Abstract
Myocardial dysfunction occurs in cats with hypertrophic cardiomyopathy (HCM), but little is known about the early stages of the disease. Strain imaging echocardiography is a method that enables the quantitative assessment of myocardial function and deformity, allowing the characterization of systolic dysfunction. The objective of this study was to assess systolic function using strain imaging echocardiography in Maine coon cats genetically tested for the A31P mutation in the MYBPC3 gene, with and without ventricular hypertrophy. For this purpose, 57 Maine coon cats of both genders, with an unknown status regarding the mutation at inclusion, were included prospectively and evaluated by conventional and strain imaging echocardiography. Comparisons were made among cats without hypertrophy (n = 45), suspect cats (n = 7), and cats with hypertrophic cardiomyopathy (n = 5), and also between the heterozygous for the mutation group (n = 26) and the negative for the mutation group (n = 28). Finally, in the group of phenotypically normal cats, heterozygous cats carrying the mutation were compared to cats without the mutation. Strain values were compared among the groups (blinded prospective study). While echocardiography demonstrated normal contractility, strain values (middle of the septum) were lower in HCM cats. Strain values (base of anterior wall of the left ventricle) were lower in heterozygous than in negative cats, even before hypertrophy. Negative correlation was observed between some values of myocardial strain and thickness. While strain imaging echocardiography was able to detect systolic abnormalities, despite apparent normality on conventional echocardiography, it was not able to identify cats that carry the A31P mutation in the MYBPC3 gene. Strain imaging echocardiography could be a useful tool, however, for detecting systolic alterations in HCM cats with an apparently normal systolic function or for detecting alterations in normal carriers of the MYBPC3 gene mutation.
Résumé
Le dysfonctionnement myocardique se produit chez des chats avec une cardiomyopathie hypertrophique (CMH), mais peu de choses sont connues sur les stades initiaux de la maladie. L’échocardiographie par imagerie de déformation (strain imaging) est une méthode qui permet l’évaluation quantitative de la fonction myocardique et de la déformation, permettant ainsi la caractérisation de la dysfonction systolique. L’objectif de la présente étude était d’évaluer la fonction systolique en utilisant l’échographie par imagerie de déformation chez des chats de race Maine Coon testés génétiquement pour la mutation A31P dans le gène MYBPC3, avec et sans hypertrophie ventriculaire. À cette fin, 57 chats Maine Coon des deux sexes, avec un statut inconnu en regard de la mutation au moment de l’inclusion dans l’étude, ont été inclus de manière prospective et évalués par échographie conventionnelle et par imagerie de déformation. Des comparaisons ont été faites parmi les chats sans hypertrophie (n = 45), les chats suspects (n = 7), et les chats avec cardiomyopathie hypertrophique (n = 5), et également entre les hétérozygotes pour le groupe avec mutation (n = 26) et les négatifs pour le groupe avec mutation (n = 28). Finalement, dans le groupe de chats phénotypiquement normaux, les chats hétérozygotes porteurs de la mutation ont été comparés aux chats sans la mutation. Les valeurs de déformation ont été comparées parmi les groupes (étude prospective à l’aveugle). Alors que l’échographie a montré une contractilité normale, les valeurs de déformation (au milieu du septum) étaient plus faibles chez les chats avec CMH. Les valeurs de déformation (à la base de la paroi antérieure du ventricule gauche) étaient plus faibles chez les chats hétérozygotes que chez les chats négatifs, et ce même avant l’hypertrophie. Une corrélation négative fut observée entre quelques valeurs de déformation myocardique et d’épaisseur. Bien que l’échographie par imagerie de déformation était en mesure de détecter des anomalies systoliques, malgré une apparence de normalité lors de l’échographie conventionnelle, elle n’était pas en mesure d’identifier les chats porteurs de la mutation A31P dans le gène MYBPS3. L’échographie par imagerie de déformation pourrait toutefois être un outil utile pour détecter des altérations systoliques chez des chats CMH avec une fonction systolique apparemment normale ou pour détecter des altérations chez des porteurs normaux de la mutation dans le gène MYBPC3
(Traduit par Docteur Serge Messier)
Introduction
Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular concentric hypertrophy with no evidence of pressure overload or hormonal stimulation as a cause (1–3). It is the main type of cardiomyopathy found in cats and is associated with the development of heart failure, systemic thromboembolism, and sudden death (4). Hypertrophic cardiomyopathy (HCM) is a genetically and phenotypically heterogeneous disease (5,6) and one cause of it in Maine coon cats is the A31P mutation in the MYBPC3 gene (4).
Myocardial thickening and myocardial collagen deposition (interstitial and replacement fibrosis) increase ventricular stiffness (7). The increase in left ventricular stiffness results in an increase in diastolic pressure for any given diastolic volume (8–10). The increased filling pressure results in increased atrial, pulmonary venous, and pulmonary capillary pressures (11–13).
Conventional echocardiography is the most commonly used test for evaluating cardiac anatomy and function (14) and is the best noninvasive diagnostic method for differentiating HCM from other cardiomyopathies (2,9,15,16). Two-dimensional, color flow Doppler, and tissue Doppler imaging are used to identify the 2 basic components of HCM (hypertrophy and diastolic dysfunction) and the common sequelae to this disease, e.g., mitral regurgitation and outflow obstruction due to systolic anterior motion (SAM) of the mitral valve and left atrial enlargement (16).
Tissue Doppler imaging (TDI) is a noninvasive diagnostic tool that is capable of evaluating the heart wall motion and permits the quantification of regional and global myocardial function (3,9,17). It is sensitive and specific for evaluating myocardial dysfunction, although as with other measures, it can be influenced by preload and afterload (3,17). It can also assist in detecting abnormalities in cats that are genetically affected by HCM before the development of myocardial hypertrophy (3,4,9). Strain is the amount of deformity of a tissue when a certain amount of force is applied to it (18,19). Measuring strain by tissue Doppler echocardiography enables a quantitative evaluation of regional myocardial function, is sensitive to the changes identified in various diseases in cats and humans (20,21), and aids in the characterization of myocardial heterogeneity in cardiomyopathies in humans (18,22). Strain eliminates the influence of the movement of the whole heart (translational movement) (20,23). Strain has been used in humans to help differentiate the causes of hypertrophy by assessing systolic contraction and lusitropy (24). Human patients with HCM have decreased strain values compared with normal individuals and a negative correlation between strain and the degree of hypertrophy has been noted (19).
While strain echocardiography is new and has rarely been used in cats, it is reliable, provides good repeatability, and enables early detection of systolic dysfunction in certain stages of feline HCM (20). A study conducted in cats in different stages of HCM showed that, although conventional echocardiography demonstrated normal contractility, strain values were lower in animals with hypertrophy, demonstrating that systolic dysfunction is already present in the early stages of the disease (20).
A study comparing strain echocardiography in humans tested for a mutation that causes HCM showed reduced strain values in patients with hypertrophy (18). No differences were observed between carriers of the mutation without hypertrophy and normal patients, which indicates that systolic function remains preserved at this stage, although diastolic dysfunction is already present.
The objective of the present study was to assess systolic function using strain echocardiography in Maine coon cats genetically tested for the A31P mutation in the MYBPC3 gene, with and without ventricular hypertrophy. Before the development of detectable changes on conventional echocardiography, strain alterations in young cats may assist in early diagnosis and increase knowledge of the pathophysiology of the disease.
Materials and methods
Animals
Fifty-seven Maine coon cats of both genders were included in this blinded, prospective study, which was approved by the Bioethics Committee of the University of São Paulo. All animals were subjected to anamnesis, physical examination, and blood work [complete blood (cell) count and serum urea, creatinine, liver enzyme, total protein, albumin, sodium, potassium, total calcium, phosphorus, and total T4 thyroid hormone concentrations]. Electrocardiography, thoracic radiography, and mensuration of arterial blood pressure (by Doppler vascular method) were conducted according to previously established methodologies (25–27).
Animals presenting with systemic arterial hypertension, nephropathy, and/or hyperthyroidism were excluded from the study, as well as cats that presented any other illness that could interfere with the cardiovascular system.
Whole blood samples were sent to the Veterinary Cardiac Genetics Laboratory at Washington State University for identification of the A31P mutation in the MYBPC3 gene (3). Based on the results, the animals were classified as negative, heterozygous, or homozygous (3,28). The authors did not receive the genetic results for the cats until the study had ended in order to reduce subjective interference in interpreting the examinations (blinded study).
Conventional echocardiography
Echocardiographic examination was carried out using a Vivid 7 Expert echocardiograph (General Electric-Standpromenaden, Horten, Norway), equipped with software for tissue Doppler echocardiography, as recommended by the Echocardiography Committee of the Specialty of Cardiology, American College of Veterinary Internal Medicine (14) and the American Society of Echocardiography (29). Simultaneous electrocardiographic monitoring was carried out during the echocardiogram, without the use of sedation and/or tranquilization, with cats positioned in left lateral decubitus.
All variables were measured 3 times on 3 different non-consecutive cycles and an average of these 3 measurements was calculated for each variable. The images for the measurement of the LV were acquired in the right parasternal window, transverse section, at the level of insertion of the chordae tendineae on the papillary muscles (M mode). The presence of myocardial hypertrophy was determined when the diastolic thickness of the interventricular septum (IVSd) and/or the free wall of the left ventricle (LVWd) were equal to or greater than 0.6 cm (4,30). Animals with a diastolic thickness less than 0.5 cm were considered normal and cats with values between 0.5 and 0.6 cm were considered suspect for HCM (4,30,31). Concentric hypertrophy was considered symmetric when the ratio IVSd/LVWd was between 0.7 and 1.3 (4). When asymmetric hypertrophy was observed, segmental hypertrophy was measured using the 2-dimensional mode. The diameters of the aortic root (Ao) and the left atrium (LA) were measured using the 2-dimensional mode (31), right parasternal window, and transverse section at the region of the base of the heart. The left atrium (LA) was considered enlarged when the ratio LA/Ao was greater than 1.5 (20).
The parameters evaluated by pulsed Doppler echocardiography were maximum velocity of aortic flow and pulmonary artery flow, maximum velocity of the transmitral flow waves E and A, E/A ratio, E-wave deceleration time, and isovolumetric relaxation time (IVRT).
After the echocardiographic examination, the animals were classified according to HCM, as normal group, suspect group, or HCM group. Moreover, to assess the animals before the development of ventricular hypertrophy, normal cats were classified according to their genotypes as normal and negative, normal and heterozygous, or normal and homozygous.
Strain echocardiography
Strain imaging echocardiography was carried out according to a recent study with cats (20), using the tissue Doppler imaging (TDI) methodology. In the strain mode, longitudinal myocardial function was evaluated using the apical 4-chamber view and the apical 2-chamber view and the radial function was evaluated using a transverse section at the level of the papillary muscles (Figures 1 and 2). Complete digital data from 3 heart cycles were stored in cine loop format for subsequent myocardial strain analysis. The evaluated parameters included: systolic movement (StS) of the LV at the base and middle region of the IVS and LVW at the apical 4-chamber view (longitudinal); and the base and middle region of the anterior left ventricular wall (ALVW) and posterior left ventricular wall (PLVW) at the apical 2-chamber view (longitudinal) and at the region of the endocardium and epicardium at the level of the papillary muscles on the lateral wall (transverse). Simultaneous electrocardiographic monitoring was carried out during the evaluation, in which the “event marker” tool was used to identify the opening and closing of the aortic valve and instantaneous heart rate was measured to observe the influence of the heart rate on each evaluated measure (correlation between heart rate and value of strain). The repeatability was evaluated for all parameters in the apical 4-chamber view, in the apical 2-chamber view, and in the transversal view by the same echocardiographer (within day variability).
Figure 1.
Strain values at base of the interventricular septum (IVS) at apical 4-chamber view (4CSB).
AVC — aortic valvular closing; AVO — aortic valvular opening; IV — interventricular; StS — systolic strain wave.
Figure 2.
Strain values at endocardium and epicardium at left ventricular wall in transversal view (papillary muscle).
AVC — aortic valvular closing; AVO — aortic valvular opening; StS — systolic strain wave.
Statistical analysis
The Shapiro-Wilk test was used to assess data normality. Mean, standard deviation, minimum value, maximum value, and median were calculated for the variables that presented a normal distribution. The P-value for Student’s t-test and/or for Mann-Whitney test (2 groups) was used to compare the averages of the continuous variables, as well as the P-value for analysis of variance (ANOVA) and/or Kruskal-Wallis test (3 or more groups). Due to the small number of homozygotes, these animals were not considered for statistical analysis. When the normality tests were rejected in at least 1 group or when little data were present, Mann-Whitney and Kruskal-Wallis tests were used instead of the respective t-test and ANOVA. Frequency tables and Pearson’s Chi-square and/or Fisher’s exact test were used for the categorical variables. In order to assess intraobserver variability (repeatability), a paired t-test was used for differences equal to zero, obtaining a coefficient of variation for all views evaluated. The level of significance was fixed at 5%, always considering a 2-tailed alternative hypothesis.
Results
Epidemiological characteristics
Among the 57 cats, 23 were male (40.4%) and 34 were female (59.6%). Body weight varied from 3.1 to 7.9 kg (5.11 ± 1.26 kg), with an average of 6.20 ± 0.81 kg (4.9 to 7.9 kg) for male cats and 4.37 ± 0.93 kg (3.1 to 6.7 kg) for female cats. The average weight of male cats was significantly higher than that of the female cats (P < 0.0001). No significant differences in weight could be noted between intact and spayed/neutered animals. The cats varied in age from 8 to 89 mo (33.72 ± 17.22 mo) and no significant difference was noted between the average ages of the male and female cats. All cats were asymptomatic for cardiovascular disorders by the time of the present study.
Genotypic and phenotypic classification
Regarding genotype classification, 28 cats were negative for the mutation (49%; mean age = 2.61 ± 1.31 y), 26 were heterozygous (46%; mean age = 3.00 ± 1.55 y), and 3 were homozygous (5%; mean age = 2.98 ± 1.66 y). Homozygous cats were excluded from the statistical analysis because of the small number. No significant differences were noted in the weight, gender, or age range of the animals.
Regarding phenotypic classification, 45 cats were considered normal (79%; mean age = 2.82 ± 1.49 y), 7 suspect (12%; mean age = 3.10 ± 1.45 y), and 5 affected by HCM (9%; mean age = 2.26 ± 0.77 y). No differences were observed in the gender or age range of the animals, although normal cats had lower body weights than the suspect (P < 0.001) and HCM group (P < 0.05). The distribution of the cats according to genotype and phenotype is shown in Table I.
Table I.
Distribution of Maine coon cats according to genotype and phenotype
| Classification | No mutation (n = 28) | Heterozygous for mutation (n = 26) | Homozygous for mutation (n = 3) |
|---|---|---|---|
| Normal (n = 45) | n = 25 | n = 19 | n = 1 |
| Suspects (n = 7) | n = 3 | n = 3 | n = 1 |
| HCM (n = 5) | n = 0 | n = 4 | n = 1 |
| Total (n = 57) | n = 28 | n = 26 | n = 3 |
HCM — hypertrophic cardiomyopathy.
With the purpose of investigating early changes (before ventricular hypertrophy), a comparison was made within the group of normal cats. Normal cats were classified according to their genotypes as: normal and negative (n = 25; mean age = 2.54 ± 1.27 y); normal and heterozygous (n = 19; mean age = 3.27 ± 1.68 y); and normal and homozygous (n = 1; mean age = 1.33 ± 0.00 y). Statistical analysis was done between normal negative and normal heterozygous animals. There were no differences in weight, age range, or sex distribution in these groups.
Conventional echocardiography results
When evaluating transmitral flow, a fusion of the E and A waves occurred, which prevented the evaluation of 26 animals (45.6%). A positive correlation was observed between the occurrence of wave fusion and heart rate (P < 0.008).
The 5 cats in the HCM group presented a symmetric form of the disease, with an IVSd/LVWd ratio ranging from 0.8 to 1.3. Hypertrophic cardiomyopathy was considered mild in 3 heterozygotes, moderate in 1 homozygote, and severe in 1 heterozygote (Table II).
Table II.
Mean and standard deviation of conventional echocardiography values in Maine coon cats
| Parameters | All (n = 57) | Negatives (n = 28) | Heterozygous (n = 26) | Homozygous (n = 03) | Normal (n = 45) | Suspects (n = 07) | HCM (n = 05) | Normal negatives (n = 25) | Normal heterozygous (n = 19) |
|---|---|---|---|---|---|---|---|---|---|
| HR (bpm) | 197.8 ± 31.5 | 193.86 ± 32.89 | 202.5 ± 30.3 | 194.6 ± 35.5 | 201.8 ± 32.5 | 186.2 ± 25.1 | 178.4 ± 21.7 | 196.0 ± 32.9 | 208.5 ± 32.0 |
| IVSd (cm) | 0.45 ± 0.08 | 0.44 ± 0.05 | 0.46 ± 0.10 | 0.56 ± 0.11 | 0.42 ± 0.04a | 0.52 ± 0.02b | 0.64 ± 0.10c | 0.42 ± 0.05 | 0.41 ± 0.04 |
| LVWd (cm) | 0.44 ± 0.09 | 0.42 ± 0.05 | 0.44 ± 0.10 | 0.57 ± 0.12 | 0.40 ± 0.04a | 0.51 ± 0.06b | 0.63 ± 0.11c | 0.41 ± 0.04 | 0.40 ± 0.04 |
| LVd (cm) | 1.69 ± 0.21 | 1.72 ± 0.22 | 1.68 ± 0.21 | 1.57 ± 0.08 | 1.68 ± 0.22 | 1.75 ± 0.22 | 1.69 ± 0.13 | 1.71 ± 0.23 | 1.65 ± 0.22 |
| LVs (cm) | 0.80 ± 0.14 | 0.81 ± 0.14 | 0.80 ± 0.14 | 0.66 ± 0.11 | 0.81 ± 0.15 | 0.76 ± 0.14 | 0.78 ± 0.06 | 0.81 ± 0.15 | 0.80 ± 0.16 |
| FS (%) | 53.05 ± 4.91 | 52.94 ± 5.05 | 52.58 ± 4.57 | 58.11 ± 5.31 | 52.44 ± 4.79 | 56.41 ± 5.75 | 53.78 ± 3.32 | 52.72 ± 4.96 | 51.91 ± 4.71 |
| Ao (cm) | 0.96 ± 0.13 | 0.94 ± 0.12 | 0.97 ± 0.14 | 0.95 ± 0.18 | 0.95 ± 0.13 | 0.91 ± 0.13 | 1.08 ± 0.07 | 0.95 ± 0.12 | 0.95 ± 0.15 |
| LA (cm) | 1.19 ± 0.20 | 1.13 ± 0.16 | 1.23 ± 0.21 | 1.44 ± 0.28 | 1.16 ± 0.18a | 1.25 ± 0.19a,b | 1.40 ± 0.29b | 1.13 ± 0.16 | 1.20 ± 0.20 |
| LA/Ao | 1.25 ± 0.17 | 1.20 ± 0.14 | 1.27 ± 0.16 | 1.54 ± 0.33 | 1.23 ± 0.13 | 1.41 ± 0.30 | 1.29 ± 0.24 | 1.20 ± 0.12 | 1.26 ± 0.14 |
| Fl Ao — Vmax | 1.20 ± 0.71 | 0.99 ± 0.19a | 1.30 ± 0.90b | 2.23 ± 0.82 | 1.06 ± 0.23a | 1.14 ± 0.49b | 2.58 ± 1.85c | 1.00 ± 0.19 | 1.11 ± 0.23 |
| Fl PA — Vmax | 1.03 ± 0.16 | 1.01 ± 0.13 | 1.04 ± 0.19 | 1.05 ± 0.19 | 1.04 ± 0.16 | 0.99 ± 0.17 | 0.96 ± 0.14 | 1.03 ± 0.14 | 1.07 ± 0.20 |
| E wave (m/s) | 0.92 ± 0.21 | 0.90 ± 0.18 | 0.93 ± 0.21 | 1.03 ± 0.40 | 0.93 ± 0.20 | 0.87 ± 0.15 | 0.93 ± 0.38 | 0.92 ± 0.19 | 0.92 ± 0.21 |
| A wave (m/s) | 0.61 ± 0.15 | 0.61 ± 0.15 | 0.60 ± 0.13 | 0.85 ± 0.00 | 0.59 ± 0.15 | 0.63 ± 0.14 | 0.75 ± 0.10 | 0.60 ± 0.16 | 0.58 ± 0.14 |
| E/A | 1.33 ± 0.29 | 1.36 ± 0.27 | 1.35 ± 0.27 | 0.68 ± 0.00 | 1.38 ± 0.27 | 1.28 ± 0.35 | 1.03 ± 0.30 | 1.39 ± 0.25 | 1.36 ± 0.30 |
| IVRT (ms) | 55.68 ± 9.21 | 53.67 ± 5.93 | 56.38 ± 9.93 | 68.60 ± 19.0 | 54.09 ± 7.4a | 56.99 ± 7.8b | 71.1 ± 16.2c | 53.45 ± 5.60 | 54.74 ± 9.51 |
HCM — hypertrophic cardiomyopathy; HR — heart rate; IVSd — interventricular septum in diastole; LVWd — left ventricular wall in diastole; LVd — left ventricle in diastole; LVs — left ventricle in systole; FS — fractional shortening; Ao — aorta; LA — left atrium; LA/Ao — left atrium aorta ratio; Fl Ao — aortic flow; Vmax — maximum velocity; Fl PA — pulmonary artery flow; IVRT — isovolumetric relaxation time; E/A = E wave A wave ratio.
Statistical differences.
Regarding genotypic classification, values for the maximum velocity (and pressure gradient) of the aortic flow were greater in heterozygotes than in negative cats (P < 0.05). No significant changes were observed for the remaining echocardiographic parameters or for the heart rate (Table II).
As to the phenotypic classification, the diameter of the LA was greater in the HCM group than in normal cats (P < 0.05). Statistical differences were noted in the IVRT, which was greater for the HCM group than for the suspect (P < 0.05) and normal cats (P < 0.001), and in the velocity of aortic flow, which was also greater for the HCM group than for the suspect group (P < 0.001) and normal cats (P < 0.001) (Table II). Three of the 5 cats with HCM had systolic anterior motion (SAM) of the mitral valve. No significant changes were observed for the remaining parameters.
When evaluating the group of phenotypically normal cats, no statistically significant differences were observed for the different parameters of conventional echocardiography between cats with and without mutation (Table II).
Strain imaging results
Strain values in relation to genotype and phenotype are described in Tables III and IV, respectively. On genotypic evaluation, a statistical difference was observed between the strain values obtained on the 2-chamber longitudinal view at the base of the ALVW, with smaller values obtained for heterozygotes compared to those animals that were negative for the mutation (P = 0.001). As for phenotypic evaluation, a significant difference was noted for strain values obtained from the apical 4-chamber view, at the middle region of the IVS, with smaller values obtained for the HCM group than for normal animals (P = 0.01).
Table III.
Mean and standard deviation of strain values in Maine coon cats according to genotype
| Parameters | All (n = 57) | No mutation (n = 28) | Heterozygous for the mutation (n = 26) | Homozygous for the mutation (n = 3) |
|---|---|---|---|---|
| 4C-StS (%) | ||||
| HR | 195 ± 27 | 192 ± 23 | 198 ± 33 | 194 ± 7 |
| 4CWB | −11.75 ± 3.71 | −11.08 ± 3.54 | −12.56 ± 3.98 | −11.06 ± 1.23 |
| 4CWM | −12.44 ± 4.46 | −13.08 ± 4.49 | −12.25 ± 4.29 | −8.02 ± 4.43 |
| 4CSB | −21.54 ± 6.52 | −22.48 ± 5.52 | −21.20 ± 7.18 | −15.77 ± 7.98 |
| 4CSM | −23.19 ± 6.86 | −24.44 ± 6.68 | −23.22 ± 5.72 | −11.30 ± 8.51 |
| 2C-StS (%) | ||||
| HR | 194 ± 26 | 189 ± 21 | 199 ± 31 | 190 ± 18 |
| 2CPB | −13.27 ± 4.69 | −13.81 ± 5.13 | −12.53 ± 4.07 | −14.48 ± 6.16 |
| 2CPM | −14.22 ± 5.93 | −13.77 ± 5.85 | −14.42 ± 5.55 | −16.83 ± 11.11 |
| 2CAB | −16.69 ± 5.66 | −18.82 ± 6.29a | −14.58 ± 3.81b | −14.41 ± 6.74 |
| 2CAM | −18.91 ± 5.65 | −18.46 ± 5.53 | −19.08 ± 5.08 | −21.72 ± 11.86 |
| Papillary | ||||
| HR | 194 ± 28 | 192 ± 29 | 196 ± 30 | 201 ± 8 |
| StS (%) | 22.42 ± 7.19 | 20.83 ± 6.44 | 24.50 ± 7.71 | 19.92 ± 7.13 |
HR — heart rate in beats per min; 4CWB — base of the left ventricular wall (LVW) at apical 4-chamber view; 4CWM — middle region of the LVW at apical 4-chamber view; 4CSB — base of the interventricular septum (IVS) at apical 4-chamber view; 4CSM — middle region of the IVS at apical 4-chamber view; 2CPB — base of the posterior left ventricular wall (PLVW) at apical 2-chamber view; 2CPM — middle region of the PLVW at apical 2-chamber view; 2CAB — base of the anterior left ventricular wall (ALVW) at apical 2-chamber view; 2CAM — middle region of the ALVW at apical 2-chamber view; StS — systolic strain wave.
Table IV.
Mean and standard deviation of strain values in Maine coon cats according to phenotype
| Parameters | All (n = 57) | No HCM (n = 45) | Suspect (n = 7) | HCM (n = 5) |
|---|---|---|---|---|
| 4C-StS (%) | ||||
| HR | 195 ± 27 | 199 ± 28 | 183 ± 16 | 172 ± 13 |
| 4CWB | −11.75 ± 3.71 | −11.80 ± 3.62 | −11.71 ± 4.94 | −11.39 ± 3.45 |
| 4CWM | −12.44 ± 4.46 | −13.10 ± 4.44 | −10.74 ± 2.96 | −8.96 ± 4.88 |
| 4CSB | −21.54 ± 6.52 | −22.14 ± 6.46 | −19.82 ± 7.39 | −18.54 ± 5.88 |
| 4CSM | −23.19 ± 6.86 | −24.27 ± 6.34a | −19.91 ± 7.51a,b | −18.07 ± 8.22b |
| 2C StS (%) | ||||
| HR | 194 ± 26 | 196 ± 28 | 187 ± 17 | 178 ± 16 |
| 2CPB | −13.27 ± 4.69 | −13.33 ± 4.89 | −12.41 ± 4.77 | −13.99 ± 3.16 |
| 2CPM | −14.22 ± 5.93 | −14.11 ± 5.98 | −15.84 ± 5.66 | −12.95 ± 6.72 |
| 2CAB | −16.69 ± 5.66 | −17.06 ± 5.82 | −17.88 ± 3.66 | −11.79 ± 4.71 |
| 2CAM | −18.91 ± 5.65 | −19.60 ± 5.70 | −16.59 ± 3.51 | −16.14 ± 6.89 |
| Papillary | ||||
| HR | 194 ± 28 | 199 ± 28 | 181 ± 24 | 174 ± 30 |
| StS (%) | 22.42 ± 7.19 | 22.08 ± 6.89 | 22.91 ± 8.34 | 24.73 ± 9.35 |
HCM — hypertrophic cardiomyopathy; HR — heart rate in beats per min; 4CWB — base of the left ventricular wall (LVW) at apical 4-chamber view; 4CWM — middle region of the LVW at apical 4-chamber view; 4CSB — base of the interventricular septum (IVS) at apical 4-chamber view; 4CSM — middle region of the IVS at apical 4-chamber view; 2CPB — base of the posterior left ventricular wall (PLVW) at apical 2-chamber view; 2CPM — middle region of the PLVW at apical 2-chamber view; 2CAB — base of the anterior left ventricular wall (ALVW) at apical 2-chamber view; 2CAM — middle region of the ALVW at apical 2-chamber view; StS — systolic strain wave.
Statistical differences.
When evaluating only the group of cats without HCM, a statistically significant difference was noted between negative and heterozygous individuals for strain values obtained at the base of the ALVW. Strain values were lower for heterozygous animals than for negative animals (P = 0.019) (Table V).
Table V.
Mean and standard deviation of strain values in negative and heterozygous phenotypically normal Maine coon cats
| Parameters | No HCM (n = 5) | No HCM and no mutation (n = 25) | Heterozygous for the mutation (n = 19) |
|---|---|---|---|
| 4C-StS (%) | |||
| HR | 199 ± 28 | 194 ± 23 | 206 ± 34 |
| 4CWB | −11.80 ± 3.62 | −11.44 ± 3.48 | −12.32 ± 3.91 |
| 4CWM | −13.10 ± 4.44 | −13.44 ± 4.56 | −12.64 ± 4.49 |
| 4CSB | −22.14 ± 6.46 | −22.32 ± 5.55 | −21.76 ± 7.76 |
| 4CSM | −24.27 ± 6.34 | −24.45 ± 6.83 | −24.20 ± 5.95 |
| 2C-StS (%) | |||
| HR | 196 ± 28 | 190 ± 22 | 206 ± 33 |
| 2CPB | −13.33 ± 4.89 | −13.7 ± 5.30 | −13.16 ± 4.30 |
| 2CPM | −14.11 ± 5.98 | −13.74 ± 6.20 | −14.49 ± 5.95 |
| 2CAB | −17.06 ± 5.82 | −18.79 ± 6.47a | −14.59 ± 3.98b |
| 2CAM | −19.60 ± 5.70 | −18.71 ± 5.75 | −20.09 ± 4.83 |
| Papillary | |||
| HR | 199 ± 28 | 196 ± 28 | 203 ± 27 |
| StS (%) | 22.08 ± 6.89 | 21.0 ± 6.23 | 23.25 ± 7.76 |
HCM — hypertrophic cardiomyopathy; HR — heart rate in beats per min; 4CWB — base of the left ventricular wall (LVW) at apical 4-chamber view; 4CWM — middle region of the LVW at apical 4-chamber view; 4CSB — base of the interventricular septum (IVS) at apical 4-chamber view; 4CSM — middle region of the IVS at apical 4-chamber view; 2CPB — base of the posterior left ventricular wall (PLVW) at apical 2-chamber view; 2CPM — middle region of the PLVW at apical 2-chamber view; 2CAB — base of the anterior left ventricular wall (ALVW) at apical 2-chamber view; 2CAM — middle region of the ALVW at apical 2-chamber view; StS — systolic strain wave.
Statistical differences.
When evaluating all groups, a statistically significant, negative correlation was found between ventricular thickness and strain values (P < 0.05; Pearson’s correlation = −0.27) at the middle region of the ALVW. There were no correlations between heart rate and strain values.
Regarding intraobserver repeatability (in all evaluated views: 4-chamber, 2-chamber, and transversal), the second measurement was, on average, 0.66 points greater than the first and the standard deviation was greater than 2.
Discussion
The evaluated population consisted of Maine coon cats genetically tested for the A31P mutation of the MYBPC3 gene. Among the 57 cats, 51% were positive for the mutation (46% heterozygous and 5% homozygous). According to previous studies (4,20,32,33), this gene mutation is present in approximately 34% of Maine coon cats worldwide, although few studies have correlated the genotype with the occurrence of HCM.
Among the evaluated animals, 8.77% already had HCM and were all positives for the MYBPC3 gene mutation (4 heterozygotes and 1 homozygote). Animals suspect for HCM accounted for 12% of the evaluated population. Among these animals, 4 had the mutation and 3 were negative. Most animals were normal (79%), despite the existence of heterozygous and homozygous cats in this group. According to previous studies (32–35), HCM is an autosomal dominant hereditable disorder in Maine coon cats. Incomplete penetrance is very common with this type of mutation in humans, however, and apparently now also in cats, which makes it more difficult to diagnose heterozygotes through echocardiography. Moreover, as there are over 1000 mutations in 10 genes that encode sarcomere proteins related to HCM in humans (12,18,22), the absence of this mutation does not exclude the possibility of the existence of other mutations that may cause cardiomyopathy. Hypertrophic cardiomyopathy is known to be a genetically and phenotypically heterogeneous disease (5,6), which may hinder the interpretation and conclusions of the present study.
Male and female distribution was homogeneous in the studied groups. However, the prevalence of male cats between the suspect and affected animals was significantly higher (60% of cats with HCM and 71% of suspect cats were male). According to some authors (2,3,36), HCM has been more commonly reported in middle-aged male animals, although it may also occur in female and young or elderly cats. Some studies have not reported gender differences, although there have been reports of earlier and more evident clinical manifestations in male animals (11).
Mean weight was higher for male animals than female animals, which may be explained by the racial pattern of the animals, based on which male cats are noticeably larger than female cats. Although the group of normal cats had lower body weights than the other groups (suspects and cats with HCM), there were more female animals in the normal group, which explains these findings.
The velocity of aortic flow was greater in cats heterozygous for the mutation than in cats without the mutation. These cats also showed phenotypic alterations related to HCM, however, which may have masked the values obtained in this study. When evaluating only the group without HCM, no significant differences were found regarding genotype. Therefore, conventional echocardiography was unable to differentiate cats without the mutation from those with it before they developed ventricular hypertrophy, which is consistent with what has been reported in the literature (2,4,37,38).
As for phenotypic classification, the diameter of the left atrium (LA) was greater in cats affected by HCM than in normal cats. Differences in IVRT and velocity of aortic flow were noted and were greater in affected animals than in suspect and normal animals. Three of the 5 cats with HCM had SAM, with increase in aortic flow.
When considering strain mode, regarding phenotypic evaluation, significant differences were observed at the middle region of the interventricular septum (IVS), with smaller values in cats with HCM than in normal cats. Strain mode can be used for early quantification of the degree of systolic dysfunction in certain stages of feline HCM (20). In a study conducted with normal cats and cats in different stages of HCM, although conventional echocardiography demonstrated a normal condition or increased contraction (normal shortening fraction), strain was lower in all animals with hypertrophy (20). In humans, patients with HCM have also shown lower septal strain values than normal individuals, especially in the middle region of the septum in relation to the basilar region (19), which is similar to the results obtained in this study.
Regarding genotypic evaluation, a statistically significant difference was found between strain values obtained at the base of the ALVW, with lower values for heterozygotes than for negative animals. According to the literature, strain enables the direct quantitative evaluation of regional myocardial function. It is sensitive to quantifying systolic function (albeit preload- and afterload-dependent systolic function) in different segments of the myocardium in the radial, longitudinal, and circumferential directions (21) and it is an ideal method for characterizing the heterogeneity of myocardial function in cardiomyopathies (18,20). Until completion of the present study, however, no studies using strain in cats genetically tested for HCM could be found. The quantification of systolic longitudinal LV motion assessed from the apical 2-chamber view, however, has not yet been validated in cats, which could be a limitation of these results. Another limitation of this study was the lack of repeatability (intraobserver coefficient of variation) observed in strain parameters.
When assessing only the normal group, a significant difference could be noted at the base of the ALVW, with smaller strain values for heterozygotes than for negative animals. Once again, it is important to emphasize the lack of studies using strain to compare genotypically different cats before ventricular hypertrophy has developed, the lack of validation to quantify strain values by apical 2-chamber view, and the lack of repeatability observed. In humans, a study comparing strain in carriers of a mutation, with or without ventricular hypertrophy, showed a reduction in longitudinal strain values in patients who had already presented increased myocardial thickness (18). As no differences were found between carriers of the mutation (without hypertrophy) and normal patients, it can be concluded that, despite diastolic dysfunction secondary to sarcomere alterations, in early stages systolic function remains preserved. In another study conducted in humans who were carriers of a mutation that causes HCM and who had no hypertrophy (39), however, peak systolic strain assessed by echocardiography and magnetic resonance was decreased before the presence of hypertrophy, which is similar to the results obtained herein.
In the present study, signs of regional systolic dysfunction were observed in cats heterozygous for the A31P mutation before ventricular hypertrophy had developed. On clinical evaluation, hypertrophic cardiomyopathy (HCM) is considered a disorder with predominantly diastolic dysfunction constituting changes in relaxation in the early stages and changes in ventricular distensibility in advanced stages (36). In humans, systolic and diastolic changes can be found on tissue Doppler echocardiography in patients with HCM. Diastolic dysfunction is a consequence of the mutation on the sarcomere, while systolic dysfunction is thought to result from the presence of the mutation in association with pathological remodeling (18).
Echocardiographic indices that assess systolic function are overestimated in the presence of ventricular hypertrophy and are dependent on preload and afterload conditions. Therefore, the ejection and shortening fractions do not always reflect the actual myocardial function when there is HCM. Strain analysis seems to be more sensitive for evaluating myocardial function. Hypertrophic cardiomyopathy (HCM) is characterized by ventricular hypertrophy, interstitial fibrosis, and disorganization of myocytes and myofibrils. When this disorder is already present, the contraction of the fibers will result in a disorganized pattern of deformation, which causes detectable changes in strain, even in the early stages.
When investigating the correlation between myocardial thickness and systolic strain values, a negative correlation could be noted at the middle region of the ALVW. Studies conducted in humans (19,39) and in cats (20) have shown a negative correlation between strain values and myocardial thickness. Therefore, the greater the degree of hypertrophy, the greater the systolic dysfunction associated with the disease.
Regarding intraobserver variability in all evaluated strain views (2-chamber, 4-chamber, and transversal), the second measurement was slightly greater than the first, with a possible bias on strain evaluation. According to the literature, the strain curve is clean and presents a smaller interobserver variation (20). However, strain is a new method that has rarely been used in cats. Care should be taken when evaluating radial strain and emphasis should be given to the fact that the septum contains fibers from both ventricles, which can mask and alter measurements (20). The coefficient of variation (repeatability) was not calculated separately for each echocardiographic view and the reproducibility test was not carried out, which is another limitation of the present study.
Another limitation that should be mentioned is that, in the present study, strain was evaluated with the tissue Doppler technique and not with speckle tracking echocardiography, which is a more recent and accurate technique for evaluating global systolic function.
The main limitations of this study are the small number of animals evaluated and the small number of homozygotes, which prevented statistical comparisons, thus reducing the chance of detecting early changes in these animals. Another limitation relates to the young age of the population. Although most cats were within the age range for the highest occurrence of HCM, 10% of the studied population were younger than 1.5 y. Therefore, the possibility of finding more evident diastolic dysfunctions, or even HCM, if these animals had been evaluated at older ages cannot be excluded. Another limitation is the lack of validation to quantify the systolic longitudinal LV motion assessed from the apical 2-chamber view. More studies of use of the strain imaging technique in the 2-chamber longitudinal view must be carried out in order to validate this method with high repeatability and reproducibility.
In many cats, tachycardia resulted in impaired echocardiographic evaluation and interpretation. The fusion of E and A waves was common on the different sections, which impaired the analyses.
In conclusion, strain imaging is a new echocardiographic mode that detects systolic abnormalities in Maine coon cats with mutations in the MYBPC3 gene, despite the apparently normal to increased shortening fraction (contraction) on conventional echocardiography. Cats with HCM and without clinical signs presented some alterations in indices of systolic function obtained through strain. Strain echocardiography could be a useful tool for detecting systolic alterations in HCM cats with an apparently normal systolic function or for detecting alterations in normal carriers of the MYBPC3 gene mutation.
Acknowledgments
The authors thank the State of São Paulo Research Foundation (FAPESP) and the Brazilian Association of Maine Coon Breeders (AMACOON) for supporting this study.
Footnotes
The authors declare that there are no financial or non-financial conflicts of interest involved in the preparation of this article.
References
- 1.Fox PR. Feline cardiomyopathies. In: Fox PR, Sisson D, Moise NS, editors. Textbook of Canine and Feline Cardiology: Principles and Clinical Practice. 2nd ed. Philadelphia, Pennsylvania: W.B. Saunders; 1999. pp. 621–641. [Google Scholar]
- 2.Chetboul V, Blot S, Sampedrano CC, et al. Tissue Doppler imaging for detection of radial and longitudinal myocardial dysfunction in a family of cats affected by dystrophin-deficient hypertrophic muscular dystrophy. J Vet Intern Med. 2006;20:640–647. doi: 10.1892/0891-6640(2006)20[640:tdifdo]2.0.co;2. [DOI] [PubMed] [Google Scholar]
- 3.MacDonald KA, Kittleson MD, Kass PH, Meurs KM. Tissue Doppler imaging in Maine Coon cats with a mutation of myosin binding protein C with or without hypertrophy. J Vet Intern Med. 2007;21:232–237. doi: 10.1892/0891-6640(2007)21[232:tdiimc]2.0.co;2. [DOI] [PubMed] [Google Scholar]
- 4.Sampedrano CC, Chetboul V, Mary J, et al. Prospective echocardiography and tissue Doppler imaging screening of a population of Maine Coon cats tested for the A31P mutation in the myosin-binding protein C gene: A specific analysis of the heterozygous status. J Vet Intern Med. 2009;23:91–99. doi: 10.1111/j.1939-1676.2008.0218.x. [DOI] [PubMed] [Google Scholar]
- 5.Haggstrom J. Hypertrophic cardiomyopathy in cats — It used to be so simple. J Feline Med Surg. 2003;5:139–141. doi: 10.1016/S1098-612X(02)00128-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Baty CJ. Feline hypertrophic cardiomyopathy: An update. Vet Clin Small Anim. 2004;34:1227–1234. doi: 10.1016/j.cvsm.2004.06.005. [DOI] [PubMed] [Google Scholar]
- 7.MacDonald K. Myocardial disease: Feline. In: Ettinger ST, Feldman EC, editors. Textbook of Veterinary Internal Medicine. 6th ed. St. Louis, Missouri: Elsevier Saunders; 2005. pp. 1328–1341. [Google Scholar]
- 8.Gundler S, Tidholm A, Häggström J. Prevalence of myocardial hypertrophy in a population of asymptomatic Swedish Maine coon cats. Acta Vet Scand. 2008;50:1–6. doi: 10.1186/1751-0147-50-22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Chetboul V, Sampedrano CC, Gouni V, Nicolle AP, Pouchelon JL. Two-dimensional color tissue Doppler imaging detects myocardial dysfunction before occurrence of hypertrophy in a young Maine Coon cat. Vet Radiol Ultrasound. 2006;47:295–300. doi: 10.1111/j.1740-8261.2006.00143.x. [DOI] [PubMed] [Google Scholar]
- 10.Severino S, Caso P, Cicala M, et al. Involvement of right ventricle in left ventricular hypertrophic cardiomyopathy: Analysis by pulsed Doppler tissue imaging. Eur J Echocardiogr. 2000;1:281–288. doi: 10.1053/euje.2000.0043. [DOI] [PubMed] [Google Scholar]
- 11.Ware W. Myocardial disease of the cat. In: Ware W, editor. Cardiovascular Disease in Small Animal Medicine. London, UK: Manson Publishing; 2007. pp. 300–319. [Google Scholar]
- 12.Kato TS, Izawa H, Komamura K, et al. Heterogeneity of regional systolic function detected by tissue Doppler imaging is linked to impaired global left ventricular relaxation in hypertrophic cardiomyopathy. Heart. 2008;94:1302–1306. doi: 10.1136/hrt.2007.124453. [DOI] [PubMed] [Google Scholar]
- 13.Koffas H, Dukes-McEwan JD, Corcoran BM, et al. Color M-mode tissue Doppler imaging in healthy cats and cats with hypertrophic cardiomyopathy. J Small Anim Pract. 2008;49:330–338. doi: 10.1111/j.1748-5827.2008.00543.x. [DOI] [PubMed] [Google Scholar]
- 14.Thomas WP, Gaber CE, Jacobs GJ, et al. Recommendations for standards in transthoracic two-dimensional echocardiography in the dog and cat. J Vet Intern Med. 1993;7:247–252. doi: 10.1111/j.1939-1676.1993.tb01015.x. [DOI] [PubMed] [Google Scholar]
- 15.Simpson KE, Devine BC, Gunn-Moore DA, et al. Assessment of the repeatability of feline echocardiography using conventional echocardiography and spectral pulse-wave Doppler tissue imaging techniques. Vet Radiol Ultrasound. 2007;48:58–68. doi: 10.1111/j.1740-8261.2007.00205.x. [DOI] [PubMed] [Google Scholar]
- 16.Ferasin L. Feline myocardial disease-2: Diagnosis, prognosis and clinical management. J Feline Med Surg. 2009;11:183–194. doi: 10.1016/j.jfms.2009.01.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Oki T, Mishiro Y, Yamada H, et al. Detection of left ventricular regional relaxation abnormalities and asynchrony in patients with hypertrophic cardiomyopathy with the use of tissue Doppler imaging. Am Heart J. 2000;139:487–502. doi: 10.1016/s0002-8703(00)90094-2. [DOI] [PubMed] [Google Scholar]
- 18.Ho CY, Sweitzer NK, McDonough B, et al. Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation. 2002;105:2992–2997. doi: 10.1161/01.cir.0000019070.70491.6d. [DOI] [PubMed] [Google Scholar]
- 19.Minoshima M, Noda A, Nishizawa T, et al. Endomyocardial radial strain imaging and left ventricular relaxation abnormalities in patients with hypertrophic cardiomyopathy or hypertensive left ventricular hypertrophy. Circ J. 2009;73:2294–2299. doi: 10.1253/circj.cj-08-0879. [DOI] [PubMed] [Google Scholar]
- 20.Wess G, Sarkar R, Hartmann K. Assessment of left ventricular function by strain imaging echocardiography in various stages of feline hypertrophic cardiomyopathy. J Vet Intern Med. 2010;24:1375–1382. doi: 10.1111/j.1939-1676.2010.0586.x. [DOI] [PubMed] [Google Scholar]
- 21.Teske AJ, De Boeck BW, Melman PG, Sieswerda GT, Doevendans PA, Cramer MJ. Echocardiographic quantification of myocardial function using tissue deformation imaging, a guide to image acquisition and analysis using Doppler and speckle tracking. Cardiovasc Ultrasound. 2007;5:27. doi: 10.1186/1476-7120-5-27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Kato TS, Noda A, Izawa H, et al. Discrimination of nonobstructive hypertrophic cardiomyopathy from hypertensive left ventricular hypertrophy on the basis of strain rate imaging by tissue Doppler ultrasonography. Circulation. 2004;110:3808–3814. doi: 10.1161/01.CIR.0000150334.69355.00. [DOI] [PubMed] [Google Scholar]
- 23.Chetboul V, Gouni V, Sampedrano CC, Tissier R, Serres F, Pouchelon JL. Assessment of regional systolic and diastolic myocardial functions using tissue Doppler and strain imaging in dogs with dilated cardiomyopathy. J Vet Intern Med. 2007;21:719–730. doi: 10.1892/0891-6640(2007)21[719:aorsad]2.0.co;2. [DOI] [PubMed] [Google Scholar]
- 24.Paraskevaidis IA, Panou F, Papadopoulos C, et al. Evaluation of left atrial longitudinal function in patients with hypertrophic cardiomyopathy: A tissue Doppler imaging and two-dimensional strain study. Heart. 2009;95:483–489. doi: 10.1136/hrt.2008.146548. [DOI] [PubMed] [Google Scholar]
- 25.Tilley LP. Essentials of Canine and Feline Electrocardiography: Interpretation and Treatment. 3rd ed. Philadelphia, Pennsylvania: Lea & Febiger; 1992. p. 470. [Google Scholar]
- 26.Buchanan JW, Bücheler J. Vertebral scale system to measure canine heart size in radiographs. J Am Vet Med Assoc. 1995;206:194–199. [PubMed] [Google Scholar]
- 27.Brown S, Atkins C, Bagley R, et al. Guidelines for the identification. Evaluation and management of systemic hypertension in dogs and cats. J Vet Intern Med. 2007;21:542–558. doi: 10.1892/0891-6640(2007)21[542:gftiea]2.0.co;2. [DOI] [PubMed] [Google Scholar]
- 28.Meurs KM, Norgard MM, Ederer MM, Hendrix KP, Kittleson MD. A substitution mutation in the myosin binding protein C gene in Ragdoll hypertrophic cardiomyopathy. Genomics. 2007;90:261–264. doi: 10.1016/j.ygeno.2007.04.007. [DOI] [PubMed] [Google Scholar]
- 29.Boon JA. Manual of Veterinary Echocardiography. 2nd ed. West Sussex: Wiley-Blackwell; 2011. p. 610. [Google Scholar]
- 30.Sampedrano CC, Chetboul V, Gouni V, Nicolle AP, Pouchelon JL, Tissier R. Systolic and diastolic myocardial dysfunction in cats with hypertrophic cardiomyopathy or systemic hypertension. J Vet Intern Med. 2006;20:1106–1115. doi: 10.1892/0891-6640(2006)20[1106:sadmdi]2.0.co;2. [DOI] [PubMed] [Google Scholar]
- 31.Abbott JA, Mclean HN. Two-dimensional echocardiographic assessment of the feline left atrium. J Vet Intern Med. 2006;20:111–119. doi: 10.1892/0891-6640(2006)20[111:teaotf]2.0.co;2. [DOI] [PubMed] [Google Scholar]
- 32.Meurs KM, Sanchez X, David RM, et al. A cardiac myosin binding protein C mutation in the Maine Coon cat with familial hypertrophic cardiomyopathy. Hum Mol Genet. 2005;14:3587–3593. doi: 10.1093/hmg/ddi386. [DOI] [PubMed] [Google Scholar]
- 33.Mary J, Chetboul V, Sampedrano CC, et al. Prevalence of the MYBPC3-A31P mutation in a large European feline population and association with hypertrophic cardiomyopathy in the Maine Coon breed. J Vet Cardiol. 2010;12:155–161. doi: 10.1016/j.jvc.2010.06.004. [DOI] [PubMed] [Google Scholar]
- 34.McTaggart DR. Tissue Doppler imaging in hypertrophic cardiomyopathy without left ventricular hypertrophy. Heart Lung Circ. 2002;11:92–94. doi: 10.1046/j.1444-2892.2002.00121.x. [DOI] [PubMed] [Google Scholar]
- 35.Wess G, Schinner C, Weber K, Küchenhoff H, Hartmann K. Association of A31P and A74T polymorphisms in the myosin binding protein C3 gene and hypertrophic cardiomyopathy in Maine Coon and other breed cats. J Vet Intern Med. 2010;24:527–532. doi: 10.1111/j.1939-1676.2010.0514.x. [DOI] [PubMed] [Google Scholar]
- 36.Fuentes VL. Cardiomyopathy: Establishing a diagnosis. In: August JF, editor. Consultation in Feline Internal Medicine. 5th ed. St. Louis, Missouri: Elsevier Saunders; 2006. pp. 301–310. [Google Scholar]
- 37.Ferasin L. Feline myocardial disease. J Feline Med Surg. 2009;11:3–13. doi: 10.1016/j.jfms.2008.11.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Simpson KE, Gunn-Moore DA, Shaw DJ, et al. Pulsed-wave Doppler tissue imaging velocities in normal geriatric cats and geriatric cats with primary or systemic diseases linked to specific cardiomyopathies in humans, and the influence of age and heart rate upon these velocities. J Feline Med Surg. 2009;11:293–304. doi: 10.1016/j.jfms.2008.08.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Germans T, Rüssel IK, Götte MJ, et al. How do hypertrophic cardiomyopathy mutations affect myocardial function in carriers with normal wall thickness? Assessment with cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2010;12:13. doi: 10.1186/1532-429X-12-13. [DOI] [PMC free article] [PubMed] [Google Scholar]