Cardiac Biopsy in Patients with “Primary” Atrial Fibrillation

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clinical invest:igati• Cardiac Biopsy in Patients with "Primary" Atrial Fibrillation* Histologic Evidence of Occult Myocardial Diseases Andrea Frustaci, M.D., F.C.C.P.; Marina Caldarulo, M.D.; Antonino Buffon, M.D.; Fulvio Bellocci, M.D.; Riccardo Fenici, M.D.; and Domenico Melina, M.D.

Fourteen patients (ten men and four women; mean age, 37 years) with lone atria) &brillation (AF) (I to 18 months' duration) were evaluated by thyroid function tests, twodimensional ec:hocardiography, hemodynamics, coronary angiography, and left ventricular endomyocardial biopsy, because of unresponsiveness to the usual antiarrhythmic therapy. The results of the T,, T., TSU, and TRH tests were normal in all patients; cardiac valves and ventricular and atria) sizes (left atrium <40 mm) were within the normal limits; also normal were LVEDP (sIO mm Hg) and EF (>0.50). Histologic 6ndings were abnormal in all cases, with three patients showing canliomyopathic changes, three other patients showing active myocarditis (lymphocytic in two and eosinophilic in one), and eight patients with nonspeci&c necrosis or fibrosis or both. Steroids (predni-

sooe; 50 mg/m1 of body surface area daily) used in addition to antiarrhythmic therapy in patients with eosinophilic and lymphocytic active myocarditis were able to cause reversion to sinus rhythm, while the other patients continued to have AF. This study documents that occult myocardial diseases (myocarditis, cardiomyopathy, and nonspecific necrosis or &brosis) can underlie "primary" AF. The addition of steroids to antiarrhythmic therapy in patients with refractory AF and histologic evidence of active myocarditis seems to be useful in controlling the arrhythmia. (Chat 1991; 100:303-06)

,l trial fibrillation (AF} is usually associated with 11 detectable organic heart diseases, with valvular

with DC shock. This population was evaluated by the usual blood and chemical analysis (including levels of Hb, BUN, SGCYf, SGPT, and serum electrolytes), thyroid function tests (T., T., TSH, and TRH tests), two-dimensional echocardiography, cardiac catheterization, coronary angiography, and left ventricular endomyocardial biopsy with extraction of three to 6ve fragments from each patient to be processed for histologic and electron microscopic studies.

and coronary disorders, hypertension, and hyperthyroidism the most common causes; however, AF may occur without clinically evident abnormalities, the socalled "primary" or "lone" AF.u This entity is poorly understood as far as the etiology is concerned, so that treatment is usually empirical and the long-term prognosis uncertain. 3-6 We report a study of the findings from cardiac biopsy in 14 patients with lone AF, in whom control of the arrhythmia through conventional antiarrhythmic therapy had been revealed to be inefficient. PATIENTS AND METHODS

Fourteen patients (ten men and four women; mean age, 37 years) with lone AF (1 to 18 months' duration) failed to have reversion to sinus rhythm with conventional therapy administered for at least three weeks at the usual dosage (lable 1) and occasionally associated *From the Departments of Cardiology (Ors Frustaci, Buffon, and Bellocci), Internal Medicine (Ors Caldarulo and Melina), and Clinical Physiology (Dr Fenici), Catholic University, Rome, Italy. Manuscript received September 4; revision accepted January 11. Reprint requests: Dr. Fnutaci, Cardiology Department, Catholic University School of Medicine, Largo Gemelli 8, Rome, Italy 00168

AF=atrial &brillation; LA=left atrium; LVEDP=left ventricular end-diastolic pressure; LVEF=left ventricular ejection fraction

Biopsy Material The samples of myocardial tissue were placed in a solution of 3 percent glutaraldehyde and transported for the electron-microscopic studies in a solution of 10 percent phosphate butler. The tissue for electron microscopic study was then washed in butlered sucrose (at 4°C and at a pH of7.4), postfixed in 1 percent osmium tetroxide, processed by the standard technique, and &nally embedded in epoxy resin (Epon). Sections were cut on an ultramicrotome and stained with uranyl acetate and lead citrate. Tissue for light microscopy was stained with hematoxylin-eosin, Millers elastic Van Gieson, 7 and, on one occasion, carbol-chromatrope stain.•

Criteria for Myocardltis and CardiomfPpathy Diagnosis of myocarditis followed the histologic criteria of the Dallas classification system.• In particular, the presence of inftammatory in6ltrates in the myocardium with necrosis or degeneration of adjacent myocytes not typical of ischemic damage was a prerequisite for the definition. The term active myocarditis was introduced to indicate potential CHEST I 100 I 2 I AUGUST, 1991

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Table I-Data on 14 lbtienta with Lone AF Patient, Sex, Age(yr)

LAD, mm•

LVEF, %t

1, M,52

39

6.5

2, M, 40

37

50

3, F, 35

38

71

4, F, 25 5 , M,42

39 37

5.5

6, M,53

39

5.5

7, M, 30

35

60

8, F, 34

30

64

9, M, 31

32

73

10, M, 33

34

78

11, F, 44

36

58

12, M, 37

39

61

13, M, 33

38

6.5

14, M, 29

34

70

60

Therapy, mwday

Histology

Atenolol, 100; Focal active quinidine, 1,200 myocarditis Digoxin, 0.125; Cardiomyopathy amiodarone, 200 Amiodarone, 200 Nonspecific necrosis and fibrosis Propafenone, 450 Cardiomyopathy Verapamil, 360; Cardiomyopathy amiodarone , 200 Flecainide, 450; Nonspecific amiodarone, 200 fibrosis Amiodarone, 200; Nonspecific DC shock fibrosis Propafenone, 900 Nonspecific necrosis and fibrosis Amiodarone, 200 Focal active myocarditis Amiodarone, 200 Nonspecific fibrosis Propafenone, 900 Eosinophilic active myocarditis Amiodarone, 200 Nonspecific fibrosis Amiodarone, 200 Nonspecific necrosis and fibrosis Amiodarone, 200 Nonspecific necrosis and fibrosis

*LAD, left atrial diameter in parasternal long-axis view. tBy single-plane 30" right anterior oblique projection. susceptibility of the in8ammatory disorder to immunosuppressive therapy (le, cellular necrosis unaccompanied by reparative phenomena). In the presence of occasional foci of myocardial necrosis or fibrosis (or both) with mild in8ammatory reaction, the descriptive expression nonspecific necrosis or fibrom has been preferred to healing or healed myocarditU. Indeed, several conditions such as toxic and hypercatecholamine states can account for it; furthermore , a previous biopsy specimen showing histologic evidence of activity was not available. The tenn cardiomyopathy was applied to define the presence (at histology and electron microscopy) of hypertrophy with various degrees of degenerative changes of myocardial fibers with or without interstitial and replacement fibrosis, with no evidence of myocarditis or small-vessel involvement.

chambers and pulmonary artery (::530 mm Hg) and a normal wedge pressure (::512 mm Hg). Two-dimensional echocardiography documented no abnormality ofleft ventricular end-diastolic dimension (diameter <56 mm) and contractility (LVEF >0.50), while left atrial size was in every case less than 40 mm in diameter.

Morphologic Study Histologic study revealed abnormal findings in all patients. In particular, in three patients an active myocarditis was identified. Inflammatory infiltrates usually had a patchy distribution and were of the lymphocytic type (Fig 1) in two cases. In one patient with hypereosinophilia in the blood and active myocarditis at histologic study, in8ammatory infiltrates were mostly represented by degranulated eosinophils following specific (carbolchromatrope) staining (Fig 2). In three other patients, hypertrophied myocytes with some degenerative changes were seen at histologic study (Fig 3), and electron microscopy revealed a cardiomyopathic process. In four patients, myocardial hypertrophy was associated with occasional foci of cellular necrosis and mild inflammatory reaction (mostly of the lymphocytic type); interstitial and replacement fibrosis was also present. In the last four patients, myocardial hypertrophy and fibrosis were unaccompanied by degeneration or necrosis of myocardiocytes. Therapeutic Considerations

Following the encouraging results in the literature, 10·11 immunosuppression (prednisone, 50 mg/m2 of body surface area) was associated with antiarrhythmic drugs in two patients with lymphocytic myocarditis and in the single patient with eosinophilic active myocarditis. At a four-week follow-up, recovery of sinus rhythm was documented in the steroid-treated patients, while all the others continued to have AF.

•

RESULTS

Blood and chemical analysis values, including serum electrolyte levels, were within normal limits in all cases, except for that of a 44-year-old woman in whom leukocytosis (12,000/cu mm) with hypereosinophilia (18 percent) was found . The valvular pattern and findings from coronary arteriography were normal in all patients. Cardiac catheterization revealed normal pressures in the right 304

.. F1cuRE 1. Endomyocardial biopsy of patient 1 with two-month duration of primary AF. Specimen shows active lymphoc-ytic myocarditis (hematoxylin-eosin, original magnification x 250). C8Rliac Biopey in Atrial Flbrillatlon (Frustaci et el)

FIGURE 2. Eosinophilic myocarditis in 44-year-old woman with lone AF. Degranulated eosinophils (arrowheads) are accompanied by fraying of adjacent myocytes (carbol-chromatrope, original magnification x 400).

DISCUSSION

Fourteen young patients (mean age, 37 years) with AF were evaluated with cardiac catheterization and coronary angiography because of unresponsiveness to the usual antiarrhythmic therapy (Tuble 1), despite normal blood and chemical analysis, thyroid function tests, and a two-dimensional echocardiogram which showed normal atrial (left atrium <40 mm in diameter) and ventricular size and cardiac function (LVEF >0.50). Endomyocardial biopsy was undertaken when abnormalities were ruled out as a possible pathogenetic mechanism and cardiac catheterization revealed normal pressures. Cardiac biopsy was obtained in our patients through a left ventricular approach. Atrial endomyocardial biopsy has also been employed to investigate atrial arrhythmias; 12 however, histologic abnormalities were detected in only 40 percent of the cases and were mostly nonspecific. Moreover, atrial biopsy, due to anatomic structure (thick endocardial and thin myocardial layer), still

FIGURE 3. Cardiomyopathic changes in patient with primary AF. Hypertrophy with vacuolar degeneration of myocardial 6bers is seen {hematoxylin-eosin, original magni6cation x 250).

remains a dangerous and diagnostically unsatisfactory approach. Our morphologic study revealed abnormal findings in all patients with primary AF. In particular, a myocarditis, mostly with focal distribution, was revealed in 21 percent (3114) and a cardiomyopathic process in another 21 percent (3114) of the cases. In the remaining 57 percent (8114) of the patients, nonspecific necrosis or fibrosis or both, without clear evidence of myocarditis, was seen. The histologic diagnosis allowed us to modify the therapeutic approach in three cases of active myocarditis (lymphocytic in two and eosinophilic in one), where the addition of steroids to antiarrhythmic therapy was able to induce the recovery of sinus rhythm. In patients with nonspecific necrosis or fibrosis (or both), as well as those with cardiomyopathy, appropriate use of agents in addition to antiarrhythmics has not been formulated; however, useful data toward the prognosis have been obtained. Indeed, the histologic observation of nonspecific fibrosis, cardiomyopathy, or active myocarditis suggests different evolutionary patterns. It can be speculated that the diagnostic sensitivity of endomyocardial biopsy, which should be high with five fragments, 13•14 might not be absolute; patchy lesions can be missed, and the diagnostic and prognostic evaluation can be inadequate. Furthermore, the histologic findings we have observed in our population might not include all of the entities in the pathologic spectrum df primary AF. In fact, our patients were selected for a biopsy due to the severity of the electrical instability that was unresponsive to the usual antiarrhythmic therapy. It can be that patients with occasional, self-limiting, or easily treatable primary AF have different pathologic findings (if any) and mechanisms; however, in our study. ventricular endomyocardial biopsy identified specific lesions in 21 percent of the cases, where it CHEST I 100 I 2 I AUGUST, 1991

305

contributed to an improvement in the control of the arrhythmia. Finally, our data are in agreement with those in previous biopsy studies on unselected supraventricular arrhythmias. 15 In conclusion. our study suggests that occult myocardial diseases (speci&cally, myocarditis, cardiomyopathy, and nonspecific necrosis or fibrosis) can underlie the so-called primary AF, particularly if it is unresponsive to antiarrhythmic therapy. Steroids can be useful for control of the arrhythmia in cases of active myocarditis, even though a more extensive study and a longer follow-up are needed. The pathologic spectrum of primary AF, particularly for patients with the milder form of arrhythmias, can be wider and needs to be further investigated. ACKNOWLEDGMENT: We thank Mr Manlio Fabrucci for bis

expert technical assistance.

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Plan to Attend ACCP's

57th Annual Scientific Assembly !rd San Francisco ~ November 4-8, 1991

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Cerdlec Blopey In Atrial Flbrillatlon(Frustacl et al)