV) hypertrophy, dilatation, and dysfunction. We hypothesized that RV function, not only systolic function but also diastolic function, could be worsened with PH progression. We aimed to compare RV systolic and diastolic function in dogs with MMVD. Twenty healthy dogs and sixty-eight dogs with MMVD were enrolled. Dogs with MMVD were classified into the probability of PH. Two-dimensional and Doppler echocardiographic indices for right heart and two-dimensional speckle tracking echocardiography indices were measured. The morphological indicators of the right heart were significantly higher only in the high probability of PH group. The RV strain, early-diastolic and systolic strain rates were significantly lower in the high probability of PH group than those in the low and intermediate probability of PH groups. Multivariate analysis showed that increased RV internal dimension normalized by body weight and RV myocardial performance index were significantly associated with the presence of right-sided congestive heart failure. Speckle tracking echocardiography-derived RV systolic and diastolic function were activated in the low and intermediate probability of PH groups. However, dogs with high probability of PH showed RV myocardial dysfunction and dilatation. Increased RV myocardial performance index and end-diastolic RV internal dimension normalized by body weight were significantly associated with the presence of right-sided congestive heart failure in dogs with MMVD.     

Evaluation of serum cardiac troponin I concentration in Boxers with arrhythmogenic right ventricular cardiomyopathy

OBJECTIVE: To evaluate serum cardiac troponin I (cTnI) concentrations in Boxers with arrhythmogenic right ventricular cardiomyopathy (ARVC), unaffected (control) Boxers, and control non-Boxers. ANIMALS: 10 Boxers with a clinical diagnosis of ARVC defined by > or = 1,000 ventricular premature complexes (VPCs)/24 h on an ambulatory ECG, 10 control Boxers assessed as normal by the presence of < 5 VPCs/24h, and 10 control non-Boxers. PROCEDURES: Serum was extracted from a blood sample from each dog. Analysis of serum cTnI concentrations was performed. RESULTS: Mean +/- SD serum cTnI concentration was 0.142 +/- 0.05 ng/mL for Boxers with ARVC, 0.079 +/- 0.03 ng/mL for control Boxers, and 0.023 +/- 0.01 ng/mL for control non-Boxers. A significant difference in serum cTnI concentrations was observed among the 3 groups. In the combined Boxer population (ie, Boxers with ARVC and control Boxers), a significant correlation was found between serum cTnI concentration and number of VPCs/24 h (r = 0.78) and between serum cTnI concentration and grade of ventricular arrhythmia (r = 0.77). CONCLUSIONS AND CLINICAL RELEVANCE: Compared with clinically normal dogs, Boxers with ARVC had a significant increase in serum cTnI concentration. For Boxers, correlations were found between serum cTnI concentration and number of VPCs/24 h and between concentration and the grade of arrhythmia. Because of the overlap in serum cTnI concentrations in control Boxers and Boxers with ARVC, future studies should evaluate the correlation of serum cTnI concentration with severity of disease in terms of degree of myocardial fibrofatty changes.     

Boxer dog cardiomyopathy: an update.

Boxer dog cardiomyopathy is an inheritable form of myocardial disease characterized most commonly by ventricular tachycardias, syncope, and, sometimes, systolic dysfunction and heart failure. Careful evaluation of boxer dog cardiomyopathy by several investigators has demonstrated that the disease may be best classified as arrhythmogenic right ventricular cardiomyopathy. Affected dogs have a variable prognosis; although some succumb to sudden cardiac death, many can remain asymptomatic or be successfully managed on antiarrhythmics for years.     

Serum Cardiac Troponin I Concentration in Retired Racing Greyhounds

Background: Cardiac troponin I (cTnI) is a polypeptide found specifically in cardiac muscle tissue that has been used as a diagnostic and prognostic indicator of cardiomyopathy. Increases in cTnI are associated with myocardial pathologic processes. However, high serum cTnI concentrations have been observed in normal Greyhounds.
Hypothesis: We hypothesized that Greyhounds have cTnI concentrations higher than non-Greyhound dogs, and that a separate reference range should be established for Greyhounds.
Animals: Blood samples were collected from the jugular vein from a group of 20 healthy Greyhound blood donors.
Methods: Analysis of serum cTnI was performed with an immunoassay system with a detection level of 0.01 ng/mL, as described previously. The Greyhound values were compared with 2 groups of Boxers with and without arrhythmogenic right ventricular cardiomyopathy (ARVC), and to a group of non-Boxer control dogs from a previous study.
Results: The mean cTnI concentration in Greyhounds was significantly higher ( P < .0001) than that in non-Greyhound control dogs, although not significantly different from normal Boxers ( P = .50), or Boxers with ARVC ( P = .58). Greyhound serum cTnI concentrations were in the range found in Boxers with ARVC. The proposed reference range for cTnI in Greyhounds is 0.05–0.16 ng/mL.
Conclusions and Clinical Importance: Greyhounds have a reference range for serum cTnI concentrations that differs from that of other previously published reference ranges for dogs of other breeds. Until a broader database and more precise reference range can be established, caution should be exercised in interpreting serum cTnI concentrations in Greyhounds with suspected cardiac disease.     

Arrhythmogenic right ventricular cardiomyopathy coincided with the cardiac fibrosis in the inner muscle layer of the left ventricular wall in a boxer dog

A 7-year-old female boxer dog died suddenly without any clinical signs. It was suspected that the dog had arrhythmogenic right ventricular cardiomyopathy (ARVC) due to ventricular premature complexes and ventricular tachycardia at 3 years of age. The final diagnosis of ARVC was confirmed by histological characteristics, such as loss of cardiocytes and fibrofatty replacement, occurring in the right and left ventricular walls. In the cardiocytes, non-lipid vacuoles were observed. Cardiac fibrosis and intimal thickening of the small arteries occurred without fatty replacement in the inner muscle layer including the papillary muscles of the left ventricular wall. This paper describes the pathomorphological details of an ARVC case with coincidental cardiac fibrosis in the inner muscle layer of the left ventricular wall.     

Arrhythmogenic right ventricular cardiomyopathy in a weimaraner

Arrhythmogenic right ventricular cardiomyopathy (ARVC) was diagnosed postmortem in a weimaraner dog. Syncope, ventricular arrhythmias, and sudden death in this patient combined with the histopathological fatty tissue infiltration affecting the right ventricular myocardium are consistent with previous reports of ARVC in non-boxer dogs. Arrhythmogenic right ventricular cardiomyopathy has not been previously reported in weimaraners.     

Effects of animal position and number of repeated measurements on selected two-dimensional and M-mode echocardiographic variables in healthy dogs

OBJECTIVE: To evaluate the effects of positioning and number of repeated measurements on intra- and interobserver variability of echocardiographic measurements in dogs. DESIGN: Prospective study. ANIMALS: 4 healthy dogs. PROCEDURE: Each observer performed 24 examinations, separately assessing each dog 6 nonconsecutive times (3 times with the dog in lateral recumbency and 3 with the dog in a standing position). Variables evaluated included M-mode measurements of left ventricular end-diastolic and left ventricular end-systolic diameters, left ventricular free-wall thickness in diastole and systole, interventricular septal thickness in diastole and systole, left ventricular shortening fraction, and 2-dimensional measurements of the left atrial diameter-to-aortic diameter ratio. RESULTS: All coefficients of variation (range, 3.4% to 26.6%) were similar between operators and positions and were < 15% for 27 of 32 values. For both operators, repeatability of the measurements was better for left ventricular end-systolic diameter, left ventricular free-wall thickness in diastole, left ventricular free-wall thickness in systole, and the left atrial diameter-to-aortic diameter in the standing position, and similar for both positions for shortening fraction and left ventricular end-diastolic diameter. No effect of cardiac cycle was observed. CONCLUSIONS AND CLINICAL RELEVANCE: Within-day variability of conventional echocardiography performed with the dog in the standing position was at least as good as that obtained with the dog in lateral recumbency for most measured variables. Single measurements of each variable may be sufficient for trained observers examining dogs that do not have an arrhythmia. The standing position should be used, particularly for stressed or dyspneic dogs.     

Comparative assessment of right ventricular performance from the pressure-volume relationship in double-muscled and conventional calves.

Forty-one and 55 records of right-sided and systemic arterial pressures, cardiac output, and end-diastolic and end-systolic right ventricular volumes were collected from a group of 6 conventional and 6 double-muscled calves, respectively. In each group, the mean right ventricular pressure-volume loop was constructed. Global cardiac performance was significantly lower in the double-muscled than in the conventional calves. The right ventricular end-diastolic and end-systolic volumes, as well as the diastolic portion of the mean pressure-volume loop, were similar in the 2 groups. Those results suggest that the reduced cardiac performance of double-muscled calves is not due to a lowered ventricular preload and that diastolic properties of their myocardium are similar to those of conventional calves. When expressed on a body weight basis, however, the right ventricular end-diastolic and end-systolic volumes were lower in the double-muscled than in conventional calves. When expressed as a function of probable metabolic demand, therefore, the volumetric capacity of the cardiac pump appears to be reduced in double-muscled calves. The significantly lower right ventricular ejection fraction, maximal rate of ventricular pressure rise and right ventricular peak-systolic pressure to end-systolic volume ratio measured in double-muscled as compared with conventional calves suggest that reduced myocardial contractility may also be partly responsible for the significantly lower stroke index of the former calves. The cardiac pump of double-muscled cattle thus seems to be less effective than that of conventional cattle because of reduced volumetric capacity and lowered strength of contraction.     

Volume loading-related changes in tissue Doppler images derived from the tricuspid valve annulus in dogs

OBJECTIVE: To investigate the relationship between preload and tricuspid valve annulus-derived tissue Doppler imaging (TDI) as an index of right ventricular (RV) filling in dogs. ANIMALS: 7 Beagles. PROCEDURES: Peak systolic RV pressure and RV end-diastolic pressure (RVEDP) were measured in anesthetized dogs. Pulsed Doppler was used to measure tricuspid valve inflow and pulmonary valve outflow velocities. The TDI velocities were measured at the lateral corner of the tricuspid valve annulus. Lactated Ringer's solution was infused at 200 mL/kg/h for 60 minutes via the cephalic vein. RESULTS: IV infusion significantly increased heart rate, RV pressure, and RVEDP. Early diastolic flow (E-wave) and ejection time significantly increased. The myocardial performance index (MPI) significantly decreased. Intravenous infusion significantly increased the ratio of the E'-wave (peak myocardial velocity during early diastole) to the A'-wave (peak myocardial velocity during late diastole; E':A' ratio) and myocardial velocity during systole (S'), early diastole (E'), and late diastole (A'). The TDI-isovolumic relaxation time and TDI-MPI decreased significantly. The RVEDP was correlated with late diastolic flow (A-wave), ratio of the E-wave to the A-wave (E:A ratio), E'-wave, A'-wave, S'-wave (peak myocardial velocity during systole), TDI-isovolumic relaxation time, TDI-MPI, and ratio of the E-wave to the E'-wave (E: E' ratio). The A-wave and E:A ratio and TDI-derived isovolumic relaxation time, S' duration, and E'-wave could predict the RVEDP. CONCLUSIONS AND CLINICAL RELEVANCE: The TDI velocities were affected by RV filling pressure in healthy dogs, whereas other TDI profiles, such as MPI and E':A' ratio, were independent of acute filling abnormalities.     

Remission of Histiocytic Ulcerative Colitis in Boxer Dogs Correlates with Eradication of Invasive Intramucosal Escherichia coli

Background: Historically, histiocytic ulcerative (HUC) (or granulomatous) colitis of Boxer dogs was considered an idiopathic immune-mediated disease with a poor prognosis. Recent reports of dramatic responses to enrofloxacin and the discovery of invasive Escherichia coli within the colonic mucosa of affected Boxer dogs support an infectious etiology.
Hypothesis: Invasive E. coli is associated with colonic inflammation in Boxer dogs with HUC, and eradication of intramucosal E. coli correlates with clinical and histologic remission.
Animals: Seven Boxer dogs with HUC.
Methods: Prospective case series. Colonic biopsies were obtained at initial evaluation in 7 dogs, and in 5 dogs after treatment with enrofloxacin. Biopsies were evaluated by standardized histopathology, and fluorescence in situ hybridization (FISH) with probes to eubacteria and E. coli .
Results: Intramucosal E. coli was present in colonic biopsies of 7/7 Boxers with HUC. Clinical response was noted in all dogs within 2 weeks of enrofloxacin (7±3.06 mg/kg q24 h, for 9.5±3.98 weeks) and was sustained in 6 dogs (median disease-free interval to date of 47 months, range 17–62). FISH was negative for E. coli in 4/5 dogs after enrofloxacin. E. coli resistant to enrofloxacin were present in the FISH-positive dog that relapsed.
Conclusions and Clinical Relevance: The correlation between clinical remission and the eradication of mucosally invasive E. coli during treatment with enrofloxacin supports the causal involvement of E. coli in the development of HUC in susceptible Boxer dogs. A poor response to enrofloxacin treatment might be due to colonization with enrofloxacin-resistant E. coli .     

Evaluation of spontaneous variability in the frequency of ventricular arrhythmias in Boxers with arrhythmogenic right ventricular cardiomyopathy

OBJECTIVE: To evaluate spontaneous variability in the frequency of ventricular arrhythmias and assess the influence of day of ECG recording and day of week on arrhythmia frequency in Boxers affected with arrhythmogenic right ventricular cardiomyopathy (ARVC). DESIGN: Prospective study. ANIMALS: 10 Boxers with ARVC with prior ambulatory ECG recordings that included > or = 500 ventricular premature complexes/24 h. PROCEDURE: Consecutive 24-hour ambulatory ECG recordings were obtained during a 7-day period in each dog. The number of ventricular premature complexes and grade of the arrhythmia were obtained from each recording. For each dog, the number of ventricular premature complexes for each recording was evaluated to identify any differences relative to the day of recording (recording 1 to 7) and day of the week (Monday through Sunday). RESULTS: Spontaneous variability accounted for as much as 80% of the change in frequency of ventricular premature complexes in dogs with frequent arrhythmias; this value was almost 100% in dogs with less frequent arrhythmias. Grade of arrhythmia was less variable but was also inversely related to frequency of arrhythmia. No significant differences in frequency values were identified among days of recording or among days of the week. CONCLUSIONS AND CLINICAL RELEVANCE: Changes of < or = 80% in the frequency of ventricular arrhythmias may be within the limit of spontaneous variability in dogs with ARVC. This degree of variability should be considered in evaluations of ambulatory ECG recordings, particularly in the assessment of the efficacy of antiarrhythmic drugs.     

Echocardiographic assessment of the left ventricular outflow tract in the Boxer

BACKGROUND: Soft, variable ejection murmurs are common in Boxers and are associated with increased left ventricular outflow tract (LVOT) ejection velocities. Whether these murmurs are physiologic or indicate mild aortic stenosis is controversial. Ejection velocity is impacted by LVOT area and ventricular stroke volume (SV), suggesting that these variables are pertinent to murmur development. HYPOTHESIS: Boxers with ejection murmurs have a smaller LVOT and equivalent SV indices, compared with values in dogs without murmurs. ANIMALS: Three age- and weight-matched groups of dogs--15 Boxers with soft ejection murmurs (group I); 15 Boxers without murmurs (group II); and 15 nonBoxer dogs without murmurs (group III)--were studied. METHODS: All dogs underwent 2-dimensional and Doppler echocardiographic examinations. The LVOT size at multiple levels; LVOT ejection velocity, stroke distance, and SV index; and right ventricular SV index were determined and compared by analysis of variance. RESULTS: Indexed LVOT areas in Boxer groups were not different, but were significantly smaller than those of non-Boxer dogs. Ejection velocities and stroke distances were significantly different across all groups, with group I having the highest and group III having the lowest values. Doppler SV indices (ml/m2) for group-I versus group-II Boxers were 70 +/- 16(SD) versus 62 +/- 12 for the LVOT (P = .27) and 58 +/- 12 versus 48 +/- 9 for the right ventricle (P = .14). CONCLUSIONS AND CLINICAL IMPORTANCE: These data suggest that a relatively smaller LVOT in Boxers predisposes them to increased ejection velocity and development of murmurs. The contribution of SV to the genesis of these often labile murmurs requires additional study.     

Hypothyroidism and myocardial failure in two Great Danes

Two Great Danes were evaluated for signs of congestive heart failure. Dilated cardiomyopathy was diagnosed in each dog. Both dogs were diagnosed concurrently with primary hypothyroidism. Following appropriate supplementation with levothyroxine, both dogs showed significant improvement in myocardial contractility, as demonstrated by increased fractional shortening and reductions in left atrial size, and left ventricular end-systolic and diastolic diameters. These observations suggest that hypothyroidism may lead to myocardial failure in Great Danes that is partially or fully reversible following thyroid hormone replacement therapy, and that hypothyroidism should be considered in all Great Danes presenting with systolic failure.