History
A 12-year-old 50-kg (110-lb) castrated male Old English Sheepdog was referred to the Veterinary Teaching Hospital of the University of Padua for evaluation of a cardiac murmur. On physical examination, an irregular cardiac rhythm and a systolic murmur (most clearly ausculted over the mitral valve area) were found. Electrocardiography revealed atrial fibrillation (AF) with a ventricular rate of 100 beats/min. Echocardiographic and echo-Doppler examinations revealed mitral valve leaflet thickening, mild-to-moderate mitral and tricuspid valve regurgitation, left atrial dilatation, and moderate left ventricular dilatation. Treatment with pimobendan was initiated, and the dog's clinical condition was stable during the following 6 months. On repeated clinical and ECG examinations, AF persisted and the ventricular rate was always < 120 beats/min. Seven months after the first evaluation, gastric dilatation-volvulus occurred and the dog died during exploratory laparotomy.
Clinical and Gross Findings
At necropsy, gross examination of the heart revealed hypertrophy of both ventricles and dilatation of the left atrium (Figure 1). Severe tracheobronchial edema was observed in the respiratory tract. The mitral valve leaflets were severely thickened and distorted with elongated and thickened chordae tendineae. The tricuspid valve had moderate thickening of the septal leaflet. Moreover, the left atrium was diffusely white, without visible jet impact lesions on the endocardium. Multiple cut sections of both atria had multifocal to coalescing transmural white areas, particularly at the level of the left atrium. At the level of the middle third of the ventricles, transverse sectioning of the heart revealed left ventricular hypertrophy; the thickness of the interventricular septum and the left ventricular free wall was 19 and 18 mm, respectively. The right ventricle was also moderately dilated with a free wall thickness of 7 mm, corresponding to a left ventricle-to-right ventricle thickness ratio of 2.6.
Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page→·
Histopathologic Findings
Multiple transmural tissue samples were collected from the caudal wall in proximity of the pulmonary vein ostia, between the pulmonary vein ostia, and near the auricle of the left atrium. Tissue samples were also collected from the crista terminalis along the right atrial lateral wall. Samples from the mitral and tricuspid valves, ventricles, lungs, kidneys, and liver were also collected for histologic examination. All samples were fixed in buffered 10% formalin and embedded in paraffin. All histologic sections (each 3 μm thick) were stained with H&E, Masson trichrome, or elastic picrosirius red stain.
On histologic examination, all left atrial samples had evidence of diffuse and severe transmural fibro-fatty infiltration around scattered groups of residual hypotrophic cardiomyocytes (Figure 2). All right atrial samples had evidence of subepicardial and subendocardial fatty infiltration with interstitial fibrosis. Both mitral valve leaflets and the tricuspid valve septal leaflet had myxomatous degeneration with moderate thickening of the spongiosa and fibrosa layer, and alteration in dense collagen fibers. In the ventricular myocardial samples (both ventricular free walls and interventricular septum), multifocal and moderate interstitial and replacement fibrosis associated with mild hypertrophy of cardiomyocytes was present. No substantive lesions were observed in the coronary arteries. Multifocal and severe congestion was detected in the liver samples as well as in the lung tissues, wherein bronchoalveolar edema was also present.
Morphologic Diagnosis and Case Summary
Morphologic diagnosis: fibro-fatty infiltration of the atria associated with myxomatous mitral valve disease (MMVD).
Case summary: fibro-fatty replacement of the atrial myocardium in a dog with chronic degenerative valvular disease and persistent AF.
Comments
Loss of ventricular cardiomyocytes and fatty or fibro-fatty replacement mainly affecting the right and left ventricular myocardium are the typical pathological features of arrhythmogenic right ventricular cardiomyopathy in humans, dogs, and cats and dilated cardiomyopathy of Doberman Pinschers, respectively.1–4 These ventricular cardiomyocyte changes interfere with electrical impulse conduction leading to development of ventricular tachyarrhythmias, which may cause sudden death in some patients.1–4 Atrial cardiomyocytes are less commonly affected by similar pathological changes.
Myxomatous mitral valve disease is the most common canine cardiac disease and mainly affects small- to medium-sized and aged dogs.5 Myxomatous degeneration of the mitral valve is characterized by malformation of the mitral valve apparatus (ie, mitral valve leaflets and annulus, chordae tendineae, papillary muscles, and left atrial and ventricular myocardium), biomechanical dysfunction, and mitral valve incompetence.5 Mitral valve regurgitation associated with MMVD leads to left-sided cardiac volume overload and left atrial and left ventricular remodeling and may cause left atrial endocardial injury and tears, chordal rupture, and congestive heart failure in most dogs that are severely affected.5 Dogs with MMVD have a low frequency of cardiac arrhythmias, compared with findings for dogs with other cardiac conditions, and only a few of them develop AF in the course of their disease.6
Cardiac pathophysiologic changes associated with persistent AF in humans include bi-atrial enlargement associated with severe cardiac tissue changes, such as degeneration and necrosis, extensive fibrosis, and fibro-fatty myocardial replacement of atrial myocardium.7 The specific mechanisms and signaling pathways involved in the development of atrial fibrosis are presently unknown, and it is still unclear whether fibrotic transformation of atrial myocardium is a cause or a consequence of AF.8 The most reliable hypothesis considers atrial fibrosis as the result of inflammation, given that a strong association between fibrosis extent and inflammatory cell count in patients with AF has been documented.8 Atrial fibrosis strongly predisposes affected humans and dogs to AF because the fibrous tissue separates atrial muscle bundles and causes localized conduction slowing that stabilizes reentry and promotes fibrillation.7,9 These changes seem to be related to inflammation and cell death, which are known to promote release of cytokines leading to replacement fibrosis.9 Anatomic and pathophysiologic myocardial changes responsible for or associated with AF in domestic animals, including dogs with naturally occurring AF, are not well understood.9 Atrial fibrillation is the most commonly diagnosed persistent supraventricular arrhythmia in dogs, and it is frequently associated with major organic heart disease that results in marked atrial enlargement.10,11 Larger left atrial weights and body sizes favor the occurrence of persistent AF, and among dogs, large and giant breeds and males are most often affected.10,11 Atrial fibrillation with a rapid ventricular rate (ie, > 160 beats/min) commonly occurs in dogs with underlying heart disease, whereas a normal ventricular rate (ie, < 140 beats/min) is usually observed in dogs with primary AF, namely AF that is not associated with clinical or echocardiographic evidence of structural and functional cardiovascular disease.10 Indeed, AF is common in dogs with both histologic forms of dilated cardiomyopathy: the attenuated wavy fiber type identified in many giant, large-sized, and medium-sized dogs and the fatty infiltration-degenerative type identified mainly in Boxers and Doberman Pinschers.12
Canine MMVD can cause atrial interstitial fibrosis and inflammation apart from progressive atrial dilatation, which is an important profibrillatory change.5,9 However, AF is not commonly observed in dogs with naturally occurring MMVD, likely because small-breed dogs are most often affected.11 Fatty or fibro-fatty replacement of the left or right (or both) atrial myocardium in 8 dogs from a case series of 23 Boxers with arrhythmogenic right ventricular cardiomyopathy has been previously reported.2 Concurrent MMVD was found in 7 of those 23 (32%) dogs, and 24-hour Holter ECG monitoring identified ventricular arrhythmias in 19 (83%) but none had AF.2 Fibro-fatty replacement of the left or right (or both) atrial myocardium and myocarditis have been reported for 2 and 9 cats, respectively, from a case series of 12 cats with arrhythmogenic right ventricular cardiomyopathy.4 Four of the 12 cats also had AF, but the relationship between pathological atrial changes and AF was not investigated.4
In the dog of the present report, myxomatous degeneration affecting leaflets of both atrioventricular valves was found associated with bi-atrial and biventricular cardiac enlargement. Severe fibro-fatty replacement of the atrial wall was the main pathological finding, and the left atrium was more severely affected than the right atrium. Left ventricular hypertrophy and fibrosis were likely the consequence of MMVD. A combination of fibro-fatty replacement of the atrial myocardium and persistent AF with low ventricular rate is unusual in dogs with MMVD.
Acknowledgments
No financial support was provided for this case report.
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