The Anatomical Basis of BradycardiaeTachycardia Syndrome in Elderly Dogs with Chronic Degenerative Valvular Disease

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1 J. Comp. Path. 2012, Vol. 146, 175e182 Available online at SPONTANEOUSLY ARISING DISEASE The Anatomical Basis of BradycardiaeTachycardia Syndrome in Elderly Dogs with Chronic Degenerative Valvular Disease S. Nakao *, A. Hirakawa, R. Fukushima, M. Kobayashi * and N. Machida * * Department of Veterinary Clinical Oncology, Tokyo University of Agriculture and Technology, Saiwai-cho, Fuchu, Tokyo , Pet Clinic Hallelujah, , Nakabaru, Kasuya, Kasuya-gun, Fukuoka and Department of Veterinary Surgery, Tokyo University of Agriculture and Technology, Saiwai-cho, Fuchu, Tokyo , Japan Summary The hearts of seven elderly dogs in which bradycardiaetachycardia syndrome (BTS) had been diagnosed electrocardiographically were examined post mortem. The clinical basis of the underlying heart disease was invariably mitral or mitral and tricuspid regurgitation. Microscopical examination of the sinoatrial (SA) node and the SA junctional region consistently revealed depletion of SA nodal cells, with a corresponding increase in fibrous or fibro-fatty tissue that interrupted contiguity between the SA node and the surrounding atrial myocardium. The left and right atrial walls showed an increased amount of fibrous tissue in the myocardium and disruption of the muscle bundle architecture (interstitial myocardial fibrosis) to varying degrees. Qualitatively, these changes in the SA node and the SA node region resembled those associated with ageing in elderly people with or without BTS. Thus, it is possible that the pathological process affecting the SA node in these dogs was fundamentally related to ageing and may have caused BTS, in combination with atrial myocardial lesions caused by mitral and tricuspid regurgitation. Ó 2011 Elsevier Ltd. All rights reserved. Keywords: bradycardiaetachycardia syndrome; dog; sinoatrial node; valvular disease Introduction Sick sinus syndrome (SSS) is a general term applied to sinoatrial (SA) node dysfunction that may be manifested electrocardiographically by severe sinus bradycardia and severe SA block and/or sinus arrest. Such electrocardiographical abnormalities associated with the SA node are frequently accompanied by recurrent episodes of atrial tachycardia, atrial fibrillation or atrial flutter, resulting in alternation of paroxysmal rapid regular or irregular tachyarrhythmias and slow atrial and ventricular beat rates. This pattern of SSS is termed bradycardiaetachycardia syndrome (BTS) and is the most common form of SSS in dogs (Kaplan et al., 1973; Tilley, 1992). Correspondence to: N. Machida ( machida@cc.tuat.ac.jp). SSS occurs most commonly in middle-aged to older female miniature schnauzers (Tilley, 1992). Other breeds that are predisposed include older dachshunds, West Highland white terriers, cocker spaniels and pugs (Hamlin et al., 1972; Miller et al., 1999; Mo ıse, 1999a; Goodwin, 2001; Johnson et al., 2007). The clinical manifestations of SSS are variable. Some dogs are asymptomatic, or the symptoms are mild and non-specific. The most common clinical signs associated with BTS are syncope and weakness. Very occasionally, heart rates may be so slow as to reduce cardiac output and cause cardiac failure, or so rapid as to preclude adequate filling. Sudden death due to BTS is rare (Tilley, 1992; Miller et al., 1999; Kittleson, 1998a). Medical therapy is usually of limited value, so permanent pacemaker implantation is the only viable treatment in symptomatic patients (Mo ıse, 1999b; /$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi: /j.jcpa

2 176 S. Nakao et al. Carr et al., 2001). Possible causes of SSS include disease affecting the SA node artery or replacement of the SA node with fibrous tissue, the morphological substratum for the arrhythmias, although this has not been clearly demonstrated. Genetic inheritance of this condition is also possible because of its frequent occurrence in female miniature schnauzers (Tilley, 1992). The aim of the present study was to characterize the histopathological features of the heart in seven cases of canine BTS. Animals Materials and Methods The study materials were the hearts of seven dogs (cases 1e7) in which BTS had been diagnosed electrocardiographically (Table 1). The dogs included two miniature Schnauzers and one each of Pomeranian, West Highland white terrier, American cocker spaniel, Yorkshire terrier and miniature dachshund. There were three males and four females, ranging in age from 10 to 16 years at death (mean age 13.0 years). These dogs had all been diagnosed previously as having mitral or mitral and tricuspid valves insufficiency due to chronic degenerative valvular disease, as confirmed by colour-flow Doppler echocardiography, and the duration of the clinical disease before the development of BTS had ranged from 6 months to 3 years. Six of the seven dogs had a history of intermittent syncope and weakness; the remaining dog (case 3) showed clinical signs of severe left-sided heart failure, including coughing, exercise intolerance and dyspnoea. Electrocardiograms showed long periods of severe SA block or sinus arrest alternating with ectopic atrial tachycardia and/or atrial fibrillation (Fig. 1). Intravenous administration of atropine failed to elicit a marked increase of heart rate in all cases. The periods of the sinus pauses (ventricular asystole) were usually 3e8 sec, the longest being 21 sec. A permanent pacemaker (demand ventricular pacing; Medtronic Japan Co., Ltd., Tokyo, Japan) had been implanted in six of the seven dogs 5e14 days after the initial diagnosis of BTS, and thereafter the animals survived for between 1 week and 6 years. One dog without pacemaker therapy died of acute pulmonary oedema associated with severe mitral regurgitation due to ruptured chordae tendineae of the mitral valve 3 months after admission. Among the six dogs that received pacemakers, death was attributable to chronic congestive heart failure in four, pneumonia in one and old age in one. Histopathology The heart was removed from each dog within 24 h of death and subjected to gross examination. The whole heart was then fixed in 10% phosphate-buffered formalin for at least 5 days. The cardiac conduction system was examined as described by James (1962, Table 1 Clinical summary of the dogs with BTS No. Breed Age (years) Sex Clinical sign(s) Pacemaker/pacing duration ECG 1 Pomeranian 16 Male Syncope +/6 years Sinus arrest, paroxysmal tachycardia 2 West Highland white terrier 14 Female Syncope +/4 years Sinus arrest, tachycardia 3 Cocker spaniel 14 Female Syncope, dyspnoea +/1 month Sinus arrest, paroxysmal tachycardia, atrial fibrillation 4 Miniature schnauzer 13 Female Syncope +/20 months Sinus arrest 5 Yorkshire terrier 12 Male Syncope +/1 week Sinus arrest, tachycardia, atrial fibrillation 6 Miniature schnauzer 10 Female Syncope +/1 month Sinus bradycardia, sinus arrest, tachycardia 7 Miniature dachshund 10 Male Syncope, weakness Sinus arrest, tachycardia

3 Valvular Heart Disease in the Dog 177 Fig.1. Electrocardiogram tracing from case 1 with BTS, showing a long duration of sinus arrest (an asystole duration is 4.1 sec) followed by paroxysmal tachycardia (Lead II, 25 mm/sec, 0.5 cm ¼ 1 mv). 1964). The atria were dissected from the ventricles at the atrioventricular (AV) sulcus. For examination of the SA node and SA junctional region, the right atrium was cut serially into 10e15 blocks perpendicular to the sulcus terminalis (at a right angle to the long axis of the SA node) (Fig. 2) so that the full thickness of endocardium, myocardium and epicardium, as well as the lower portion of the cranial vena cava (CVC) and right atrial (RA) wall, were included. In addition, 5e10 sections were taken from the left atrium transversely across the atrial appendage. For examination of the AV conduction system consisting of the AV node and its approaches, and the AV bundle and bundle branches, the AV junctional region was sliced into sections approximately 3 mm thick, perpendicular to the line of the junction of the atrial and ventricular septa. Moreover, 3e5 tissue blocks were taken from the mitral and tricuspid valves. Samples were processed routinely and embedded in paraffin wax, and sections (5 mm) were stained with haematoxylin and eosin (HE), elastica van Gieson and Masson s trichrome for light microscopical examination. Gross Findings Results In all cases, the hearts were enlarged and globular in shape and the left ventricle revealed various degrees of eccentric hypertrophy. Diffuse mild thickening of the endocardium was evident in the left ventricle and atrium. The mitral and tricuspid valves showed large coalescing plaque-like deformities that had resulted in shortening, thickening and rolling of the leaflets, with thickening in four cases and lengthening or rupture of the chordae tendineae in three cases. The tricuspid valve was involved to a lesser degree in most cases. Both atria were slightly to markedly dilated due to increased intra-atrial pressure resulting from the AV valvular insufficiency. The changes were more severe in the left atrium, associated with thinning of the wall due to muscle loss with apparent fibrous tissue replacement. In addition, roughened fibrotic areas were present on the endocardium of the left atrium at the impact point of the regurgitation jet in five cases. Fig. 2. (A) The dissected RA wall from an 8-year-old female beagle dog is cut serially on white lines drawn perpendicular to the sulcus terminalis (black broken line). CVC; atrial septum (AS). Scale, 1 mm. (B) The tissue blocks taken from the RA and the lower portion of the CVC in order to examine histologically the SA node and SA junctional region. Scale, 1 mm. Microscopical Findings Microscopical findings are summarized in Table 2. SA Node and SA Junction. All seven dogs with BTS showed significant and common histopathological

4 178 S. Nakao et al. Table 2 Histopathological findings in the conduction system in dogs with bradycardiaetachycardia syndrome No. Breed Age (years) Sex Pathological findings/degree of changes SA node SA junction Atrial myocardium AV conduction system Right Left 1 Pomeranian 16 Male Atrophy/3+, Fib-Fat/3+ Fib-Fat/3+ Fib/1+ Fib/3+ Fib-Fat/1+ 2 West highland white terrier 14 Female Atrophy/3+, Fib-Fat/3+ Fib-Fat/3+ Fib/1+ Fib/3+ Fib-Fat, Myxo/1+ 3 Cocker spaniel 14 Female Atrophy/3+, Fib-Fat/3+ Fib-Fat/3+ Necrosis, Fib/1+ Fib/2+ Fib-Fat/1+- 4 Miniature schnauzer 13 Female Atrophy/3+, Fib-Fat/3+ Fib-Fat/2+ Fib/1+ Fib/3+ Fib-Fat, Myxo/1+ 5 Yorkshire terrier 12 Male Atrophy/2+, Fib/2+ Fib/2+ Fib/1+ 6 Miniature schnauzer 10 Female Atrophy/2+, Fib-Fat/+ Fib-Fat/2+ Fib/1+ Fib/2+ 7 Miniature dachshund 10 Male Atrophy/2+, Fib/1+ Fib/+ Fib/1+ Fib/3+ Fib/1+ Degree of lesion severity: 3+, severe; 2+, moderate; 1+, mild;, slight. Abbreviations: Fib, fibrosis; Fib-Fat, fibro-fatty infiltration; Myxo, myxomatous degeneration. changes in the SA node and SA junctional region. The main pathological changes that were consistently evident in the present series included severe atrophy of the SA node due to degeneration and disappearance of the nodal cells and replacement of the SA node with fibrous or fibro-fatty tissue, leaving less than 30% of the nodal cells remaining and isolating the SA node from the surrounding atrial myocardium (Figs. 4e6). The SA nodes were so severely damaged that only the SA node artery could be indentified with certainty in cases 1, 2 and 3 (Figs. 4 and 6), and even the sections best displaying the tissue in cases 5, 6 and 7 showed little of the node remaining (Fig. 7). Sclerotic changes in the intramural coronary arteries supplying the SA node (SA node arteries) (i.e. thickening of the vessel walls and a slight to moderate decrease in luminal size), were observed in all cases, but one case showed severe narrowing of the lumen. The wall thickening was due mainly to proliferation of smooth muscle, fibrous tissue or both in the intima and media (Figs. 4, 6 and 7). In addition, the normal SA node region from a young adult beagle dog is shown in Fig. 3 as a control image. Atrial Myocardium. Increased fibrous tissue in the myocardium and disruption of the muscle bundle architecture (interstitial myocardial fibrosis) were seen in the left and right atrial walls to varying degrees. In the mild to moderate lesions observed in the right atrium of all cases and the left atrium of cases 3, 5 and 6, there was diffuse interstitial fibrosis with preservation of the muscle mass and muscle bundle architecture (Fig. 8). In the severe lesions observed in the left atrium of cases 1, 2, 4 and 7, there was an extensive and marked loss of muscle mass, with replacement by dense collagen and elastic fibres, indicating progressive fibrosis. AV Conduction System. In all seven dogs, the AV node and its approaches appeared normal, except for slight to moderate age-related changes characterized by an increase of fibrous tissue, fatty infiltration or both. There was slight to moderate fibrosis of the central fibrous body and the endocardium and subendocardium of Fig. 3. The SA node region from an 8-year-old female beagle dog. The SA node (region surrounded by white arrowheads) consisting of a fibrous tissue matrix with closely packed cells, located in the subepicardium. The black arrowhead indicates the sulcus terminalis. Masson s trichrome. Endo, endocardium; Epi, epicardium; RA, RA myocardium; SN, SA node; asterisk, SA node artery. Bar, 400 mm.

5 Valvular Heart Disease in the Dog Fig. 4. Case 1. (A) The SA node region, showing severe atrophy of the SA node associated with loss of nodal cells and severe infiltration of fibro-fatty tissue that has replaced the myocardial cells in the SA node region. The arrowhead indicates the sulcus terminalis. Masson s trichrome. Bar, 400 mm. (B) Higher magnification of the outlined area in (A). Masson s trichrome. Bar, 50 mm. 179 Fig. 5. Case 2. (A) The SA node region, showing marked loss of nodal cells, and marked infiltration of fibro-fatty tissue that has replaced the myocardial cells in the SA node region. The arrowhead indicates the sulcus terminalis. Masson s trichrome. Bar, 400 mm. (B) Higher magnification of the outlined area in (A). Masson s trichrome. Bar, 50 mm.

6 180 S. Nakao et al. Fig. 7. Case 5. The SA node region, showing moderate atrophy of the SA node, fibro-fatty tissue proliferation and mild to moderate sclerotic changes of the SA node arteries. The arrowhead indicates the sulcus terminalis. Masson s trichrome. Bar, 400 mm. the uppermost ventricular septum; these fibrotic changes affected the underlying penetrating and branching portions of the AV bundle and the upper portions of the left and right bundle branches, resulting in Fig. 6. Case 3. (A) The SA node region, showing replacement of the SA node by extensive fibro-fatty tissue proliferation. The arrowhead indicates the sulcus terminalis. Masson s trichrome. Bar, 400 mm. (B) Higher magnification of the outlined area in (A). Masson s trichrome. Bar, 50 mm. Fig. 8. Case 1. The left atrial wall, showing diffuse interstitial fibrosis with wavy attenuated myocardial fibres. Masson s trichrome. Endo, endocardium; Epi, epicardium. Bar, 400 mm.

7 Valvular Heart Disease in the Dog 181 proliferation of fibrous or fibro-fatty tissue with an apparently slight reduction of conduction fibres. AV Valves. The leaflets of the mitral and tricuspid valves consistently showed primary myxomatous proliferation of the spongiosa with secondary interruption and dissolution of the fibrosa and fibrosis of the atrialis and ventricularis, being characteristic of chronic degenerative valvular disease (AV valvular endocardiosis). Discussion Histopathological examination of the heart, particularly the SA node, was carried out on seven canine cases of chronic degenerative AV valvular disease with BTS in an attempt to clarify the anatomical basis for the arrhythmia. Significant pathological changes that were observed commonly in the present series included extensive damage to the SA node with depletion of the nodal cells and an increase of fibrous or fibro-fatty tissue, interrupted contiguity between the SA node and the surrounding atrial myocardium and interstitial fibrosis of the left and right atrial walls. There have been many histopathological studies of human BTS and it has been consistently shown that there are conspicuous alterations of the SA node and its approaches with involvement of the RA wall. These changes have included total or subtotal destruction of the SA node, areas of nodalatrial discontinuity, inflammatory or degenerative changes in the nerves and ganglia surrounding the SA node and pathological changes in the atrial wall (Kaplan et al., 1973; Kulbertus et al., 1973; Thery et al., 1977; Sugiura and Ohkawa, 1980; Bharati, 2001; Olgin and Zipes, 2008). Thus, the cardiopathological findings observed in the present study were substantially similar to those of human BTS, suggesting that the degenerative process involving the SA node, combined with fibrosis of the atrial myocardium, may represent morphological changes that underlie BTS in elderly dogs with chronic degenerative AV valvular disease. The present study has provided a relatively clear picture of the close relationship between the lesions of the SA node and atrial walls and the presence of BTS. The most significant change was depletion of the SA nodal cells with a corresponding increase in fibrous or fibro-fatty tissue that interrupted contiguity between the SA node and the surrounding atrial myocardium. It was obvious that the damaged node and/or SA junctional region were incapable of generating and/or conducting an activating potential sufficient to stimulate the surrounding atrial muscle, resulting in severe sinus arrest and/or SA block. In addition, the loss of pacemaker function would account for the predisposition of the injured atrial myocardium to delayed and non-homogenous conduction, which is the electrophysiological basis for atrial arrhythmias such as atrial tachycardia, atrial fibrillation and atrial flutter. It is well known that such atrial arrhythmias occur most commonly in dogs with chronic mitral regurgitation (myxomatous mitral valve degeneration) (Kittleson, 1998b; Sisson et al., 1999). While it is conventional to regard the loss of SA nodal cells as the main cause of BTS, it could also result from disuse atrophy of the musculature in the area of the SA node associated with pacemaker therapy. In the present study, the lesions of the SA node observed in all of the six dogs that had undergone pacemaker implantation were qualitatively and quantitatively similar, regardless of the duration of artificial pacing. The similarity of the SA nodal lesions after various durations of artificial pacing suggests that these histological alterations are the cause of BTS. Although the aetiology of the extensive damage to the SA node (i.e. depletion of the nodal cells with a corresponding increase of fibrous or fibro-fatty tissue) is not clear, it is interesting to note that qualitatively the pathological changes resembled those associated with ageing in human patients with atrial arrhythmias (Kaplan, et al., 1973; Kulbertus, et al., 1973; Thery et al., 1977; Sugiura and Ohkawa, 1980; Bharati, 2001). Thus, it is possible that the pathological process in the SA node of the dogs was also fundamentally a phenomenon related to accelerated ageing. Interestingly, all seven dogs with BTS were elderly, the youngest being 10 years of age at the development of arrhythmia. In addition, the pathological changes in and around the AV conduction system were similar to the agerelated changes that have been designated as sclerosis of the left side of the cardiac skeleton (Lev, 1964). In conclusion, we consider that the histopathological lesions in the SA node and the atrial myocardium of these dogs may represent the anatomical basis for BTS, and that in this case series there appeared to be an association between old age, chronic mitral regurgitation and BTS. References Bharati S (2001) Pathology of the conduction system. In: Cardiovascular Pathology, 3rd Edit., MD Silver, AI Gotliev, FJ Schoen, Eds., Churchill Livingstone, Philadelphia, pp. 607e628.

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