An Animal Model of Human Disease
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Background Necropsy studies in domestic cats have suggested the occurrence of a primary cardiac disease resembling hypertrophic cardiomyopathy (HCM) in humans. We used two-dimensional echocardiography to define morphological and functional features of HCM during life in 46 domestic cats evaluated in a subspecialty veterinary clinic. Cats were 8 months to 14 years old (mean, 6 years).
Methods and Results During the follow-up period of as long as 49 months, 18 cats died (or were euthanatized) due to congestive heart failure, peripheral embolization, or both, and 3 other cats experienced out-of-hospital sudden, unexpected death. Echocardiography showed a small left ventricular cavity, associated with a variety of patterns of hypertrophy. Wall thickening was most often diffuse (involving ventricular septum and free wall) in 31 cats (67%) and segmental in 15 (33%), including 12 with thickening confined to anterior septum; wall thickening was judged to be asymmetrical in 42 and symmetrical (concentric) in 4. In 30 cats (65%), marked mitral valve systolic anterior motion produced dynamic obstruction to left ventricular outflow (Doppler estimated gradients, 25 to 110 mm Hg). Compared with survivors, cats with HCM that died with heart failure had greater left ventricular thickness (8.1±1.5 versus 7.3±0.9 mm; P<.05) and larger left atria (20.1±4.6 versus 16.8±3.4 mm;P=.01) and more often had the nonobstructive form (89% versus 48%; P<.01).
Conclusions A spontaneously occurring disease of domestic cats was identified by echocardiography and was similar in its phenotypic expression to HCM in humans; it was characterized by unexplained left ventricular hypertrophy in a variety of patterns with or without evidence of outflow obstruction. Unfavorable prognosis was associated with greater magnitude of hypertrophy and absence of outflow obstruction. Feline HCM may prove to be a valuable animal model of the human disease.
A number of spontaneously occurring animal models of human diseases have been described, including a variety of cardiovascular conditions.1 2 3 4 5 6 7 8 9 In particular, forms of hypertrophic cardiomyopathy (HCM), resembling in many morphological respects the human disease entity, have been reported in necropsy studies of cats,8 9 10 11 dogs,8 9 12 and pigs.3However, the features of HCM in animals during life and their relation to those in patients with this disease have not been completely defined. The recent introduction of echocardiography into clinical veterinary medicine permitted us to define in some detail the morphological and functional features of the feline form of HCM and to assess its applicability as an animal model for the human disease.
Selection of Animals
Between July 1990 and July 1992, 143 cats were referred to the Hypertrophic Cardiomyopathy Clinic at the Animal Medical Center (Caspary Research Institute and Bobst Hospital) for evaluation. These animals were suspected of having cardiac disease due most often to the presence of a heart murmur, gallop rhythm, arrhythmias, history of a thromboembolic event, dyspnea or tachypnea, or radiographic evidence of pulmonary congestion. Thirty of these 143 cats were excluded because their echocardiograms were of inadequate technical quality to assess the thickness of all left ventricular wall segments; 67 other cats were excluded on the basis of identification of another disease known to increase left ventricular wall thickness in cats, such as hyperthyroidism, severe systemic hypertension with or without renal insufficiency, or other congenital heart malformations.
The remaining 46 cats were judged to have HCM on the basis of the echocardiographic demonstration of a hypertrophied, nondilated left ventricle in the absence of another cardiac or systemic disease,13 and they constitute the present study group. These 46 cats ranged in age from 8 months to 14 years (mean, 6.1±3.6 years), and 34 (74%) were male. Breeds included 41 domestic short hair, 3 Persian, 1 domestic long hair, and 1 Maine coon. Body weights were 2.8 to 7.4 kg (mean, 4.8±1.1 kg).
Thirty-seven other domestic short-hair cats without structural or functional evidence of cardiovascular disease or dysfunction were selected for echocardiographic study as normal control animals. These animals were 7 months to 15 years old (mean, 5.3±3.1 years); 22 (59%) were male. Body weights ranged from 2.1 to 8.0 kg (mean, 4.3±1.6 kg). Control cats did not differ significantly from those with HCM with regard to age, sex distribution, or body weight.
Echocardiographic studies were performed with a commercially available Vingmed CFM 700 Sonotron instrument and a 5-mHz transducer. M-mode, two-dimensional M-mode and Doppler echocardiographic images were recorded simultaneously at 100 mm/s on -in format videotape with the subjects unsedated and manually restrained by a technician.
The ultrasound transducer was introduced from below through a hole in a table specially designed for the echocardiographic imaging of veterinary subjects.14 To achieve the parasternal long- and short-axis views, the cat was imaged in the right lateral decubitus position. The probe was placed in the right fourth or fifth intercostal space with the ultrasound beam directed cephalad and to the left. The two- and four-chamber apical views were obtained with the cat in the left lateral decubitus position with the ultrasound beam directed cephalad, dorsal, and to the left, usually in the left fifth to seventh intercostal spaces near the sternum. This examination was performed to achieve, as closely as possible, the standard cross-sectional planes described in humans.15 M-mode echocardiograms were derived from the two-dimensional images under direct anatomic visualization.16 Measurements of chamber dimensions were made from the M-mode echocardiogram (average of measurements from three to five consecutive cycles).17 The presence and magnitude of mitral regurgitation were graded with the use of color flow imaging.18
Assessment of Left Ventricular Hypertrophy
To assess the distribution of left ventricular hypertrophy, the left ventricle as viewed in the parasternal short-axis plane was divided into four relatively equal segments: anterior and posterior ventricular septa and anterolateral and posterior left ventricular free walls.19 End-diastolic thicknesses (ie, at maximum cavity dimension) of these four left ventricular wall segments were measured at both the mitral valve and papillary muscle levels with the use of a television monitor, calipers, and the calibration scale produced by the instrument, as previously described.16 19 Anterior ventricular septal and posterior free wall thicknesses were derived from an integrated analysis of the two-dimensional and M-mode echocardiograms.
The maximum wall thickness measurement within each left ventricular segment was considered to be the thickness for that particular region of the ventricle. In addition, the distribution of left ventricular hypertrophy was assessed in the cephalocaudal (longitudinal) plane. For this purpose, the ventricle was divided into two segments: the proximal (basal) portion extending from the cardiac base to the inferior margins of the mitral leaflets and the distal (apical) portion that includes that portion of the left ventricle visualized caudal to the mitral leaflets.16
A segment of left ventricular wall was judged to be hypertrophied if ≥6 mm in thickness for >50% of its area. This cutoff value was selected because it clearly exceeded the greatest wall thickness measurement attained in any cat in the control group or in normal domestic cats studied by echocardiography as reported from other institutions.20
It has not been our clinical practice to perform cardiac catheterization in cats with cardiovascular disease, and therefore we used echocardiography in each animal to assess dynamic outflow obstruction. Obstruction to left ventricular outflow was assessed from the presence and extent (magnitude and duration) of systolic anterior motion of the mitral valve21and by using continuous-wave Doppler when possible.22 23
Data are expressed as mean±SD values. Differences between continuous variables were analyzed with the unpaired Student’s t test. Differences between proportions were assessed with Fisher’s exact test.
Extent and Distribution of Left Ventricular Hypertrophy
In the 46 cats with HCM, the maximal ventricular septal thickness ranged from 3.4 to 12.3 mm (mean, 6.5±1.4 mm). For the group, these thicknesses greatly exceeded that in the normal control animals (3.7±0.7 mm; P<.001) (Table⇓).
Four patterns of left ventricular hypertrophy were identified with two-dimensional echocardiography (Fig 1⇓). Most often (31 cats; 67%), hypertrophy was diffuse and substantial, involving portions of ventricular septum as well as the contiguous anterolateral and posterior free wall (Fig 1A⇓); 15 of these 31 showed hypertrophy involving all segments of left ventricle, including 4 that were judged to be concentric in distribution by virtue of differences in thickness between the thickest and thinnest left ventricular segments of <2 mm, and 16 others had involvement of the anterior portion of the septum as well as the anterolateral and posterior free wall (but not posterior septum). The remaining 15 cats (33%) had segmental patterns of hypertrophy (Fig 1D⇓). In 13 of these, wall thickening was confined to one left ventricular segment (anterior septum in 12 and posterior free wall in 1); in 2 other animals (4%), wall thickening involved noncontiguous segments of left ventricle, ie, anterior septum and posterior free wall.
When viewed in the longitudinal (cephalocaudal) axis, 26 of the 46 cats (57%) showed substantially greater wall thickening in the proximal (basal) portion of left ventricle than in the distal (apical) region (Fig 1D⇑); 7 of these cats demonstrated a localized and prominent area of proximal septal thickening that protruded into the left ventricular outflow tract. The other 20 cats (43%) had wall thickening that was similar in magnitude in the proximal and distal portions of the left ventricle (Fig 1C⇑), and none showed hypertrophy confined to or predominant in the apical region of left ventricle.
Other Cardiac Dimensions
Compared with normal control animals, the 46 cats with HCM showed similar left ventricular end-diastolic dimensions but the end-systolic dimensions were significantly smaller; consequently, percent fractional shortening in cats with HCM significantly exceeded that of control animals (P<.001). Fractional shortening was within normal limits (30% to 60%) in 39 cats with HCM and hyperdynamic (>60%) in the other 7. In addition, left atrial size was greater in cats with HCM than in control animals (P<.001).
At the time of echocardiographic study, 22 cats (48%) had no apparent signs of cardiac dysfunction and at routine examination had a cardiac murmur, gallop rhythm, or arrhythmia. The remaining 24 cats (52%) were initially identified by the clinical profile of heart failure, including dyspnea, radiographic evidence of pulmonary congestion or pleural or pericardial effusion, or acute thromboembolism.
Of the 46 cats, 3 were lost to follow-up and 43 were followed for as long as 49 months (mean, 20 months). Eighteen of these 43 animals survived, including 13 that have remained asymptomatic, 3 that have been treated for congestive heart failure, and 2 that continue to have syncopal episodes. The remaining 25 cats died (including 10 who were euthanatized); 4 of these deaths were due to noncardiac causes. Of the remaining 21 cats that died of cardiac disease (if the clinical state before euthanasia is considered), the most common cause of death was congestive heart failure (in 16); in 7 of these 16 cats, clinical deterioration occurred in the setting of peripheral thromboembolism to the distal aortic bifurcation or iliac arteries. Two additional cats who died presented with peripheral thromboembolism but without clinical or radiographic evidence of congestion. The 3 remaining cats experienced out-of-hospital sudden and unexpected death.
The following analysis of natural history was performed after eliminating the 7 cats that were lost to follow-up or that died of noncardiac causes. Of the 17 cats that were asymptomatic at initial presentation, 13 (76%) have survived; in contrast, of the 22 cats that were symptomatic at presentation, only 5 (23%) survived (P<.001).
Of the 46 cats, 32 received cardioactive medications in standard dosages during the period of follow-up. Twenty-five of these cats received either a β-adrenoceptor–blocking agent (propranolol or atenolol) and/or a calcium channel blocker (diltiazem), frequently in combination with a diuretic (usually furosemide); 7 received diuretics alone. In 10 cats that developed fulminant and refractory heart failure, angiotensin-converting enzyme inhibitor (enalapril) was also administered.
Dynamic Obstruction of Left Ventricular Outflow
Systolic anterior motion of the mitral valve (SAM) was identified in 31 (67%) of the 46 cats (Figs 2⇓ and 3⇓). In 30 of these 31 animals, the SAM was marked and the anterior leaflet appeared to make a sharp-angled bend (Fig 2A⇓ and 2C⇓) with the distal tip effecting brief or prolonged midsystolic contact with the ventricular septum (Fig 2B⇓ and 2D⇓); the other cat showed milder SAM without septal contact. Partial midsystolic closure of the aortic valve (Fig 3A⇓) was demonstrated in 23 of 25 cats with SAM in which technically acceptable M-mode images of the aortic valve were obtained.
Continuous-wave Doppler assessment of left ventricular outflow tract obstruction was achieved in 25 of the 31 cats with SAM; velocities ranged from 2.6 to 5.2 m/s, (estimated subaortic gradients of 25 to 110 mm Hg). Doppler waveforms typically showed outflow velocities that increased relatively slowly in early systole but then rose abruptly and peaked in midsystole, resulting in the concave and asymmetrically shaped waveform (Fig 3B⇑) previously described as characteristic of patients with obstructive HCM.22 23 Cats with and without SAM did not differ with regard to maximal left ventricular wall thickness (6.8±1.5 versus 6.1±1.2 mm). SAM also occurred with equal frequency in cats with diffuse or segmental hypertrophy (21 of 31 [68%] versus 10 of 15 [67%], respectively).
Each of the 31 cats with SAM had mitral regurgitation identified by color flow imaging (mild in 9 and moderate in 22). Regurgitant jets were typically eccentric and directed toward the posterior aspect of the left atrial wall (Fig 2E⇑ and 2F⇑). Of the 15 cats without SAM, mitral regurgitation was absent in 2, mild in 7, and moderate in 6.
Predictors of Clinical Outcome
The 18 cats surviving at follow-up and the 21 nonsurvivors (with HCM-related death) differed with regard to certain clinical and morphological features. Nonsurvivors showed greater magnitude and extent of left ventricular hypertrophy with more marked maximum wall thickness than survivors (8.1±1.5 versus 7.3±0.9 mm; P<.05) and more diffuse and extensive distribution of hypertrophy (15 of 21 [71%] versus 10 of 18 [55%]), although this latter difference did not achieve statistical significance. Nonsurvivors also showed a larger left atrial dimension (20.1±4.6 mm) than survivors (16.8±3.4 mm; P=.01). In addition, SAM was more common in survivors (16 of 18 [89%]) than in nonsurvivors (10 of 21 [48%]; P<.01), suggesting that the nonobstructive form of feline HCM without SAM had a more unfavorable prognosis.
Heart weight normalized for body weight (6.0±1.4 g/kg) significantly exceeded that of a group of 36 normal control animals (4.8±1.2 g/kg; P=.005).11 In 6 of the 13 cats (each with SAM on echocardiogram), a fibrous mural endocardial plaque was present on the basal ventricular septum in apposition to anterior mitral leaflet, and in 5 of the 6, the anterior leaflet (Fig 4B⇑) showed fibrous thickening.
Left ventricular wall thicknesses assessed by echocardiography (at end diastole) were compared with values obtained at necropsy in the same areas of the ventricle in 8 cats, and, in each, the anatomic location of maximal wall thickness identified by echocardiography was confirmed in the necropsy specimen (anterior septum in 6 and posterior free wall in 2). Values for left ventricular wall thickness, measured from necropsy specimens (10.4±2.2 mm), exceeded those obtained with echocardiography (8.1±2.2 mm; P=.05).
Disorganized cardiac muscle cells24 were present in left ventricular myocardium from 8 of 13 cats studied at necropsy, and the extent was judged to be mild in 2, moderate in 4, and marked in 2 (Fig 5A⇑). One or more abnormal intramural coronary arteries25 with thickened walls and narrowed lumen were present in septal tissue sections from 9 of the 13 cats and were particularly prominent in 5 of these (Fig 5B⇑). Areas of substantial interstitial or replacement fibrosis25 26 were observed in 8 of the 13 cats, ranging in severity from mild (in 3), moderate (in 1), and severe (in 4) (Fig 5C⇑).
HCM is a diverse disease entity that has intrigued clinicians and generated intense investigation since its initial description in the late 1950s.27 28 Nevertheless, many questions remain regarding the pathophysiology, clinical course, and morphological evolution of HCM that would undoubtedly benefit from access to an animal model of this disease. There have been a few reports, based in large part on necropsy data, of spontaneously occurring cardiac disease entities in animals such as dogs,8 9 12 cats,8 9 10 11 and pigs3 that resemble HCM in humans.16 24 25 26 27 28 29 30 For many years, we9 10 11 12 and others31 32 33 have been interested in the morphological appearance of a cardiomyopathy in the domestic cat, which incorporates several of the anatomic hallmarks of HCM in humans, including asymmetrical left ventricular hypertrophy, cardiac muscle cell disorganization, abnormal intramural coronary arteries, and myocardial fibrosis. We believe, however, that the present study offers the first comprehensive clinical analysis of the feline model of HCM by virtue of documenting in detail the natural history of this disease entity, its full morphological and functional spectra by echocardiographic demonstration of the patterns of left ventricular hypertrophy and dynamic outflow obstruction, and correlations and validation with necropsy data.
In the present study, we used transthoracic echocardiography to better define the morphological and functional features of this disease, which we have come to regard as the clinical equivalent of HCM in humans,16 24 25 26 27 28 29 30 in a sizable group of cats evaluated in an ambulatory outpatient subspecialty clinic of a major New York City veterinary hospital. Approximately one half of the cats were identified clinically because of the development of congestive heart failure or other cardiovascular events, and the remainder were recognized fortuitously. Morphological profiles, including the patterns of left ventricular hypertrophy, were in many respects closely reminiscent of the phenotypic expression of HCM in humans.16 24 2526 27 28 29 30 34 35 36 37 For example, most cats had a diffuse but asymmetrical distribution of hypertrophy involving substantial portions of septum and free wall, whereas others demonstrated more segmental patterns of hypertrophy, often with abrupt transitions in wall thickness or involvement of noncontiguous segments of the wall.
It should be pointed out that as a clinical model of human disease, the domestic cat has potential limitations that are in large part related to its relatively small body size and the dimensions of the heart (in particular, left ventricular wall thickness). In an effort to limit uncertainties that could have an impact on the diagnosis of HCM in the cat, we chose ≥6.0 mm as the arbitrary cutoff for the upper normal limits of wall thickness because this value exceeded the range of our control animals and that of previously reported normal populations.20
Approximately two thirds of the cats studied showed a pattern of systolic anterior motion of the mitral valve, typical of patients with HCM.30 38 39 40 In this regard, the mitral leaflets made an abrupt and sharp, right-angled bend with only the distal tip of the anterior leaflet effecting localized contact with the ventricular septum, thereby producing increased left ventricular outflow tract velocities reflecting dynamic subaortic obstruction, as well as mitral regurgitation. Also, our morphological data showed no significant differences between the magnitude and pattern of left ventricular hypertrophy and the obstructive and nonobstructive forms (ie, with and without SAM) of feline HCM. This observation supports the proposition that HCM in cats is a primary form of hypertrophy with its morphological phenotype in large part unrelated to the presence or absence of a hemodynamic burden. This circumstance is virtually identical in the human disease entity of HCM, supporting the important similarities between HCM in cats and humans.16 30 41
There also is considerable evidence in the present study and previous reports10 11 31 32 33that feline HCM has an important impact on the clinical course of the animals. In our series, almost two thirds of the cats ultimately experienced congestive heart failure with or without peripheral thromboembolism (often progressive and leading to death despite medical treatment), syncope, or sudden cardiac death.
Of note, in our study group, unfavorable prognosis was associated with a more-marked morphological expression of HCM and the absence of mitral valve systolic anterior motion and left ventricular outflow tract obstruction. The cats that died of HCM during the period of follow-up proved to have greater left ventricular wall thickening and left atrial enlargement and more frequently had the nonobstructive form of HCM.
Feline HCM, as described in the present report, is remarkably similar to its HCM counterpart in patients with regard to numerous clinical and pathological features. Consequently, HCM occurring spontaneously in cats would appear to have considerable potential value as an animal model of human disease. Specifically, we believe that our feline model of HCM in humans is a potentially important investigative tool for the study of genetic factors and clinical and pathophysiological mechanisms operative in this disease, as well as the molecular mechanisms responsible for its genesis. At present, however, data are in large part lacking with regard to the genetic basis and transmission of feline HCM.42 Future definition of the heritability of HCM in cats and efforts at breeding would be stimulated by more widespread recognition of this disorder. Such investigations will be crucial to the full development of this animal model of human disease and the ultimate judgment of its research potential.
- Received February 27, 1995.
- Revision received May 22, 1995.
- Accepted May 30, 1995.
- Copyright © 1995 by American Heart Association
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