J. ELECTROCARDIOLOGY 11 (2), 1978, 191-196
A Case of Sick Sinus Syndrome in Primary Systemic Amyloidosis BY NORIKO ISOKANE, M.D.,* NORIKO FUKUSHIMA, M.D.,t TADAHIKO MIYAZAKI, M.D.** AND ICHIRO DOHI, M.C.**
A case of sick sinus syndrome due to primary systemic amyloidosis which involved mainly the heart and lungs is presented. The electrocardiogram showed various changes; low voltage, bradyarrhythmia with junct i o n a l escape beats, paroxysmal atrial tachyarrhythmia that terminates abruptly with subsequent long asystole, junctional rhythm from different origins and complete right bundle branch block which appeared at shorter and longer diastolic intervals. Histological examination showed an extensive amyloid infiltration in the upper parts of the conduction system, with major damage in the sinus node and also elsewhere in the heart. The patient died despite pacemaker implantation. Cardiac amyloidosis, including some degree of amyloid deposition t h a t is often seen in aged hearts, frequently associated with diverse electrocardiographic abnormalities, has been reported by m a n y authors. 1-14 It is, however, rare to find a case with both detailed clinical and pathological indications of sick s i n u s s y n d r o m e (SSS) d u e to c a r d i a c amyloidosis, as compared with the n u m b e r of h i t h e r t o r e p o r t e d c a s e s on s i n u s n o d e dysfunction. 1~-21 The purpose of this paper is to report a case of SSS which showed v a r i o u s cardiac arr h y t h m i a s and conduction disturbances, a consequence of extensive amyloid deposition in the conduction system, particularly in the sinus node (SAN).
A 66 year old woman was admitted to the D e p a r t m e n t of I n t e r n a l Medicine of Doai Memorial Hospital on August 20, 1976, because of increasing dyspnea on exertion and edema of the lower extremities t h a t appeared about two months prior to admission. At age 27, she had suffered from a high fever associated with pain in the right knee and was treated for three months. At age 58, she often experienced palpitation but received no treatment. For three or four years prior to admission, she had frequently felt dizziness and a slight headache but never had syncopal episodes or chest pain. There is no significant illness in her family history. Clinical findings. The patient was of small stature with clear consciousness. There were no gingival swelling and macroglossia. Petechiae were found all over the body. Her eyelids and lower extremities were slightly edematous, but there was no ascites. She had slight dyspnea and a slow, irregular pulse at a rate of about 40/rain. Blood pressure was 140/70. The cardiac silhouette on the chest X-ray was enlarged to the left with CTR 0.58. The second heart sound was split with 0.06 sec and a loud 4/6 ejection-type systolic murmur was heard at the third intercostal space of the left sternal border. There were no r~les over either lung, and neither the liver nor spleen were palpable. L a b o r a t o r y d a t a showed slight anemia, hypogammaglobulinemia and weak capillary resistance. Otherwise, serum enzymes, electrolytes, bleeding time, coagulation factors and thyroid gland functions were all normal. As the authors did not suspect amyloidosis, n e i t h e r tongue nor rectal biopsy was p e r formed. An electrocardiogram ( E C G ) t a k e n j u s t prior to admission (Fig. 1) showed low voltage, marked b r a d y a r r h y t h m i a interspersed with junctional escape beats in the limb leads, slight lengthening of the P-R interval (0.22 sec) with some degree of morphologic variation in the P waves suggesting chaotic atrial activity and complete right bundle branch block (RBBB). The atrial rate was even more
*Department of Internal Medicine, Doai Memorial Hospital. ~Department of Pathology,Doai Memorial Hospital. **Department of Internal Medicine, Tokyo University, Tokyo,Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. 1734 solely to indicate this fact. Reprint requests to: Noriko Isokane,M.D.,Departmentof Internal Medicine, Doai Memorial Hospital, Yokoami, 2-1-11, Sumida-ku, Tokyo,Japan. 191
ISOKANE ET AL
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irregular and faster when the precordial leads were recorded. In an ECG on the second day of hospitalization (Fig. 2), complete RBBB was observed at shorter and longer diastolic intervals; at an intermediate range, the intravent r i c u l a r conduction became normal. These phenomena were considered to be phase 3 and phase 4 block, respectively. Atropine sulfate 1 mg intravenously accelerated the atrial rate by only 5 beats/min. Oral administration of isoproterenol 60 mg a day produced atrial and junctional r h y t h m at a slightly faster rate. A few days later, however, the patient complained of lightheadedness lasting for a short period. Her ECG (Fig. 3) showed paroxysmal atrial flutter with variable conduction ratio, followed by a long asystole. His bundle recording performed on September 4, showed PH and HV intervals 160 msec and 50 msec, respectively. During this procedure repeated t a c h y a r r h y t h m i a occurred and overdrive pacing was not therefore done. One offl-blocking agents, pindrol 10 mg
Fig. 1. ECG shows the following features: bradyarrhythmia with some junctional escape beats in the limb leads, more irregular and faster R-R intervals in the precordial leads. Morphology of the P waves is to some degree variable. There are low voltage and complete RBBB.
a day orally, was effective in suppressing the t a c h y a r r h y t h m i a . The a t r i a l or j u n c t i o n a l rate, however, became gradually slow. Prednisolone was used to accelerate the impulse formation or conduction, but there was no response. E p h e d r i n e h y d r o c h l o r i d e also remained ineffective. For two months after admission, the patient's condition worsened and chest X-ray showed pulmonary congestion and pleural effusion, in spite of continuous administration of furosemide. In an ECG (Fig. 4) recorded on October 20, one hour before pacemaker imp l a n t a t i o n , the h e a r t r a t e was less t h a n 30/min and there were two types of QRS complex of lower p a c e m a k e r origin. After ins e r t i o n of a b i p o l a r d e m a n d p a c e m a k e r (Minilith, Model No. 0602, rate 71/min, Cardiac Pacemakers, Inc., USA), the symptoms of congestive heart failure were obviously improved and the patient seemed to be better. On the fifth day, however, she suddenly had an episode of severe dyspnea and died within
Vl V2 V3
Fig. 2. Panels A and B are a continuous recording. The ECG (V1-V3) shows irregular R-R intervals. Complete RBBB appears when the R-R intervals vary from 0.84 to 1.28 sec and more than 1.90 sec. Conduction is normal at the R-R intervals of 1.48 sec up to 1.60 sec.
J. ELECTROCARDIOLOGY, VOL. 11, NO. 2, 1978
SICK SINUS SYNDROME
. . . .
- " ' w ' ~
r v " ~ ' ~ '
Fig. 3. Panels A and B are continuous. Atrial flutter with various conduction ratio, followedby long asystole.
an hour. The ECG showed the pacemaker to be functioning regularly with a slightly widening QRS complex and there were no ectopic beats.
Principal necropsy findings. 1. Macroscopic examination. Heart: It weighed 310 gm, the left ventricular free wall was 1.5 cm thick, and the right was 0.4 cm thick. The ventricular myocardium was not rigid and there was no vitreous opacity. The aortic and mitral valves showed thickening. Lungs: They were not edematous but had a h y a l i n m e m b r a n e - l i k e appearance, and weighed 300 gm for the left and 330 gm for the right. Skin: It showed multiple petechiae through the body. The epidermis was abnormally exfoliative. Other organs: There were no significant findings suggestive of amyloidosis. 2. Histological examination. Heart: The cardiac conduction system: The regions of the SAN, atrioventricular node (AVN) and upper part of the His bundle were removed and sectioned serially along the atrial epicardial and subendocardial surfaces, respectively. The lower part of the His bundle and bundle branches were also serially sectioned parallel to the frontal plane of the interventricular septum (IVS), at 7 /xm thickness; every tenth section for the SAN, AVN and upper part of the His bundle, and every twentieth for the lower portions of the conducJ. ELECTROCARDIOLOGY, VOL. 11, NO. 2, 1978
tion system, were retained and stained with Hematoxylin-Eosin, Masson Goldner trichrome and Congo Red. The SAN was most conspicuously infiltrated by amyloid. The specialized fibers showed swelling, vacuolization and atrophy because of massive nodular or diffuse amyloid deposition between the cells (Fig. 5). The regions of the AVN were also of similar findings but with fewer deposits of amyloid, and the upper part of the His bundle had more frequently characteristic amyloid rings. The middle and lower parts of the His bundle were spared severe involvement. Among the bundle branches, a small amount of amyloid was observed in the anterior division of the left branch and in the upper and middle portions of the right branch. Fluorescent microscopy using Congo Red Stain clearly demonstrated different degrees of intensity of amyloid infiltration in the conduction system. The SAN and AVN arteries had amyloid in their walls without singificant narrowing of the lumen, but the invasion was severe in the smaller arteries. Myocardium: Of the four chambers, the right atrium was most extensively involved with nodular or diffuse amyloid infiltration and showed significant loss of the muscle fibers and disruption of the architecture. The surviving cells were atrophic. The IVS revealed similar findings, and the ventricular myocardium was also affected considerably. Endo- and E p i c a r d i u m : N o d u l a r a n d stratified deposition of amyloid was found in
ISOKANE ET AL
Vl B Vz Fig. 4. Panels A and B are continuous.
ECG recorded on October 20, 1 hour beVs fore pacemaker implantation, shows very slow pulse rate of less than 30/rain. There are two types of QRS complex of lower pacemaker origin. the connective tissue of the atria and ventricles, with m a n y amyloid rings in t h e epicardium. Valves: There were m a r k e d amyloid deposits in the aortic and mitral valves. Coronary arteries: Amyloid infiltration was slight in the wall of larger lumen but abundant in the smaller intramyocardial vessel walls. Atherosclerotic change was minimal. Lungs: Severe amyloid deposits were observed in the alveolar septa, in the small pulmonary and bronchial arteries. Skin: Diffuse amyloid deposits were found in the upper dermis, subcutaneous adipose tissue and small arteries. The epidermis was atrophic. Other organs: Except in the small arteries throughout the body, amyloid infiltration was not so prominent; interstitial tissue of the pancreas, the Bowmann capsule and arteries of both kidneys, small arteries of the liver and spleen were affected.
DISCUSSION The electrocardiographic features of SSS were proposed b y F e r r e r . 22'23 T h e pathogenesis or etiology is, however, very diverse in nature. ~-2~ With advancing age, the h u m a n cardiac conduction system, especially the SAN, internodal tracts and upper portions of the IVS, shows progressive significant loss of muscle fibers and increase of fibrous and adipose tissues. 2~-27 Indeed, it is common to find SSS in subjects of older age, b u t it also occurs in the young26,2s Our patient showed minimal aging changes in the conduction system, despite her age of 66. However, extensive amyloid infiltration was found, mainly in the SAN. This seemed to
be the most important etiologic factor of the SSS in this case. According to previous reports, 1,~,5,9 senile cardiac amyloidosis is not rare in those over the 6th decade, occuring with higher incidence in subjects over 90. Cardiac amyloid deposits in our patient were too severe to be explained as the senile variety. It was considered to be a primary systemic type of unknown origin, in p a r t i c u l a r involving the heart and lungs because there were no other causes of amyloidosis in her past history and pathological examination. There are a few reports 2'4'14 containing detailed histological studies of the conduction system in cardiac amyloidosis. J a m e s 2 stated that the conduction system was not spared in cardiac amyloidosis. ECGs in his five patients showed a t r i a l f i b r i l l a t i o n in two, p a r t i a l atrioventricular (A-V) block in one and sinus arrest with A-V junctional escape r h y t h m in two cases. With the exception of one case having partial A-V block, the major destruction by amyloid was in the SAN. Buja et al 4 reported 15 cases of cardiac amyloidosis, from clinical and pathological points of view. In eight of the 15 cases, the conduction system was examined, and in five of these, extensive amyloid deposits were observed in the SAN or AVN or both. However, the authors did not describe in detail the electrocardiographic abnormalities in these five cases. Ridolfi et aP 4 studied 23 autopsied cases with different d e g r e e s of cardiac amyloidosis, and t h e y found that only three of the 23 had severe amyloid infiltration in the SAN, AVN, His bundle or bundle branches, with extensive deposits in the SAN in two of the three. The electrocardiographic findings of the three patients were, however, stable sinus r h y t h m J. ELECTROCARDIOLOGY, VOL. 11, NO. 2, 1978
SICK SINUS SYNDROME
with first degree A-V block and left anterior hemiblock. Thus, these authors stated that conduction and rhythm disturbances in cardiac amyloidosis did not imply direct amyloid i n f i l t r a t i o n of t h e c o n d u c t i o n s y s t e m . Schroeder at a111 described two patients with cardiac amyloidosis diagnosed by transvenous endomyocardial biopsy. One of them was considered to be SSS, and a demand pacemaker was installed before the biopsy, but the authors did not discuss the histological findings of the conduction system. In our case, the intraventricular conduction varied between normal and complete RBBB, despite the absence of severe histological destruction of the right bundle branch. Significant changes were more conspicuous in the AVN and upper part of the His bundle t h a n in the right branch. With respect to mechanism of i n t e r m i t t e n t bundle branch block (BBB), Rosenbaum et al 2s s t a t e d t h a t t h e r e was t a c h y c a r d i a dependent BBB (phase 3 block) and bradycardia-dependent BBB (phase 4 block), and conduction was normal at intermediate cycle l e n g t h . The occurrence of complete RBBB in our patient seemed to be explained by the same mechanisms; the phase 3 block was probably related to the changes in the AVN and upper part of the His bundle, while the phase 4 block was due to the delay of impulse formation from the SAN. On the fifth day after implantation of a pacemaker, our patient died suddenly from severe dyspnea. Ventricular fibrillation or pacing failure was not observed in continuous ECG monitoring at this time. As the authors lack sufficient hemodynamic data to explicate d e f i n i t i v e l y t h e m y o c a r d i a l function, t h e cause of death in this case can only be a subject of speculation; it appears likely t h a t the pacing rate of 71/min was not reasonable for her low compliant myocardium and resulted in malfunction. We decided upon a p e r m a n e n t p a c e m a k e r i n s t a l l a t i o n when the patient's condition deteriorated. However, if we had noted while she was alive t h a t the SSS was a consequence of s y s t e m i c amyloidosis, we would have used a temporary pacemaker to find a more suitable pacing rate.
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Fig. 5. A section of the SAN, severely infiltrated by amyloid. (Masson Goldner trichrome stain, x 125).
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sinus syndrome. A study of 15 cases. Br Heart J 34:942, 1972 RUBENSTEIN,J J, SCHULMAN,C L, YURCHAK,P M AND DESANCTIS,R W: Clinical spectrum of the sick sinus syndrome. Circulation 46:5, 1972 LLOYD-MOSTYN,R H, KIDNER, P H AND ORAM, S: Sinoatrial disorder including the bradytachycardia syndrome. A review with addition of 11 cases. Quart J Med 42:41, 1973 KULBERTUS, H E, LEVAL-RUTTEN, F AND DEMOULIN,J C: Sino-atrial disease: A report on 13 cases. J Electrocardiol 6:303, 1973 Moss, A J AND DAVIS, R J: Brady-Tachy syndrome. Prog Cardiovasc Dis 16:439, 1974 STRAUSS, H C, BIGGER, J T, JR, SAROFF, A L AND GIARDINA, E-G V: Electrophysiologic evaluation of sinus node function in patients w i t h sinus node dysfunction. C i r c u l a t i o n 53:763, 1976 FERRER,M I: The sick sinus syndrome in atrial disease. JAMA 206:645, 1968
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