Dilated cardiomyopathy (DCM) is the most common acquired cardiac disease in large-breed dogs. Especially Doberman Pinschers have a high prevalence for this disease.[1-3] In this breed, an autosomal dominant pattern of inheritance is assumed. Typically, the progression of DCM in Doberman Pinschers can be classified into several different stages. The diseases start with disturbances at the cellular level of the myocardium, which are currently not detectable with routinely applied diagnostic methods. This phase is followed by an occult stage of the disease, during which patients do not show clinical signs. Commonly seen characteristics of the occult stage are ventricular tachyarrhythmias, whereas echocardiographic changes may or may not be appreciated during this stage of disease, ie, the dogs might have only arrhythmias or a combination of both, arrhythmias and echocardiographic changes.[2, 5] Syncope or sudden death caused by ventricular tachyarrhythmias can occur. Diagnosis of cardiomyopathy in Doberman Pinschers is based upon the detection of ventricular arrhythmias by 24-hour ambulatory electrocardiography (Holter) or the findings of myocardial systolic dysfunction and volume overload of the left ventricle by echocardiography, or both.[2, 7]
In order to provide a standardized protocol for the identification and staging of DCM, the European Society of Veterinary Cardiology (ESVC) taskforce proposed guidelines for the diagnosis of DCM using echocardiography. A scoring system was recommended which is based on M-mode left ventricular dimensions, left ventricular geometry and indices of systolic function. Major and minor criteria were proposed to establish the diagnosis of DCM, including SI as major and increased mitral valve M-mode E-point-to-septal-separation (EPSS) as minor criterion. Little is known about the SI and EPSS in veterinary medicine. However, both parameters are part of the proposed scoring system of the ESVC.
In DCM ventricular dilatation develops and the chamber becomes rounder (spherical) as the disease progresses. The geometrical shape, ie, the sphericity of the left ventricle (LV), can be assessed by comparing left ventricular length obtained from a right parasternal four-chamber view to the M-mode measurement of diastolic dimension as shown in Figure 1. The SI is calculated by dividing the length of the LV through the width of the LV and a value of SI <1.65 account for an increased sphericity and is considered abnormal according to the ESVC guidelines. Ljungvall et al evaluated left ventricular sphericity using real-time 3-dimensional echocardiography in dogs with myxomatous mitral valve disease. Their results proposed that the assessment of LV volume and shape could allow early detection of dogs being at risk for rapid progression into congestive heart failure. No study assessed the clinical value of the SI measured by conventional echocardiography as proposed in the ESVC-DCM guidelines in veterinary medicine—there are only experimental studies using models published so far.[12, 13]
Figure 1. Echocardiographic right parasternal long axis. The horizontal solid line denotes the left ventricular length starting at the level of the mitral annulus (dotted vertical line) to the apex. The vertical line depicts the end-diastolic diameter as assessed by M-Mode measurement leveled at the tip of the opened mitral valve.
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EPSS is defined by the shortest distance from the E-point of the mitral valve (during rapid ventricular filling) to the ventricular septum as shown in Figure 2. It is a parameter for the evaluation of left ventricular filling and function. Kirberger et al showed that EPSS has a strong negative correlation with ejection fraction in the absence of aortic and mitral valve insufficiencies. Two studies have evaluated EPSS in dogs with DCM and found it to be a sensitive and specific parameter for left ventricular function.[16, 17] However, in those studies, EPSS has not been compared to newer echocardiographic methods to detect DCM, such as the Simpson method of disk (SMOD), which has recently been shown to be more sensitive to diagnose early DCM in Doberman Pinschers.
Figure 2. M-Mode recording of right parasternal long axis at the level of the tip of the cranial mitral valve leaflet. The vertical line shows the distance of the maximal cranial motion (E-Point) of the cranial mitral leaflet to the interventricular septum (IVS) during the rapid filling phase of diastole; LVPW, Left ventricular caudal wall.
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No prospective longitudinal study has evaluated the SI and EPSS in Doberman Pinschers in order to diagnose DCM. Therefore, the aim of this study was to establish cutoff values for those 2 parameters and to evaluate their role as diagnostic parameters in Doberman Pinschers with dilated cardiomyopathy.
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- Materials and Methods
For the first part of the study, 179 Doberman Pinschers (79 female and 100 male) with a mean age of 6.2 ± 2.8 years and a mean body mass of 35.8 ± 5.5 kg were included into the study. Ninety-seven of those dogs (53 female, 44 male; 5.4 ± 2.6 years; 35.3 ± 5.3 kg) were considered as being healthy according to the criteria stated above; 75 dogs had DCM (25 female, 50 male; 7.4 ± 2.7 years; 36.1 ± 5.7 kg) and 7 dogs were assigned to the “last normal” group (1 female, 7 male; 5.1 ± 2.2 years; 39.5 ± 1.8 kg). Echocardiographic values are shown in Table 1.
Table 1. Echocardiographic values of the healthy, DCM and “last normal” groups. LVEDV/BSA and LVESV/BSA denoted the left ventricular diastolic and systolic volume normalized to the body surface area—all values given in milliliters per square meter. LVIDd and LVIDs show the left ventricular inner diameter in diastole and systole with values given in centimeters. EPSS depicts the E-point-to-septal-separation in centimeters; SI denotes an index without numeric dimensions
| ||Control||DCM||Last Normal|
Of the dogs in the DCM group, 7 animals were decompensated and had evidence of pulmonary edema on radiographs, 4 of the remaining dogs had a history of syncope. The remaining dogs did not have clinical symptoms. The dogs in the DCM group received Pimobendan in 54 cases, Sotalol in 23 cases, and Amiodarone in 14 cases. All dogs with pulmonary edema received furosemide, an ACE-inhibitor and Pimobendan.
Measurements of SI and EPSS were Normally Distributed within the Groups
The SI (1.44 ± 0.16) was significantly smaller (P < .001) in the DCM group compared to the healthy Doberman pinscher group (1.86 ± 0.17). ROC analysis determined that the optimal cutoff value was <1.65. Using this cutoff value the sensitivity was 86.8% and specificity was 87.6% to differentiate dogs with DCM form the control group (Fig 4). Of the dogs in the “last normal” group, 0/7 had an SI < 1.65.
Figure 4. Dot diagram of the SI (A) and EPSS (B) on the y-axis and the different groups on the x-axis. The horizontal line denotes the estimated cutoff value to distinguish healthy dogs from dogs with DCM. There was a significant difference between DCM and control group (P < .001). Sensitivity and specificity are displayed.
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EPSS was significantly higher in the DCM group (12.1 ± 3.21) compared to the control group (4.66 ± 0.69, P < .001). ROC analysis revealed an EPSS >6.5 mm as the value with the highest sensitivity (100%) and specificity (99%) to detect DCM. None of the dogs in the “last normal” group had an EPSS >6.5 mm (Fig 4). Therefore, neither EPSS nor SI was abnormal before changes detected with the SMOD method, which is considered the gold standard to detect echocardiographic changes as mentioned earlier.
For the evaluation, if EPSS, or SI, or both would be abnormal using the herein established cutoff values in dogs having M-Mode measurements below the published DCM cutoff values, but with Simpson measurements consistent with DCM, EPSS and SI were measured in a substudy. Thirteen dogs were found in the database to fulfill these inclusion criteria. All dogs developed typical M-Mode measurements consistent with DCM within 1.5 years. All of the 13 dogs had an EPSS >6.5 mm, whereas only 2/13 dogs had an SI below the cutoff value <1.65.
Intraobserver coefficients of variation for SI and EPSS were 1.53 and 2.29%, respectively. Interobserver coefficients of variation were 3.53% for the SI and 4.83% for EPSS.
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- Materials and Methods
The results of this study revealed that the SI using a cutoff value of 1.65 had a good sensitivity (86.8%) and specificity (87.6%) to differentiate dogs with DCM from control dogs. The best (calculated) cutoff value in this study was 1.65, which is the same cutoff value suggested by the ESVC DCM guidelines, although this cutoff value was published without an evaluation study. However, there was a considerable overlap between the control and DCM group and as neither sensitivity nor specificity is very high, the question arises, if it is necessary or useful to perform this parameter as an additional diagnostic tool. Adding this value to the standard echocardiographic examination does not prolong the examination considerably, as only the length of the left ventricle (LV) needs to be measured in addition to the M-Mode examination. If an SMOD measurement is done routinely, the LV length is already part of that measurement and no additional measurements need to be performed. The SI aims to detect a geometrical change of the LV when the dog develops DCM, ie, that the heart becomes rounder. Therefore, the index includes the diastolic LV chamber diameter, and, as a matter of fact, the sphericity can only be changed, if there is an LV volume overload already present. As the volume of the LV is already assessed using the SMOD measurements, it is not surprising that the SI is inferior to the SMOD measurements. In humans, the SMOD is the preferred echocardiographic method to perform left ventricular volume measurements. Recently, this method has been shown to be more sensitive than to M-Mode to diagnose early echocardiographic changes in Doberman Pinschers and has been therefore recommended as new echocardiographic gold standard to detect DCM in Doberman Pinschers. It was surprising to see how well EPSS performed compared with SMOD measurements in this study—having a sensitivity of 100% and a specificity of 99% to detect Doberman Pinschers with DCM using a cutoff value >6.5 mm. The “last normal” group was selected in order to evaluate if this parameter might actually be better compared to the Simpson method, to detect even earlier echocardiographic changes, but neither SI nor EPSS was abnormal in this group of dogs. This was expected, as the Simpson method adjusts to geometrical changes of the LV. M-Mode does not necessarily detect early geometrical changes. It has been shown that M-Mode is less sensitive to evaluate early echocardiographic changes in dogs with DCM, and thus, a substudy was performed using dogs that were abnormal in their SMOD-derived ventricular volumes, but still had normal M-Mode measurements. Whereas SI was abnormal in only 2/13 dogs in this group, all EPSS measurements were already above the cutoff value. Therefore, EPSS seems to be a valuable parameter, especially if M-Mode instead of Simpson measurements is used, as EPSS might be earlier abnormal than M-Mode.
EPSS has already been evaluated in Doberman Pinschers in 1986. EPSS was the most sensitive and specific criterion for early cardiomyopathy—showing no overlap between healthy and dogs with advanced DCM. A mean value of 4.8 mm ± 1.51 (range 3–7) was proposed and later a cutoff value of >9 mm was suggested to diagnose DCM by the same authors. Those results are in agreement with this study, concerning the fact that EPSS appears to be more sensitive than M-Mode, at least when the published references for M-Mode are used, which might be too high. However, there is a discrepancy of the cutoff values for EPSS suggested earlier and this study. This might be explained by the fact that in this study the Simpson method was used as gold standard, which is more sensitive to detect early changes—this explains why EPSS in this study was 12.1 ± 3.2 and in the previous study 17.2 ± 8.59. The higher EPSS values in the Calvert study in the normal group might be explained by the fact that dogs were included in the control group, which had M-Mode values (LVIDd: control group range 41–55 mm), which are considered to be clearly too high today. EPSS has been also evaluated in Irish Wolfhound suggesting to be a sensitive parameter to detect DCM.
No distinct EPSS value has been published by the ESVC taskforce for the diagnosis of DCM. Because of the fact that neither breed, age, sex, body mass nor heart rate showed a significant correlation with EPSS, an overall value can be proposed. But still care must be taken when regional or general hypertrophy is seen—this can cause a decrease in EPSS because of restricted motion of the mitral valve. In the presence of mitral or aortic regurgitation, EPSS as a parameter of systolic function cannot be assessed objectively anymore because of a change in hemodynamics and cardiac contractility.
A limitation of the study is the natural progression of the disease. As the occult phase of DCM in Doberman Pinschers can last for several years and might be difficult to detect in the early stage, we cannot exclude that there were some dogs in the control group that might have developed DCM at a later time point or already had very early cardiac changes that were not detectable. This could have led to a higher EPSS or lower SI in the control group, but as the control group was quite large, the effect is most likely not relevant. Another limitation is the potential effect of medical treatment on the SI and EPSS measurements, as most dogs in the DCM group received Pimobendan and about half of the dogs received antiarrhythmic drugs. The cardiac medication and its potential hemodynamic effects could have had an effect on preload, afterload, and systolic function, and therefore theoretically on SI and EPSS. However, SI and EPSS were significantly different despite treatment.
In conclusion, EPSS (>6.5 mm) is a valuable parameter, which is almost as good, but not better than the Simpson method for the diagnosis of DCM in Doberman Pinschers. EPSS seems to be especially valuable as an additional echocardiographic parameter if M-Mode is used or in addition to the Simpson method. The SI does not appear to be more sensitive than the M-Mode and is inferior to the Simpson measurements.