Hypertrophic cardiomyopathy is the most common form of heart disease in cats. Multiple genetic mutations have been identified in humans with HCM; however, to date, a myosin-binding protein C mutation in Maine Coon cats and Ragdoll cats is the only gene mutation identified in association with HCM in felids.1–4 However, a genetic basis of this disease is suspected in cats affected with HCM.
Although genetic factors may predispose cats to the development of HCM, the interaction between genetics and environmental factors may also play a role in the development or manifestation of the HCM phenotype. Environmental factors such as diet and growth patterns may influence disease severity and the time of onset for this condition. Such a link between cardiac function, early growth, and diet has been determined in other species. For example, mice that express a mutant β-myosin heavy chain have significantly depressed cardiac contractile function when fed a soy-rich diet, compared with the effect of being fed a casein-rich diet.5 This change in cardiac function is especially pronounced in male mice.5 In hamsters, environmental stress such as exercise has also been found to affect the development of cardiomyopathy.6 By increasing the amount of exercise during infancy, both the expression of β-myosin heavy-chain mRNA and the degree of degenerative mitochondrial changes in cardiomyocytes were decreased.6 Among humans, individuals with fast early growth and those who are fed high-nutrient diets as infants will later develop higher adult body weight, higher adult blood pressure, and a predisposition for the development of cardiovascular diseases than other individuals.7–11 In utero nutritional conditions may also play a role; studies12–14 in sheep have revealed that maternal nutrient restriction results in left ventricular hypertrophy in the offspring. This is thought to be related to increased circulating IGF-1 activity, but could also be the result of increased blood angiotensin-II concentration or upregulation of myocardial genes for α-cardiac actin, caveolin-1, and titin.13–15 Therefore, in cats, it seems plausible that dietary intake during early developmental stages that results in faster growth may be a determinant in the severity of HCM; if this proves to be true, then dietary manipulations may be able to alter the disease progression or phenotypic expression of HCM in cats.
In a previous study,16 cats with HCM had significantly higher concentrations of serum growth hormone, compared with concentrations in healthy control cats. Growth hormone secretion is pulsatile, and a single measurement might not provide a complete assessment of growth hormone secretion. Because IGF-1 is the mediator of the growth-promoting effects of growth hormone, measurement of serum IGF-1 concentration may be a better method of assessment for growth hormone status. Insulin-like growth factor is also of interest because of its correlation with body size and nutritional status.17
Typically, the heart size of a dog or cat will vary proportionally with the animal's body size or vertebral length.18,19 In contrast, cats with HCM have higher heart-to-body weight ratios20 and larger heart dimensions for their body sizes.21 To our knowledge, no other morphometric measurements have been assessed in cats with HCM. The purpose of the study reported here was to compare morphometric measurements and serum IGF-1 concentration in cats with and without HCM. Dietary history was also assessed. Our hypothesis was that cats with HCM would have larger body size and skeletal features and higher serum IGF-1 concentrations than healthy cats.
Materials and Methods
Cats—Cats with HCM that were evaluated by the Cardiology Service at the Foster Hospital for Small Animals at Tufts Cummings School of Veterinary Medicine were eligible for inclusion in the study. To be included, HCM-affected cats had to have echocardiographic measurements consistent with HCM (ie, left ventricular free wall or interventricular septal thickness in diastole > 0.60 cm in combination with other echocardiographic findings consistent with HCM).21 On the basis of results of serum total thyroxine concentration measurement for all cats > 6 years of age, cats with hyperthyroidism were excluded. Cats with hypertension (defined as a systolic arterial blood pressure > 170 mm Hg) were excluded by measurement of blood pressure via a Doppler technique. Because of the extreme head dimensions of brachycephalic cats, cats of this skull type were excluded from the study. Maine Coon cats also were excluded because of their large body size. Furthermore, on the basis of results of laboratory assessments, cats known to have diabetes mellitus, renal failure, neoplasia, congenital aortic stenosis, or other major systemic diseases were excluded from the study. Healthy cats that were owned by clients, faculty, students, and staff were considered eligible for inclusion in the study if the cats had no abnormal cardiovascular findings detected during physical and echocardiographic examinations. As for the HCM-affected cats, apparently healthy cats with hyperthyroidism, hypertension, or other known major diseases were excluded. The study was approved by the Tufts Cummings School of Veterinary Medicine Institutional Animal Care and Use Committee, and all owners signed an informed consent form before enrolling their cats in the study.
Assessments—For each cat, body weight and BCS were recorded. Body condition score was assessed on a scale of 1 to 9, in which a score of 1 was emaciated, 5 was ideal, and 9 was obese.22 Echocardiography (2-dimensional and M-mode assessments) was performed specifically for study purposes or as part of the cats' medical care; all echocardiographic data were collected at the time of each cat's enrollment for the study. Lateral and dorsoventral thoracic radiographic views were obtained for measurement of V4, V12, VHS,18,19 maximal chest width at the level of the eighth rib (measured on the dorsoventral view), and humerus length (measured on the lateral view). The VHS was not calculated for cats with pleural effusion. The mean thickness of each cat's subcutaneous adipose tissue layer at the level of the eighth rib in the dorsoventral radiographic view was calculated from measurements taken from the right and left sides of the thorax, and the thickness of the adipose tissue layer ventral to the sternum at the level of the seventh rib in the lateral radiographic view was also measured. Radiography was performed by use of a digital radiography system, and measurements were performed by 1 investigator (JER) who was provided only with the cat's medical record number (ie, the investigator was not aware of the group to which the cat had been allocated).
In addition to measurements obtained from the thoracic radiographs, morphometric measurements were assessed in each cat as follows: head width (measured from the left zygomatic arch to the right zygomatic arch by use of a commercial calipera) and length (measured as the distance from the occipital protuberance to the tip of the nose by use of a commercial calipera [Figure 1]) and the circumference of the abdomen, just cranial to the tuber coxae (measured by use of a tape measure).
Photograph of a cat obtained during head width measurement (distance from the left zygomatic arch to the right zygomatic arch; A) and head length measurement (distance from the occipital protuberance to the tip of the nose; B) by use of a caliper.
Citation: American Journal of Veterinary Research 69, 8; 10.2460/ajvr.69.8.1061
Dietary histories of the enrolled cats were obtained. Each owner was asked to complete a survey that included questions regarding diet, current feeding methods (eg, ad libitum feeding or provision of measured meal amounts and provision of treats or dietary supplements), age at which the cat underwent ovariohysterectomy or castration, whether the cat had ever been over-weight, and the owner's assessment of his or her cat's size at 6 months of age (eg, very small, somewhat small, normal size, somewhat large, or very large). A blood sample (5 mL) was collected via jugular venipuncture with minimal restraint after food had been withheld for 8 hours. Serum was separated from each blood sample and then frozen at −80°C until analysis; serum IGF-1 concentrations were measured via high-performance liquid chromatography.
Statistical analysis—On the basis of results of a small pilot study, sample size calculations revealed that 20 cats/group would provide at least 80% power to detect a difference between the HCM-affected and control groups, with α set at 0.05. Data distributions were examined graphically. Because many of the continuous variables were not normally distributed, nonparametric statistical tests were used. Categoric variables, such as sex and breed, were compared between the HCM-affected and control groups by use of χ2 analysis. The continuous variables, such as age, body weight, and head width and length, were compared by use of a Mann-Whitney U test. Statistical analyses were performed by use of a commercial statistical software program.b A value of P < 0.05 was considered significant.
Results
Forty-seven cats were enrolled in the study, of which 25 were assigned to the HCM-affected group and 22 were assigned to the control group. For the HCM-affected group, other systemic diseases were excluded on the basis of historical information and results of clinicopathologic analyses performed in 24 of 25 cats. Results of a CBC and serum biochemical profile were unavailable for 1 of the 25 cats in the HCM-affected group (a 3-year-old castrated male domestic shorthair cat that had no history of other medical issues; systolic arterial blood pressure value and serum thyroxine concentration were within reference limits). Age (P = 0.58), sex (P = 0.32), and breed distribution (P = 0.25) in the HCM-affected and control groups were not significantly different (Table 1). Values of echocardiographic variables indicative of HCM were greater in HCM-affected cats, compared with values in the control cats; differences in the thickness of the left ventricular free wall in diastole and systole (P < 0.001), thickness of the interventricular septum in diastole and systole (P < 0.001), the size of the left atrium (P < 0.001), and the left atrial-to-aortic diameter ratio (P < 0.001) were evident. Cardiac size (based on the VHS in both thoracic radiographic views) was larger in the HCM-affected group, compared with the control group. There were no significant differences in systolic arterial blood pressure (P = 0.92) or heart rate (P = 0.89) between the 2 groups.
Comparison of age, breed, sex, and cardiovascular variables (physical, echocardiographic, and radiographic assessments) in 25 cats with HCM and 22 healthy control cats. Data are reported as median (range).
| Variable | Control group | HCM-affected group | P value* |
|---|---|---|---|
| Age (y) | 6(2-14) | 6(2-14) | 0.58 |
| Sex | 0.32 | ||
| Sexually intact male | 2 | 0 | |
| Castrated male | 15 | 22 | |
| Sexually intact female | 0 | 0 | |
| Spayed female | 5 | 3 | |
| Breed | 0.25 | ||
| DSH | 17 | 22 | |
| DLH | 5 | 3 | |
| Heart rate (beats/min) | 170(130-210) | 170(140-210) | 0.89 |
| Systolic arterial blood pressure (mm Hg) | 138(118-175) | 132(90-178) | 0.92 |
| IVSd(cm) | 0.49 (0.40-0.58) | 0.72(0.54-1.15) | < 0.001 |
| LVWd (cm) | 0.47 (0.36-0.56) | 0.72(0.26-1.16) | < 0.001 |
| LVIDd(cm) | 1.47(1.25-1.65) | 1.39(1.22-2.18) | 0.52 |
| IVSs(cm) | 0.76 (0.55-0.90) | 0.95(0.66-1.29) | < 0.001 |
| LVWs (cm) | 0.81 (0.62-0.97) | 0.98(0.30-1.37) | < 0.001 |
| LVIDs(cm) | 0.67 (0.49-0.94) | 0.67(0.35-1.57) | 0.94 |
| Left atrium (cm)† | 1.23(0.95-1.44) | 1.80(1.04-3.14) | < 0.001 |
| Aorta (cm) | 1.04(0.88-1.10) | 1.06(0.83-1.29) | 0.27 |
| Left atrial-to aortic diameter ratio | 1.23(0.89-1.54) | 1.59(1.04-3.54) | < 0.001 |
| VHS (lateral radiographic view assessment) | 7.6 (6.9-9.0) | 8.6(7.5-11.0) | < 0.001 |
| VHS (dorsoventral radiographic view assessment) | 8.0 (7.0-9.3) | 9.1 (7.9-12.0) | < 0.001 |
DSH = Domestic shorthair. DLH = Domestic longhair. IVSd = Interventricular septal wall thickness during diastole. LVWd = Left ventricular free wall thickness during diastole. LVIDd = Left ventricular internal dimension during diastole. IVSs = Interventricular septal wall thickness during systole. LVWs = Left ventricular free wall thickness during systole. LVIDs = Left ventricular internal dimension during systole.
A value of P < 0.05 was considered significant.
Left atrium measurement obtained at end-systole from standard M-mode location.
Compared with the control group, body weight was significantly (P = 0.047) higher in the HCM-affected group. Seventy percent (33/47) of all cats in the study were overweight (BCS, 6 to 7) or obese (BCS, 8 to 9). Measures of body fat, including BCS (P = 0.17), subcutaneous fat thickness measured on the dorsoventral (P = 0.75) and lateral (P = 0.99) radiographic views, and abdominal circumference (P = 0.13), were not significantly different between groups (Table 2). However, mean values of V4 (P = 0.02) and V12 (P = 0.01), chest width (P < 0.001), humerus length (P = 0.02), head length (P = 0.006), and head width (P = 0.02) were all significantly larger in the HCM-affected group, compared with findings in the control group. No significant difference in median serum IGF-1 concentration in HCM-affected cats (n = 16) and control cats (16) was detected.
Comparison of body condition, morphometric measurements (physical and radiographic assessments), and serum IGF-1 concentration in 25 cats with HCM and 22 healthy control cats. Data are reported as median (range).
| Variable | Control group | HCM-affected group | P value* |
|---|---|---|---|
| Weight (kg) | 5.2 (3.4-7.8) | 6.0 (3.2-7.9) | 0.047 |
| BCS† | 6.0 (4.5-8.5) | 6.5(5.0-8.5) | 0.17 |
| V4(mm) | 10.1(8.4-11.5) | 10.4(8.9-11.9) | 0.02 |
| V12(mm) | 14.0(12.9-16.1) | 15.0(12.2-17.1) | 0.01 |
| Chest width (mm) | 75.7 (66.4-89.5) | 85.0 (68.4-99.8) | 0.001 |
| Subcutaneous fat thickness (dorsoventral radiographic view assessment [mm]) | 18.2(7.3-42.7) | 21.9(7.0-39.6) | 0.75 |
| Subcutaneous fat thickness (lateral radiographic view assessment [mm]) | 16.1 (7.7-29.7) | 15.0(7.0-33.9) | 0.99 |
| Head length (cm) | 10.59(10.02-12.16) | 11.66(8.55-12.70) | 0.006 |
| Head width (cm) | 7.43(6.71-8.50) | 8.11(6.24-8.75) | 0.02 |
| Abdominal circumference (cm) | 44.7 (30.8-54.0) | 48.0(37.0-61.0) | 0.13 |
| Humerus length (mm) | 95.8(86.2-107.0) | 99.7(81.3-115.5) | 0.02 |
| IGF-1 (nmol/L)‡ | 98.0(26.3-179.8) | 98.5(56.0-130.0) | 0.84 |
Assessed on a scale of 1 to 9.
Number of cats evaluated in the HCM-affected group or control group was 16.
See Table 1 for remainder of key.
On the basis of information received from each owner, there were no significant differences between the HCM-affected and control groups with regard to the number of owners that fed treats (n = 5 and 7, respectively; P = 0.31), the number of cats being fed ad libitum (6 and 8, respectively; P = 0.30), or owners' estimates of their cat's size at 6 months of age (P = 0.41). Cats in the HCM-affected group were neutered at a median age of 8 months (range, 3 to 48 months), whereas cats in the control group were neutered at a median age of 6 months (range, 2 to 120 months; P = 0.74). However, because some owners had adopted their cat when it was > 6 months old, questions regarding the age at which it was neutered (HCM group, n = 18; control group, 16) and size at 6 months of age (HCM group, 17; control group, 10) could not be answered by all owners. Most owners (HCM group, 21/25; control group, 16/22) responded that their cats were or had been overweight (P = 0.35).
Discussion
The most striking finding of the present study was that cats with HCM had a larger body size than healthy cats; skeletal components, including the vertebrae, skull, and long bones such as the humerus, were larger in HCM-affected cats. The larger skeletal size in HCM-affected cats may indicate faster early growth, which possibly results from differences in early nutritional status or genetic traits. Because the pedigrees of the study cats were unknown, it also is possible that some were descendants of Maine Coon cats, which have a predisposition for HCM and large body size.
Another interesting finding was that, although cats with HCM had larger skeletal features, they were not more frequently overweight than were cats in the control group. Nonetheless, 70% of all cats in the study were overweight or obese. The most recent estimate of prevalence for overweight and obese body conditions in cats is 35%.23 Therefore, even though most of the control cats and many of the HCM cats were owned by veterinary students and staff, the prevalence of over-weight and obese body conditions in this cat population was extremely high.
In the present study, significant differences between the current feeding patterns, the age at the time of castration or ovariohysterectomy, the owner's impression of the cat's size at 6 month of age, and whether the cat had ever been overweight were not identified. Gathering accurate long-term diet history from owners proved to be difficult in our study. Not all cats had been cared for by the same owner since they were kittens; some owners had adopted their cats after 6 months of age. Therefore, many owners could not accurately report the body condition of their cat at a young age and were not aware of its early-age feeding pattern; some owners did not know the exact age at which their cat had been neutered. Furthermore, as reported by Scarlett et al,24 a high percentage of cat owners cannot accurately diagnose obesity in their pets and most tend to underestimate their pet's actual body size. Therefore, the owners in the present study could also have underestimated the actual body size of their pet at 6 month of age. As a result, the relationship between early nutritional status and larger skeletal size of cats with HCM cannot be reliably established on the basis of these data alone and remains a topic for future investigation.
A difference in serum IGF-1 concentration between HCM-affected and control cats was not detected in our study, but measurement of serum IGF-1 concentration in adult animals might not reflect their nutritional status during the neonatal period or episodes of fast growth. In humans, circulating IGF-1 concentration is low at birth but increases quickly during the first year; a peak value is attained during puberty, after which time the concentration decreases.25 Therefore, if the pattern of changes in IGF-1 concentration is similar in cats, serum IGF-1 concentrations measured in adult cats in the present study will reflect postpubertal IGF-1 concentrations because all of those cats were > 2 years old. Future investigations might be devised to evaluate circulating IGF-1 concentrations in young, growing cats that are predisposed to HCM or that carry a genetic mutation that is known to cause HCM.
There are a number of limitations to the study of this report. Among the study cats, the length of hair differed and was a potential source of measurement error. The variation in hair length could have affected abdominal circumference measurements. However, head length and width measurements were less influenced by variation in hair length because those assessments used bony protuberances as landmarks. Distribution of adipocytes can vary among animals; in cats, adipocytes are often preferentially distributed to the abdominal region in cats and differential fat distribution could alter metabolic effects. In markedly obese cats, the cardiac border was difficult to trace on the dorsoventral radiographic view, which could have affected the accuracy of the VHS derived from those views. Another potential measurement error in VHS in cats was the variable degree of vertebral column curvature in the lateral thoracic radiographic views; the calculated VHS values could have been anomalously low for cats with extremely curved vertebral columns. Investigators may have been aware of a cat's group allocation (HCM affected or control) during measurement of head size and abdominal circumference. Although radiographic measurements were performed by 1 investigator who was unaware of the cats' group allocations, measurements for cats with cardiomegaly or pleural effusion were not obtained in a blinded manner. In future studies, a blinded investigator should perform all morphometric measurements to avoid possible investigator bias.
The results of the present study support the hypothesis that cats with HCM have different morphometric features than healthy control cats. On the basis of multiple skeletal measurements, cats with HCM were larger, but not more obese, than control cats. Studies to examine the relationships among genetics, dietary intake, early growth patterns, and adult skeletal size and the effects these factors have on the development of cardiovascular disease in cats are warranted.
ABBREVIATIONS
| BCS | Body condition score |
| HCM | Hypertrophic cardiomyopathy |
| IGF-1 | Insulin-like growth factor-1 |
| V4 | Length of the fourth thoracic vertebra |
| V12 | Length of the 12th thoracic vertebra |
| VHS | Vertebral heart score |
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