Evaluation of the cardiac actin gene in Doberman Pinschers with dilated cardiomyopathy

OBJECTIVE: To evaluate the coding region of the cardiac actin gene in Doberman Pinschers with dilated cardiomyopathy (DCM) for mutations that could be responsible for the development of the condition ANIMALS: 28 dogs (16 Doberman Pinschers with DCM and 12 mixed-breed control dogs). PROCEDURE: Ten milliliters of blood was collected from each dog for DNA extraction. Polymerase chain reaction (PCR) primers were designed to amplify canine exonic regions, using the sequences of exons 2 to 6 of the cardiac actin gene. Single-stranded conformational polymorphism analysis was performed for each exon with all samples. Autoradiographs were analyzed for banding patterns specific to affected dogs. The DNA sequencing was performed on a selected group of affected and control dogs. RESULTS: Molecular analysis of exons 2 to 6 of the cardiac actin gene did not reveal any differences in base pairs between affected dogs and control dogs selected for DNA evaluation. CONCLUSIONS: Mutations in exons 5 and 6 of the cardiac actin gene that have been reported in humans with familial DCM do not appear to be the cause of familial DCM in Doberman Pinschers. Additionally, evaluation of exons 2 to 6 for causative mutations did not reveal a cause for inherited DCM in these Doberman Pinschers. Although there is evidence that DCM in Doberman Pinschers is an inherited problem, a molecular basis for this condition remains unresolved. Evaluation of other genes coding for cytoskeletal proteins is warranted.     

Assessment of diastolic function by Doppler echocardiography in normal Doberman Pinschers and Doberman Pinschers with dilated cardiomyopathy

BACKGROUND: Assessment of diastolic function in patients with dilated cardiomyopathy (DCM) has the potential to add valuable information regarding hemodynamics, disease severity, and prognosis. The purpose of this study was to determine transmitral flow (TMF), isovolumic relaxation time (IVRT), pulmonary venous flow (PVF), flow propagation velocity (Vp), and mitral annular velocities by tissue Doppler in Doberman Pinschers with and without DCM. HYPOTHESIS: It was anticipated that normal and DCM Dobermans would differ with respect to these parameters, and that associations with time to congestive heart failure (CHF) or death would be found. ANIMALS: Thirty client-owned Doberman Pinschers (10 each of normal, occult DCM, and overt DCM) were studied. METHODS: Each dog underwent echocardiography with or without thoracic radiography (to confirm CHF) for classification as normal or DCM-affected, followed by collection of echocardiographic diastolic parameters. RESULTS: The group with occult DCM exhibited features of pseudonormal TMF, reduced systolic to diastolic PVF ratio, and reduced Vp. Shorter early TMF deceleration time (DTE) was associated with shorter time to CHF or sudden death. The group with overt DCM exhibited restrictive TMF, blunted systolic PVF, and reduced early and late diastolic mitral annular velocities. CONCLUSIONS AND CLINICAL IMPORTANCE: Doberman Pinschers showed evidence of moderate and severe diastolic dysfunction in occult and overt DCM, respectively. Short DTE may be a useful predictor of onset of CHF or sudden death.     

Assessment of mechanical ventricular synchrony in Doberman Pinschers with dilated cardiomyopathy

Objectives

Loss of temporal synchrony of myocardial contraction has been shown to reduce systolic function and be responsible for disease progression in people. The objective of this study is the assessment of inter- and intra ventricular synchrony in healthy Doberman Pinschers and those with dilated cardiomyopathy (DCM) by use of conventional Doppler and tissue velocity imaging.

Animals

A total of 60 scans from 35 client-owned Doberman Pinschers presented for cardiac evaluation were analysed.

Methods

Retrospective analysis of data. Using the European Society of Veterinary Cardiology DCM taskforce scoring system, Doberman Pinschers were classified into 4 groups: Control (Group 1; n = 12), depressed systolic function other than DCM (Group 2; n = 9), preclinical DCM (Group 3; n = 8) and symptomatic DCM (Group 4; n = 6). The time intervals between the beginning of the QRS complex and the peak velocity of pulmonic flow (Q-P) and the peak aortic flow (Q-Ao) were used to assess global synchrony between both ventricles. The time intervals between the beginning of the QRS complex and the peak myocardial systolic velocity (Q-peak S) and the onset of myocardial systolic velocity (Q-start S) were measured at the base of the right and left ventricular free wall (RVFW and LVFW) and interventricular septum (IVS), and used to determine segmental longitudinal inter- and intra ventricular synchrony.

Results

No significant loss of global or segmental longitudinal inter- or intra ventricular synchrony was identified between the groups.

Conclusion

Impairment of longitudinal fibre synchrony does not appear to be significantly associated with clinical status of DCM in Doberman Pinschers, although it was identified in certain individuals.     

Heart rate variability in Doberman Pinschers with and without echocardiographic evidence of dilated cardiomyopathy

OBJECTIVE: To characterize the salient variables of the time-domain analysis of heart rate variability (HRV) in clinically normal Doberman Pinschers and to compare those variables with those of Doberman Pinschers with cardiomyopathy and mild to moderate myocardial failure. ANIMALS: 46 Doberman Pinschers. PROCEDURE: HRV was analyzed in the time-domain from 24-hour Holter recordings obtained from 28 Doberman Pinschers with normal echocardiograms and 18 Doberman Pinschers with echocardiograms consistent with mild to moderate myocardial failure. RESULTS: Significant differences in HRV variables between the 2 groups of dogs were not detected. The HRV was greater during the nighttime (12 AM to 6 AM), compared with the 24-hour day and an 18-hour (6 AM to 12 AM) period. CONCLUSIONS AND CLINICAL RELEVANCE: HRV of dogs with mild to moderate myocardial failure was not different from that of clinically normal dogs, because there were no disturbances of autonomic balance, baroreceptor function, and other factors that influence HRV in the dogs with cardiomyopathy, or the sensitivity of time-domain analysis was overwhelmed by normal sinus arrhythmia. The techniques now used to study HRV have important limitations, especially in dogs, and better noninvasive tests of autonomic function are needed.     

European Society of Veterinary Cardiology screening guidelines for dilated cardiomyopathy in Doberman Pinschers

Background

Dilated cardiomyopathy (DCM) is the most common cardiac disease in large breed dogs and is inherited in Doberman Pinschers with a high prevalence (58%).

Plasma big endothelin-1, atrial natriuretic peptide, aldosterone, and norepinephrine concentrations in normal Doberman Pinschers and Doberman Pinschers with dilated cardiomyopathy

BACKGROUND: Dilated cardiomyopathy (DCM) results in progressive myocardial and circulatory dysfunction causing activation of a number of neurohormonal systems, including the endothelin (ET) system, which is only beginning to be described in clinical veterinary medicine. Measurement of these circulating neurohormones possesses potential utility in the diagnosis, staging, and assessment of prognosis in cardiac disease. HYPOTHESIS: We hypothesized that plasma big ET-1, norepinephrine (NE), aldosterone, and atrial natriuretic peptide (ANP) concentrations in normal Dobermans would differ from those in Dobermans with DCM, and that concentrations of these hormones would be associated with time to congestive heart failure (CHF) or death. ANIMALS: Thirty client-owned Dobermans (10 each of normal, occult DCM, and overt DCM) were included in the study. METHODS: Dogs underwent an echocardiogram, ECG, and blood sample collection. Neurohormones were measured by high-pressure liquid chromatography (NE) or commercial assays. RESULTS: Dogs with occult DCM had significantly higher ANP concentrations compared with normal dogs (least squares means [95% confidence interval, CI]: occult female 53.7 pg/mL [40.2-71.7] versus normal female 31.6 pg/mL [24.8-40.3], P = .026; occult male 86.1 pg/mL [64.7-115] versus normal male 12.1 pg/mL [5.1-28.7], P = .011). Dogs with overt DCM had significantly higher concentrations of all neurohormones compared with the normal group. Furthermore, increasing big ET-1 (risk ratio [RR] 2.7, CI 1.3-8.6, P = .01) and NE concentrations (RR 3.9, CI 1.1-18.1, P = .03) over 1 month were associated with a shorter survival time. CONCLUSIONS AND CLINICAL IMPORTANCE: High ANP concentrations can identify dogs with advanced occult DCM. Increasing big ET-1 or NE concentrations over time can be useful predictors of poor prognosis.     

Results of ambulatory electrocardiography in overtly healthy Doberman Pinschers with equivocal echocardiographic evidence of dilated cardiomyopathy

OBJECTIVE: To determine results of ambulatory electrocardiography in and outcome of overtly healthy Doberman Pinschers with equivocal echocardiographic evidence of dilated cardiomyopathy. DESIGN: Case series. ANIMALS: 44 overtly healthy (25 male, 19 female) Doberman Pinschers. PROCEDURE: 24-hour ambulatory electrocardiographic (Holter) recordings with > 90% scan quality obtained the same day that echocardiography was performed were reviewed. RESULTS: Holter recordings from 42 of 44 (95%) dogs contained ventricular premature complexes (VPC). Fifteen of 44 (34%) dogs had > 100 VPC, 9 (20%) had > 500 VPC, and 5 (11%) had > 1,000 VPC. Nonsustained (< 30 seconds) ventricular tachycardia was detected in 4 dogs. Eighteen of 27 (67%) dogs with > 100 VPC, any couplets or triplets of VPC, or ventricular tachycardia developed dilated cardiomyopathy within 1 year, compared with 8 of 17 (47%) dogs with < 100 VPC, no couplets or triplets of VPC, and no ventricular tachycardia. Of the 18 dogs that did not develop dilated cardiomyopathy within 1 year, 11 (61%) did so within 3 years. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that a high percentage of Doberman Pinschers with equivocal echocardiographic evidence of dilated cardiomyopathy will be found to have VPC during 24-hour ambulatory electrocardiography and that most will develop echocardiographic abnormalities indicative of cardiomyopathy.     

Effect of pimobendan on case fatality rate in Doberman Pinschers with congestive heart failure caused by dilated cardiomyopathy

BACKGROUND: Despite traditional therapy of a diuretic, angiotensin converting enzyme inhibitor, digoxin, or a combination of these drugs, survival of dogs with dilated cardiomyopathy (DCM) is low. Pimobendan, an inodilator, has both inotropic and balanced peripheral vasodilatory properties. HYPOTHESIS: Pimobendan when added to conventional therapy will improve morbidity and reduce case fatality rate in Doberman Pinschers with congestive heart failure (CHF) caused by DCM. ANIMALS: Sixteen Doberman Pinschers in CHF caused by DCM. METHODS: A prospective randomized, double-blind, placebo-controlled study with treatment failure as the primary and quality of life (QoL) indices as secondary outcome variables. Therapy consisted of furosemide (per os [PO] as required) and benazepril hydrochloride (0.5 mg/kg PO q12h) and dogs were randomized in pairs and by sex to receive pimobendan (0.25 mg/kg PO q12h) or placebo (1 tablet PO q12h). RESULTS: Pimobendan-treated dogs had a significant improvement in time to treatment failure (pimobendan median, 130.5 days; placebo median, 14 days; P= .002; risk ratio = 0.35, P= .003, lower 5% confidence limit = 0.13, upper 95% confidence limit = 0.71). Number and rate of dogs reaching treatment failure in the placebo group precluded the analysis of QoL. CONCLUSIONS AND CLINICAL IMPORTANCE: Pimobendan should be used as a first-line therapeutic in Doberman Pinschers for the treatment of CHF caused by DCM.     

Prospective evaluation of the combined value of physical examination and biomarker variables in screening for preclinical dilated cardiomyopathy in Doberman Pinschers

IntroductionScreening to assess likelihood of preclinical dilated cardiomyopathy (PC-DCM) prior to advanced diagnostic tests in Doberman Pinschers (DP) is desirable.ObjectiveTo investigate the combined value of physical examination (PE), N-terminal pro B-type natriuretic peptide (NTproBNP) and cardiac troponin I (cTnI) for identifying PC-DCM in DP.Animals, materials and methodsAll dogs underwent: PE, echocardiogram, 3-min ECG and cardiac biomarker measurement. Asymptomatic DP (414) were classified based on 3-min ECG and echocardiogram as: No-DCM/MMVD or myxomatous mitral valve disease (MMVD), PC-DCM based on echocardiogram (PC-DCM-Echo), PC-DCM based on arrhythmias with a normal echocardiogram (PC-DCM-ECG), equivocal DCM (EQ-DCM), and MMVD. Receiver operator characteristic curves and prediction models were derived.ResultsHeart murmurs and arrhythmias were rare and gallop sounds were absent in No-DCM/MMVD DP. Dogs ≥ four years old and males had higher probabilities of PC-DCM-Echo. Prediction models incorporating PE variables with NTproBNP had an area under the curve (AUC) of 0.940 for distinguishing between PC-DCM-Echo and all other groups, which was similar to the AUC for NTproBNP (0.939) or cTnI (0.932) alone. Discrimination between No-DCM/MMVD and all other groups was similar for NTproBNP (0.781) and cTnI (0.742) as individual tests, however, models combining PE variables and NTproBNP increased the AUC to 0.812. An NTproBNP cut-off of ≥548 pmol/L, was 100% sensitive and 77.3% specific for detecting PC-DCM-Echo.ConclusionsBoth NTproBNP and cTnI had good utility as sole tests to discriminate PC-DCM-Echo DP from all others. Models differentiating No-DCM/MMVD DP from all other DP were improved by using PE and NTproBNP together.     

A prospective genetic evaluation of familial dilated cardiomyopathy in the Doberman pinscher

BACKGROUND: The Doberman Pinscher is one of the most common breeds of dogs to develop dilated cardiomyopathy (DCM), a primary heart muscle disorder characterized by myocardial dysfunction, cardiac arrhythmias, and congestive heart failure. In the Doberman Pinscher, the disease is typically adult onset, and a familial etiology has been suggested. HYPOTHESIS: DCM in the Doberman Pinscher, is a familial disease linked to a specific genetic marker. ANIMALS: The study comprised an extended family of Doberman Pinschers with a history of DCM. METHODS: Participating dogs were prospectively evaluated over an 8-year period. Phenotype of participating dogs was determined by annual echocardiography and ambulatory electrocardiography, and the pedigree was evaluated to determine a specific mode of inheritance. Three hundred seventy-two microsatellite markers were selected and genotyped to cover the 38 autosomal chromosomes. Phenotyping, genotyping, and pedigree information was entered into a database, and parametric, 2-point analysis was performed. Markers were considered to be linked to the development of DCM if the logarithm of odds LOD score was >/= 3.0. RESULTS: An autosomal dominant mode of inheritance was defined by the appearance of the disease in multiple generations, equal gender representation (P = .973) and male-to-male transmission. A maximum LOD score of 1.31 was obtained for I marker on chromosome 20, a score not high enough to be associated with DCM. CONCLUSION: DCM in the Doberman Pinscher is a familial disease inherited as an autosomal dominant trait. The causative gene(s) responsible for this condition remain unresolved. Association studies by means of array technology may provide new insights into gene identification.     

Craniomandibular osteopathy in Doberman Pinschers

Two young Doberman Pinschers with painless, firm enlargement of the mandibles were investigated. Craniomandibular osteopathy was diagnosed in each case on the basis of characteristic radiographic and gross and microscopic lesions.     

Signal-Averaged Electrocardiograms in Normal Doberman Pinschers

Signal-averaged electrocardiograms (SAECGs) were performed on nonsedated normal dogs in left-lateral recumbency. Following signal averaging, both time-domain and 3-dimensional frequency-domain analyses were performed. For time-domain analysis, the high-frequency QRS (HFQRS) duration, duration of the terminal QRS complex less than 40 μV (LAS₄₀), and root mean square (RMS) voltages (μV) of the terminal 40 milliseconds (RMS₄₀) and 30 milliseconds of the QRS complex were calculated. For frequency-domain analysis, correlation ratios were calculated for 30-, 40-, 50-, and 60-millisecond segment lengths begun 10, 15, or 20 milliseconds before the end of the QRS complex. Spectro-temporal mapping was also performed. All of the parameters of the SAECGs analyzed in the time domain were associated with each other. LAS₄₀ and RMS voltages regressed significantly ( P < .0000) on the HFQRS duration. Ninety-five percent of the HFQRSs were 55–75 milliseconds, 95% of the LAS₄₀ s were 9–26 milliseconds, and 95% of the RMS₄₀ voltages were 177–444 μV. None of the SAECGs contained evidence of ventricular late potentials. Spectro-temporal maps were similar in each dog when the same segment lengths and starting points were compared. No evidence of ventricular late potentials was observed. Correlation ratios were lower when windowed segments included 15 or 20 milliseconds (versus 10 milliseconds) of the terminal QRS complex. When only 10 milliseconds of the terminal QRS complex were included in windowed segments, the mean correlation ratios for 30-and 40-millisecond segment lengths were > 0.8 and > 0.61 in 67% of all analyses, respectively.     

Cardiac Troponin I in Doberman Pinschers with Cardiomyopathy

Background: Cardiac troponin I (cTnI) is useful for detection of cardiac myocyte damage, but its efficacy in detecting various stages of dilated cardiomyopathy (DCM) in Doberman Pinschers is unclear. Objectives: To evaluate the diagnostic value of cTnI in various stages of DCM in Dobermans. Animals: Six hundred and fifty‐three cTnI measurements of 336 Doberman Pinschers. Methods: Using a longitudinal study design, staging of the disease was based upon 24‐hour‐ambulatory‐ECG (Holter) and echocardiography. A total of 447 cTnI measurements were performed in 264 healthy Dobermans, and 206 cTnI measurements in 75 Dobermans with cardiomyopathy. Eighty‐eight cTnI samples were from dogs with >100 ventricular premature contractions (VPCs)/24 hour, but without echocardiographic changes (“VPC group”). Additional 19 samples originated from dogs with only echocardiographic changes (“ECHO group”), and 56 samples from dogs with both VPCs and echocardiographic changes (“VPC plus ECHO group”). Twenty samples were from dogs with clinical signs (“clinical group”). The group “incipient” included 23 dogs, that were considered to be normal according to Holter and echocardiography at the time of the exam, but that developed DCM within 1.5 years. Results: cTnI values of dogs in all disease groups, including the “incipient” (0.30 ± 0.20) and “VPC group” (0.36 ± 0.34), were significantly (P= .04, P < .001) higher than the control group (0.07 ± 0.16). A cut‐off value of >0.22 ng/mL had a sensitivity of 79.5% and a specificity of 84.4% to detect all forms of cardiomyopathy. Conclusions and Clinical Importance: cTnI measurement is a valuable diagnostic test that can detect cardiomyopathy in dogs that are otherwise clinically normal.     

Blanket and flank sucking in Doberman Pinschers

OBJECTIVE: To evaluate blanket and flank sucking and any association with pica in Doberman Pinschers. DESIGN: Survey and case-control study. ANIMALS: 153 Doberman Pinschers (77 dogs with blanket or flank sucking and 76 unaffected dogs). PROCEDURES: Owners of Doberman Pinschers with blanket sucking, flank sucking, or both were surveyed regarding the age of onset, triggers, frequency, duration, interruptability, and associated medical and behavioral consequences. A putative association of blanket sucking and flank sucking with pica was examined by comparison of affected dogs with unaffected dogs. RESULTS: Apart from the difference in the object of oral activity between blanket and flank suckers, age of onset was the only variable that differed between dogs with the 2 conditions. Dogs with blanket or flank sucking had a higher prevalence of pica than the unaffected population. CONCLUSIONS AND CLINICAL RELEVANCE: Blanket and flank sucking are apparently related conditions that can occur with sufficient intensity to cause medical sequelae. These nonnutritive suckling behaviors share similarities with other canine compulsive disorders and are associated with pica. Veterinarians should advise owners that flank and blanket sucking are abnormal, potentially harmful behaviors in dogs. Treatment should be considered for severely affected dogs or when flank or blanket sucking is associated with medical problems.