Ultrastructural findings in endomyocardial biopsy Kearns-Sayre syndrome is clinically defined by...

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  • 1522 JACC Vol. 12, No.6 December 1988: 1522-8

    Ultrastructural Findings in Endomyocardial Biopsy of Patients With Kearns-Sayre Syndrome


    Kearns-Sayre syndrome is clinically defined by progressive external ophthalmoplegia, atypical retinitis pigmentosa and the potential occurrence of complete atrioventricular (A V) block. Right septal endomyocardial biopsy specimens from nine patients (four men and five women with a mean [:!::SEM] age of 36.3 :!:: 14.4 years) with chronic progressive external ophthalmoplegia and mitochondrial skeletal my- opathy were studied. Three patients had atypical retinal pigmentation. An atrioventricular or intraventricular con- duction defect was observed in five patients. A pacemaker was prophylactically implanted in one patient because of abnormal conduction distal to the His bundle.

    Ultrastructural investigations revealed mitochondriosis in many heart muscle cells and an increased variability of mitochondrial form and size in all patients. In seven patients, 0.4 to 2.1 % of all examined myocytes contained

    Progressive external ophthalmoplegia can be associated with various clinical symptoms and a variety of neuromuscular disorders (1-3). Cardiac involvement and the occurrence of heart block were observed by Sandifer (4) in 1942. In 1958 Kearns and Sayre (5) described in two patients the clinical triad that now bears their names: progressive external oph- thalmoplegia, atypical retinal pigmentation and complete atrioventricular (A V) block.

    Kearns-Sayre syndrome is a rare disease. Fewer than too cases have been reported (2,6). Incomplete forms and com- binations with various other symptoms have been described,

    From the 'Department of Cardiology, Pneumology and Angiology and the Departments of tPathology and :j:Neurology, Medical Hospital of the University of Diisseldorf, Diisseldorf, West Germany. This study was sup- ported by a grant from the Sonderforschungsbereich 242 (Koronare Herz- krankheit-Prophylaxe und Therapie akuter Komplikationen, Teilprojekt D) of the Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg. West Ger- many.

    Manuscript received April 4, 1988, accepted July 20, 1988. Address for reprints: B. Schwartzkopff, MD, Department of Cardiology,

    University of Diisseldorf, Moorenstrasse 5, 4000 Diisseldorf, West Germany.

    © 1988 by the American College of Cardiology

    exclusively abnormal mitochondria. Three main types were observed: huge, mainly round mitochondria with concen- tric cristae; large, round or oval mitochondria with trans- verse or curved cristae; and small, vacuolated mitochon- dria. The volume density of myofibrils was reduced (41.9 :!:: 11.1 compared with the normal value of 56.5 :!:: 2.5 volume density [in percent], p < 0.01) in these myocytes. Increas- ing numbers of vacuolated mitochondria correlated signif- icantly with a reduction of myofibrils (r = -0.64, p < 0.01).

    The data suggest that the ventricular myocardium of most patients with complete and even incomplete Kearns- Sayre syndrome is affected by disseminated mitochondrial cytopathy.

    (J Am Coil CardioI1988;12:1522-8)

    including weakness of facial, pharyngeal and peripheral muscles, increased cerebrospinal fluid proteins, cerebellar ataxia, lactic acidosis, short stature and deafness (1,2,6-8). Skeletal muscles are typically affected by a disseminated mitochondriopathy with so-called ragged-red fibers that con- tain mitochondria of abnormal structure (3). Kearns-Sayre syndrome is now considered a distinct, sporadic form of mitochondrial myopathy (2,6). Only a few hereditary cases have been described (9). The pathogenesis and the biochem- ical defect are unknown; therefore, the diagnosis of mito- chondrial cytopathy is mainly based on morphologic find- ings.

    It is controversial whether or to what extent the myocar- dium is involved in the process of mitochondrial cytopathy. In this report, we describe qualitative and quantitative morphologic findings based on right septal endomyocardial biopsy in nine consecutively studied patients with complete and incomplete Kearns-Sayre syndrome. These data indi- cated that mitochondrial cardiomyopathy was the underlying disorder in all nine.



    Table 1. Clinical Symptoms in Nine Patients with Kearns-Sayre Syndrome


    2 4 5 6 7 8

    Age at onset (yr) 9 30 19 16 14 18 40 6 Ptosis + + + + + + + + CPEO + + + + + + + + Retinal pigmentation + + Prox. myopathy + + + + + + + Defective vision + + Cerebellar ataxia + + + Deafness + Short stature + LAHB + RBBB + Incomplete RBBB + + +


    9 + + + +


    CPEO = chronic progressive external ophthalmoplegia; prox. myopathy = accentuated proximal weakness of the skeletal muscle; LAHB = left anterior hemiblock; RBBB = right bundle branch block; + = present.

    Methods Study patients. Nine patients (five women and four men

    with a mean [±SEM] age of 36.3 ± 14.4 (range 16 to 62) years were studied from 1981 through 1987. The clinical features are presented in Table 1. Skeletal muscle biopsy, performed on either the deltoid or quadriceps muscle in all patients, disclosed ragged-red fibers with use of the modified Gomori trichrome stain (3). Electron microscopy revealed structural abnormalities of mitochondria with paracrystalline inclusions and abnormal cristae mitochondriales, supporting the diagnosis of a mitochondrial myopathy (2,3,6). Cardio- logic investigations were performed to exclude A Y conduc- tion defects and to look for involvement of the myocardium.

    All patients underwent complete cardiologic investiga- tion including right heart catheterization and intracardiac electrophysiologic study, according to a previously de- scribed protocol (8). Coronary angiography, performed in patients 7 and 8, revealed normal coronary arteries in both. All patients had given informed written consent.

    Biopsy specimens. At least two endomyocardial biopsy specimens (maximum five, mean three per patient) were obtained from the right ventricular septum and immediately fixed by immersion in 2.5% cacodylate-buffered glutaralde- hyde. The specimens were halved. One half was processed for light microscopy by embedding in paraffin and 4 to 6 JLm thick sections were stained with hematoxylin-eosin and elastic van Gieson. The other half was postfixed in 1% osmium tetroxide (OS04) solution, dehydrated in a graded ethanol series and embedded in Epon. Ultrathin sections were contrasted with uranyl acetate and lead citrate. The specimens were examined with a Zeiss electron microscopy EM 109 at 50 kY.

    Morphometry. All available biopsy specimens were eval- uated; 100 randomly selected, longitudinally sectioned, he-

    matoxylin-eosin-stained cardiomyocytes per patient were measured across the nucleus by light microscopy at a magnification of XI ,250. A square lattice with a fixed dis- tance between the lines was used to determine the content of interstitium and fibrous tissue in the van Gieson-stained sections (x 1,250) by counting cross points according to well established morphometric rules (10). Seventy-five fields per patient were randomly evaluated; red stained tissue was interpreted as collagen.

    Each biopsy specimen was examined by electron micros- copy. All available fibers were counted and classified. Heart muscle cells containing mitochondria with parallel or con- centric cristae or being vacuolated were regarded as patho- logic (Fig. O. They were photographed and their number was given as a percent of the total number of observed heart muscle cells. Ten randomly chosen electron micrographs of structurally normal myofibers from different biopsy speci- mens were evaluated per patient at a magnification of x 13,400. The fractional volumes of myofibrils, mitochondria and sarcoplasm were determined by counting cross points with a superimposed grid excluding the nucleus. Mean mitochondrial diameter was determined from 300 normal mitochondria from every patient. Micrographs of all myo- cytes with abnormal mitochondria were evaluated by the same procedure. All abnormal mitochondrial profiles were counted and their mean diameter was evaluated from their area; they were classified according to the arrangement of their cristae (n = 1,768) (Fig. O. Morphometric analysis was carried out with use of an interactive image analyzing system (IBAS I; Kontron).

    Statistical analysis was performed with use of Student's t test for unpaired data at p < 0.05 comparing the mean of each variable for normal and abnormal myocytes.

    Results Clinical presentation (Table 1). Family history was unre-

    markable for neuromuscular diseases in all patients. The onset of the disease was marked by a ptosis at a mean age of 17.6 years (range 9 to 40). None of the patients had had syncope or clinical signs of cardiac insufficiency.

    The routine electrocardiogram (ECG) showed an intra- ventricular conduction defect in five patients. Exercise ECG disclosed ST segment depression only in Patient 7, who had normal coronary arteries. His bundle electrography showed a normal atrionodal conduction time (AH interval) in all nine patients (79.4 ± 16.9 ms). The mean His-Purkinje interval (HY interval) was 46.7 ± 10.3 ms; it was prolonged (60 ms) in Patients 1 and 4. Rate-corrected sinus node recovery time