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Embolism and atrial fibrillation
The American
Journal of Cardiology APRIL
VOLUME IX
1962
NUMBER 4
EDITORIAL Embolism
and Atria1 Fibrillation
The Effect of Restoration
of Normal
T
o PREVENT THE FORMATION of thrombi in fibrillating cardiac atria two measures are drug therapy and widely used : anticoagulant restoration of normal rhythm with quinidine. Anticoagulant drug therapy has become accepted slowly and steadily, in spite of early misgivings, over the past 15 years.’ Quinidine conversion, earlier regarded as dangerous in the presence of embolism,2r3 has in the past 20 years been accepted clinically and endorsed by the National Research Council as clearly indicated in cases with a history of systemic embolization.4-10 Quinidine conversion has been accepted without regard to distinctions in the causes of atria1 fibrillation and the mechanism of atria1 thrombosis which have now become apparent through statistical and pathological studies. The assumption has been that thromboembolism occurring in the presence of atria1 fibrillation has been basically due to stasis resulting from the arrhythmia. The “fibrillating” heart, regardless of the type of heart disease, usually is mentioned as a primary cause of cardiogenic emboThe thrombotic effect of the arrhythmia lism. is presumed to be limited to the atria regardless of the cause.6 The only cardiac condition in which atria1 fibrillation can be correlated with atria1 thrombosis, however, is rheumatic heart disease with left atria1 thrombosis. The highest correlation of atria1 fibrillation and atria1 thrombi in rheumatic heart disease is with mitral stenosis. To assume that a statistical correlation demonstrates a causal relationship, however, violates a basic tenet in interpretation. (Pearln cautions measures statistical associathat “correlation Atria1 fibrillation cannot tion, not causation.“) be correlated with either right or left atria1 thrombosis in nonrheumatic heart disease.
Rhythm
by Quinidine
If the loss of coordinated atria1 contractility due to fibrillation does indeed give rise to more frequent clotting, then atria1 clots should be more frequent in patients with fibrillation, and fibrillation should be correspondingly more frequent than normal rhythm in patients with atria1 of the left atrium at necropsy clots. Examination reveals a correlation of these conditions only in rheumatic heart disease, for which the statistical correlation is highly significant (Tables I and II) .I*,13 This correlation is corroborated by observations at cardiotomy. In nonrheumatic heart disease, there is no such correlation (Tables III and IV).‘~ Garvin,i5 for example, found no such correlation in 374 persons dying from coronary arterial disease. Regardless of rhythm, few left atria1 thrombi are found in purely arteriosclerotic heart disease (Table v),i4-i6 and the chance of emboli arising from them seems slight; moreover, emboli occur as frequently in normal rhythm as in atria1 fibrillation. Many systemic arterial emboli attributed to arteriosclerotic heart disease are really due to unrecognized rheumatic heart as necropsy reveals. Soderstromn disease, concluded from his studies (Tables VI and VII) that the chief determinants of thrombosis in the right atrium are underlying wall damage and congestive failure, and that fibrillation is important only insofar as it contributes to congestive failure. He suggested that since right atria1 infarction is frequent in patients with right atria1 thrombosis and congestive failure, the infarction rather than the failure may have been the important correlate with thrombosis. Mural thrombi in either ventricle cannot be correlated with atria1 fibrillation regardless of cause. They are uncommon in the right ventricle,i4fi6 and in the left ventricle their frequency of occurrence is correlated with the size 491
Editorial TABLE I
TABLE III
Frequency of Left Atria1 Mural Thrombi in Patients With Rheumatic Heart Disease and Atria1 Fibrillation and Those With Normal Rhythm (Necropsy)*
Frequency of Left Atria1 Thrombi in Patients With Acute or Healed Myocardial Infarction and Atria1 Fibrillation or Normal Rhythm
Rhythm
Normal Atria1 fibrillation Total
Patients (No.)
Number With Left Atria1 Thrombi
Percentage
150
17
11t
170 320
76 93
44t 29
Rhythm
Atria1 fibrillation Normal Rhythm
27 300
* From compiled data by Soderstrom12 and Graham, et a1.13 t Highly significant. P less than 0.001.
Number With Left Atria1 Thrombi
Patients (No.)
*Not significant. by Jordan.)14
-i
(Necropsy
Percentage
1
3.7*
13
4.3*
study
of 327 patients
TABLE II
TABLE IV
Frequency of Atria1 Fibrillation in Patients With Rheumatic Heart Disease and Left Atria1 Thrombi (Necropsy ) *
Frequency of Atria1 Fibrillation in Patients With Acute or Healed Myocardial Infarction and Left Atria1 Thrombi or Without Left Atria1 Thrombi”
Left Atria1 Thrombi
Patients (No.) I
Thrombi Thrombi * From et a1.13
present absent
93 227
/ Number With Atria1 Fibrillation
1
I
, I
,
Percentage
76 94
8lt 41t
compiled data of Soderstrom12 and Graham t Highly significant. P less than 0.001.
Left Atria1 Thrombi
1
Patients (No.)
Number With Atrial Fibrillation
Per ._ cent: vze
Present Absent * Not significant.
is ascribed to the stasis of blood in the ineffectively contracting diseased atrium, and quinidine therapy was advocated in the belief that restoration of normal rhythm would restore atria1 contraction enough to overcome The occasional occurrence of embolism stasis. following restoration of normal rhythm by quinidine seemed to confirm this opinion, though it presented the added danger that thrombi formed in the period of stasis might then be expelled. It gradually became the consensus that this danger was less than the danger from repeated thromboembolism in established atria1 fibrillation.5-s Atria1 fibrillation in mitral stenosis is an index of atria1 stasis, as illustrated by angiocardiographic timing of opacification in the left atrium,18 with an increase from a normal time of 5 seconds to a period of 9.4 seconds in mitral stenosis with normal rhythm, and 11.9 seconds Cliniin mitral stenosis with atria1 fibrillation. cally, fibrillation is a hallmark of prolonged stasis following longstanding rheumatic heart fibrillation
of the underlying infarct and with congestive heart failure, regardless of the rhythm.14 If atria1 fibrillation is not an important factor in the formation of atria1 thrombi in arteriosclerotic heart disease, it cannot be an important factor in embolism arising from clots in the atria.” HEMODYNAMIC
CONSIDERATIONS
Clotting in a chamber of the heart, as in thrombosis elsewhere, can occur only when the three thrombotic factors are present in sufficient damage, coagulability of degree : endothelial Atria1 the blood and retardation of flow. thrombosis is not inevitable even in the most strongly conducive circumstances, in “pure” mitral stenosis which has progressed to atria1 fibrillation. There is no reason to believe this arrhythmia alone can cause endothelial damage When it is present or increased coagulability. in otherwise normal hearts, there is no mural thrombosis because there is no endothelial The thrombotic effect of atria1 damage.
THE AMERICANJOURNAL OF CARDIOLOGY
Editorial
493
TABLE v
TABLE
Frequency of Left Atria1 Thrombi in Patients With Coronary Artery Disease With or Without Myocardial Infarction and With or Without Hypertension
Frequency rheumatic
Number Patients
Author
(No.1
TyrrzLi
300 327 374 1001
B.ZXl’~ Jordan’4 Garvinl” TOtal
Left Sided
L~f~~~~a, Thrombi
17 14 21 52
139 108 141 388
I
Number Left Ventricular Thrombi Associated
Left Atria1 Thrombi Only
14 8 8 30
3 6 13 22
I
WI
of Atria1 Fibrillation in Patients With NonHeart Disease With and Without Right Atria1 Thrombi (Soderstrom)‘z
Right Atria1 Thrombi Present Absent Total
I-
(No.)
Number With Atria1 Fibrillation
Percentage
115 413 528
53 164 217
46* 40* 41
Patients
* Not significant.
(Data
from compiled
TABLE
necropsy
series)
VI
Frequency of Right Atria1 Thrombi in Patients With Nonrheumatic Heart Disease and Atria1 Fibrillation or Normal Rhythm
Rhythm
Patients (No.)
Atria1 fibrillation Normal rhythm Total Necropsy study * Not significant.
of
Number With Right Atria1 Thrombi
Percentage
217
53
24*
311 528
62 115
20* 22
528
patients
by
Soderstrom.‘*
The patients are older and the endodisease. thelium has been subjected to the damaging All three thrombotic effect of prolonged stasis. Atria1 factors simultaneously are maximal. fibrillation, therefore, frequently coincides with the left atria1 thrombosis but does not primarily The two conditions apparently result cause it. from coincident causes. In arteriosclerotic heart disease atria1 fibrillation alone does not give rise to sufficient stasis for mural clotting in the atria unless congestive failure is also present. Even then, with both atria fibrillating, thrombosis characteristically occurs only in the right atrium which is the site of endothelial damage. Rheumatic heart disease is the only disease in which atria1 fibrillation can be correlated with a greater frequency of cardiac mural thrombi, and the left atrium is the only chamber in which clots are more frequent in fibrillation. What effect has restoration of normal rhythm Hechtig meason effective atria1 contraction? APRIL
1962
ured left heart pressure by catheterization in patients with mitral stenosis and atria1 fibrillation; he calculated by the laws of fluid dynamics that restoration of atria1 contraction could not appreciably augment atrioventricular flow. The left atrium observed at cardiotomy for mitral stenosis has no discernible effective contraction regardless of rhythm, nor has there been any report of significant contraction on fortuitous restoration of normal rhythm during this operation. Postoperative roentgen studies disclose no significant reduction in size of the left atrium except that due to removal of the auricle.20 Studies by Rowe and his co-workers,21 and Selzerz2 indicate that after restoration of normal rhythm even though the ventricular rate remains the same, the flow per minute increases. This increase is generally ascribed to greater atria1 contraction, but it can better be ascribed to the related improvement in left ventricular contractility with a longer effective diastolic filling time. In rheumatic mitral stenosis which has progressed to atria1 fibrillation, the average volume of the left atrium is estimated as 230 cc. (normal, 50 cc.).23 If this volume is not significantly reduced after commissurotomy, the improvement in atrioventricular flow per second can only reduce a residual volume slightly which may be more than four times normal. Therefore, localized left atria1 stasis remains a significant thrombotic factor, as shown by the continued occurrence of systemic arterial embolism after commissurotomy.24 If opening of the narrow fixed mitral valve fails to relieve atria1 stasis sufficiently to prevent thrombosis, it is difficult to believe restoration of faint contraction to At the dilated atrium can be of greater value. present, such improvement is an assumption that cannot be accepted without proof.
Editorial CESSATION OF EMBOLIW FOLLOWING RESTORATION OF NORMAL RHYTHM If quinidine conversion of atria1 fibrillation does not reduce atria1 stasis, what accounts for that cessation of clinically recognized embolism which is attributed to restoration of normal rhythm? The explanation lies in the natural history of thromboembolism, which in the case of mitral stenosis is fairly well documented. In one group of 47 patients with systemic arterial embolism due to mitral stenosi~,~r 12 died from the first cfinically recognized embolus. Of the 35 who survived the first episode, only 16 had a second recognized embolus, which in 8 cases did not occur until a year or more after the first. In another group,25 the first clinically recognized systemic arterial embolism was fatal in 18 of 75 cases, but only 28 of the surviving 57 had another recognized embolus. Although there was no prophylactic antithrombotic drug treatment in either of these series, more than half the patients who survived a recognized embolism clid not have another. Even in patients with rapidly recurring embolism, a cessation of six munths or more may not be significant, 26 for the clinical recognition of an embolism depends largely on the point of impact. Towbin”? has shown that small cerebral emboli from left ventricular thrombi may be frequent but unrecognized in patients with old myocardial infarction. MacFarlanez8 has reported one case in which repeated embolism (six episodes in two months) required repeated embolectomy, and in which embolism ceased without treatment. Before any prophylactic therapy can be judged effective, it must be observed as long and as widely as the natural course of the disease deFurthermore, as Mainlandzg emphamands. sizes, follow-up observations must be made at regular intervals from the start of therapy in treated patients and controls. By these criteria, a period of six months without recurrence, even after repeated embolism, is probably not In arteriosclerotic heart disease significant. the formation of left ventricular thrombi has not been statistically associated with atria1 fibrillation; accordingly, cessation of systemic arterial emboli following conversion cannot be demonIf a significant period strated as significant. without embolism does occur after conversion, it is probably due to relief of congestive failure, which has been correlated with ventricular thrombosis. Pulmonary embolism from the right atrium is likewise associated with conges-
tive failure but not with atria1 fibrillation; furthermore, it must not be overlooked that the pulmonary emboli may have been derived from peripheral venous thrombi and not from the right atrium. With these qualifications, the evidence for cessation of embolism through restoration of normal rhythm is not convincing. DISCUSSION The efficacy of any antithrombotic measure must at present be judged against that of anticoagulant drugs, whose value has been established by long and broad experience. Since embolism may occur at any time following an episode, the prophylactic effect must be both prompt and sustained. Antithrombotic drugs in proper combination give an immediate effect which continues as long as such therapy Most clinicians agree that this continues. method, unless seriously contraindicated, is the prime measure to be used after a single embolism, though they differ on the length of time it shouid be continued. In rheumatic heart disease with mitral stenosis, some would continue indefinitely, but others would reevaluate the need after six weeks.30 As long as this therapy is continued, there is no need to convert atria1 fibrillation as a measure to inhibit further embolism.“’ Collective data on survivors of the first systemic arterial embolism in rheumatic heart disease indicate that the average interval between embolic episodes was seven months before treatment and seven years during treatment3’ By comparison, conversion of atria1 fibrillation in rheumatic heart disease is neither as reliable nor as effective. Conversion can be obtained in, at most, 80 per cent of cases, and only after one to several days; maintenance of normal rhythm is difficult and unpredictable. The prophylactic value of conversion is often obscured by the fact that most investigators favor a course of antithrombotic drug therapy for ten to fourteen days before conversion. Freedom from embolism, therefore, can better be credited to the antithrombotic drug therapy, as Freeman and Wexler3’ observe. Even if antithrombotic drugs are discontinued after six weeks, and normal rhythm has been restored, continued freedom from embolism can still be ascribed as logically to the natural course of the disease as to maintenance of normal rhythm. In arteriosclerotic heart disease embolism is characteristically in the right atrium and left ventricle, and the correlation is with endoTHE
A.MERICAN
JOURNAL
OF CARDIOLOGY
Editorial The cardial damage and congestive failure. only thrombotic effect of atria1 fibrillation is Occasionally to increase congestive failure. conversion of atria1 fibrillation may be desirable to help relieve congestive failure, and decrease Since antithrombotic the thrombotic tendency. drugs are usually given for such embolism, the beneficial effect of returning normal rhythm is probably negligible. In either condition, the danger is that concern with conversion of atria1 fibrillation may detract attention from reliable and effective antithrombotic drug therapy. ACKNOWLEDGMENT The author wishes to express his appreciation to Sol Bernstein, M.D., Oscar Magidson, M.D., F.R.CP. and John M. Weiner, PH.D. for their assistance in the preparation of this paper. JOHN MARTIN
ASKEY, M.D.
Department of Medicine University of Southern California School of Medicine Los Angeles, California REFERENCES 1. WRIGHT, I. S. and FOLEY, W. T. Use of anticoagulants in treatment of heart disease. Am. J. Med., 3: 718, 1947. 2. LEWIS, T. The value of quinidine in cases of auricular fibrillation. Am. J. M. SC., 163: 781, 1922. 3. KOHN, C. N. and LEVINE, S. A. An evaluation of the use of quinidine sulphate in persistant auricular fibrillation. Ann. Znt. Med., 8: 923, 1935. 4. BECKWITH, J. R., IBARRA, J. A. and WOOD, J. E. The problem of established atria1 fibrillation. Am. J. M. SC., 231 : 519, 1956. 5. FLEISCHMANN,C. A. The use of quinidine in auricular fibrillation. Am. J. M. SC., 225: 617, 1953. The management of chronic 6. GOLDMAN, M. J. Indication for and methods of atria1 fibrillation. conversion to sinus rhythm. Progr. Cardiov. Dir., 2: 465, 1960. 7. MCMILLAN, R. L. and WELFARE, C. R. Chronic auricular fibrillation. J.A.M.A., 135: 1132, 1947. Quinidine in the treatment of 8. SOKOLOW, M. benign auricular fibrillation with repeated emboli. Am. Heart J., 18: 494, 1939. 9. YOUNT, E. H., ROSENBLUM,M. and MCMILLAN, R. L. Use of quinidine in the treatment of Arch. Znt. Med., 89 : chronic auricular fibrillation. 63, 1952. 10. Recommendations of National Research Council J.A.M.A., 124: 239, restricting use of quinidine. 1944. 11. PEARL, R. Introduction to Medical Biometry and Statistics, p. 435, 3rd ed. Philadelphia, 1940. W. B. Saunders.
APRIL 1962
12. SODERSTROM,N. Myocardial infarction and mural thrombosis in the atria of the heart. Acta. med. scandinau. supp. 132: 217, 1948. 13. GRAHAM, G. K., TAYLOR, J. A., ELLIS, L. B., GREENBERG, D. J. and ROBBINS,S. L. Studies in mitral stenosis; correlations of post-mortem findings with clinical course of disease in 101 cases. Arch. Znt. Med., 88: 532, 1951. 14. JORDAN, R. A., MILLER, R. D., EDWARDS, J. E. and PARKER, R. L. Intracardiac mural thrombosis, thromboembolism in acute and healed myocardial infarction. Circulation, 6 : 1, 1952. 15. GARVIN, C. F. Mural thrombi in the heart. Am. Heart J., 21: 713, 1941. 16. BEAN, W. B. Infarction of the heart. III. Clinical course and morphological findings. Ann. Znt. Med., 12: 71, 1938. 17. BEER, D. T. and GHITMAN, B. Embolization from the atria in arteriosclerotic heart disease. J.A.M.A., 177: 287, 1961. 18. ZINSSER, H. F., JR. and JOHNSON,J. The use of angiocardiography in the selection of patients for mitral valvular surgery. Ann. Znt. Med., 39: 1200, 1353. 19. HECIXT, H. The hemodynamic consequences of atria1 fibrillation. Mod. Conqbts Cardiouas. Dir., 25 : 351, 1956. 20. GARY, J. E. Late follow-up of radiologic changes after mitral valvuloplasty. iVew England J. Med., 254: 831, 1956. 21. ROWE, J. C., BLAND, E. F., SPRAGUE, H. B. and WHITE, P. D. The course of mitral stenosis without surgery: ten and twenty year perspectives. Ann. Znt. Med., 52: 741, 1960. 22. SELZER, A. Effect of atria1 fibrillation upon the cirAm. culation in patients with mitral stenosis. Heart J., 59: 518, 1960. 23. ARVIDSSON,H. Angiocardiographic observations in mitral disease. Acta Radial. supp. 158, Stockholm, 1958. 24. KELLOGG, F., CHI KONG Lm and FISHMAN, W. Systemic and pulmonary emboli before and after mitral commissurotomy. Circulation, 24: 263,1961_ 25. OLESEN, K. H. Mitral Stenosis, p. 143. Copenhagen, 1955. Ejnar Munksgaards Forlag. 26. DALEY, R., MATTINGLY, T. W., HOLT, C. L., BLAND, E. F. and WHITE, P. D. Systemic arterial embolism in rheumatic heart disease. Am. Heart J., 42: 566, 1951. 27. TOWBIN, A. Recurrent cerebral embolism. Arch. Neural. & Psychiat., 73: 173, 1955. 28. MACFARLANE, J. A. Multiple emboli treated surgically. Brit. Med. J., 1 : 971, 1940. 29. MAINLAND, D. Notes on the planning and evaluation of research, with examples from cardioPart III. Am. Heart J., vascular investigation. 55: 838, 1958. 30. CARTER, S. A., MCDEVITT, E., GATJE, B. W. and WRIGHT, I. S. Analysis of factors affecting the recurrence of thromboembolism off and on anticoagulant therapy. Am. J. Med., 25: 43, 1958. 31. ASKEY, J. M. Systemic Arterial Embolism, p. 102. Grune and Stratton. New York, 1957. 32. FREEMAN,I. and WEXLER, J. Quinidine in chronic atria1 fibrillation. Am. J. M. SC., 239: 181, 1960.
Journal of Cardiology APRIL
VOLUME IX
1962
NUMBER 4
EDITORIAL Embolism
and Atria1 Fibrillation
The Effect of Restoration
of Normal
T
o PREVENT THE FORMATION of thrombi in fibrillating cardiac atria two measures are drug therapy and widely used : anticoagulant restoration of normal rhythm with quinidine. Anticoagulant drug therapy has become accepted slowly and steadily, in spite of early misgivings, over the past 15 years.’ Quinidine conversion, earlier regarded as dangerous in the presence of embolism,2r3 has in the past 20 years been accepted clinically and endorsed by the National Research Council as clearly indicated in cases with a history of systemic embolization.4-10 Quinidine conversion has been accepted without regard to distinctions in the causes of atria1 fibrillation and the mechanism of atria1 thrombosis which have now become apparent through statistical and pathological studies. The assumption has been that thromboembolism occurring in the presence of atria1 fibrillation has been basically due to stasis resulting from the arrhythmia. The “fibrillating” heart, regardless of the type of heart disease, usually is mentioned as a primary cause of cardiogenic emboThe thrombotic effect of the arrhythmia lism. is presumed to be limited to the atria regardless of the cause.6 The only cardiac condition in which atria1 fibrillation can be correlated with atria1 thrombosis, however, is rheumatic heart disease with left atria1 thrombosis. The highest correlation of atria1 fibrillation and atria1 thrombi in rheumatic heart disease is with mitral stenosis. To assume that a statistical correlation demonstrates a causal relationship, however, violates a basic tenet in interpretation. (Pearln cautions measures statistical associathat “correlation Atria1 fibrillation cannot tion, not causation.“) be correlated with either right or left atria1 thrombosis in nonrheumatic heart disease.
Rhythm
by Quinidine
If the loss of coordinated atria1 contractility due to fibrillation does indeed give rise to more frequent clotting, then atria1 clots should be more frequent in patients with fibrillation, and fibrillation should be correspondingly more frequent than normal rhythm in patients with atria1 of the left atrium at necropsy clots. Examination reveals a correlation of these conditions only in rheumatic heart disease, for which the statistical correlation is highly significant (Tables I and II) .I*,13 This correlation is corroborated by observations at cardiotomy. In nonrheumatic heart disease, there is no such correlation (Tables III and IV).‘~ Garvin,i5 for example, found no such correlation in 374 persons dying from coronary arterial disease. Regardless of rhythm, few left atria1 thrombi are found in purely arteriosclerotic heart disease (Table v),i4-i6 and the chance of emboli arising from them seems slight; moreover, emboli occur as frequently in normal rhythm as in atria1 fibrillation. Many systemic arterial emboli attributed to arteriosclerotic heart disease are really due to unrecognized rheumatic heart as necropsy reveals. Soderstromn disease, concluded from his studies (Tables VI and VII) that the chief determinants of thrombosis in the right atrium are underlying wall damage and congestive failure, and that fibrillation is important only insofar as it contributes to congestive failure. He suggested that since right atria1 infarction is frequent in patients with right atria1 thrombosis and congestive failure, the infarction rather than the failure may have been the important correlate with thrombosis. Mural thrombi in either ventricle cannot be correlated with atria1 fibrillation regardless of cause. They are uncommon in the right ventricle,i4fi6 and in the left ventricle their frequency of occurrence is correlated with the size 491
Editorial TABLE I
TABLE III
Frequency of Left Atria1 Mural Thrombi in Patients With Rheumatic Heart Disease and Atria1 Fibrillation and Those With Normal Rhythm (Necropsy)*
Frequency of Left Atria1 Thrombi in Patients With Acute or Healed Myocardial Infarction and Atria1 Fibrillation or Normal Rhythm
Rhythm
Normal Atria1 fibrillation Total
Patients (No.)
Number With Left Atria1 Thrombi
Percentage
150
17
11t
170 320
76 93
44t 29
Rhythm
Atria1 fibrillation Normal Rhythm
27 300
* From compiled data by Soderstrom12 and Graham, et a1.13 t Highly significant. P less than 0.001.
Number With Left Atria1 Thrombi
Patients (No.)
*Not significant. by Jordan.)14
-i
(Necropsy
Percentage
1
3.7*
13
4.3*
study
of 327 patients
TABLE II
TABLE IV
Frequency of Atria1 Fibrillation in Patients With Rheumatic Heart Disease and Left Atria1 Thrombi (Necropsy ) *
Frequency of Atria1 Fibrillation in Patients With Acute or Healed Myocardial Infarction and Left Atria1 Thrombi or Without Left Atria1 Thrombi”
Left Atria1 Thrombi
Patients (No.) I
Thrombi Thrombi * From et a1.13
present absent
93 227
/ Number With Atria1 Fibrillation
1
I
, I
,
Percentage
76 94
8lt 41t
compiled data of Soderstrom12 and Graham t Highly significant. P less than 0.001.
Left Atria1 Thrombi
1
Patients (No.)
Number With Atrial Fibrillation
Per ._ cent: vze
Present Absent * Not significant.
is ascribed to the stasis of blood in the ineffectively contracting diseased atrium, and quinidine therapy was advocated in the belief that restoration of normal rhythm would restore atria1 contraction enough to overcome The occasional occurrence of embolism stasis. following restoration of normal rhythm by quinidine seemed to confirm this opinion, though it presented the added danger that thrombi formed in the period of stasis might then be expelled. It gradually became the consensus that this danger was less than the danger from repeated thromboembolism in established atria1 fibrillation.5-s Atria1 fibrillation in mitral stenosis is an index of atria1 stasis, as illustrated by angiocardiographic timing of opacification in the left atrium,18 with an increase from a normal time of 5 seconds to a period of 9.4 seconds in mitral stenosis with normal rhythm, and 11.9 seconds Cliniin mitral stenosis with atria1 fibrillation. cally, fibrillation is a hallmark of prolonged stasis following longstanding rheumatic heart fibrillation
of the underlying infarct and with congestive heart failure, regardless of the rhythm.14 If atria1 fibrillation is not an important factor in the formation of atria1 thrombi in arteriosclerotic heart disease, it cannot be an important factor in embolism arising from clots in the atria.” HEMODYNAMIC
CONSIDERATIONS
Clotting in a chamber of the heart, as in thrombosis elsewhere, can occur only when the three thrombotic factors are present in sufficient damage, coagulability of degree : endothelial Atria1 the blood and retardation of flow. thrombosis is not inevitable even in the most strongly conducive circumstances, in “pure” mitral stenosis which has progressed to atria1 fibrillation. There is no reason to believe this arrhythmia alone can cause endothelial damage When it is present or increased coagulability. in otherwise normal hearts, there is no mural thrombosis because there is no endothelial The thrombotic effect of atria1 damage.
THE AMERICANJOURNAL OF CARDIOLOGY
Editorial
493
TABLE v
TABLE
Frequency of Left Atria1 Thrombi in Patients With Coronary Artery Disease With or Without Myocardial Infarction and With or Without Hypertension
Frequency rheumatic
Number Patients
Author
(No.1
TyrrzLi
300 327 374 1001
B.ZXl’~ Jordan’4 Garvinl” TOtal
Left Sided
L~f~~~~a, Thrombi
17 14 21 52
139 108 141 388
I
Number Left Ventricular Thrombi Associated
Left Atria1 Thrombi Only
14 8 8 30
3 6 13 22
I
WI
of Atria1 Fibrillation in Patients With NonHeart Disease With and Without Right Atria1 Thrombi (Soderstrom)‘z
Right Atria1 Thrombi Present Absent Total
I-
(No.)
Number With Atria1 Fibrillation
Percentage
115 413 528
53 164 217
46* 40* 41
Patients
* Not significant.
(Data
from compiled
TABLE
necropsy
series)
VI
Frequency of Right Atria1 Thrombi in Patients With Nonrheumatic Heart Disease and Atria1 Fibrillation or Normal Rhythm
Rhythm
Patients (No.)
Atria1 fibrillation Normal rhythm Total Necropsy study * Not significant.
of
Number With Right Atria1 Thrombi
Percentage
217
53
24*
311 528
62 115
20* 22
528
patients
by
Soderstrom.‘*
The patients are older and the endodisease. thelium has been subjected to the damaging All three thrombotic effect of prolonged stasis. Atria1 factors simultaneously are maximal. fibrillation, therefore, frequently coincides with the left atria1 thrombosis but does not primarily The two conditions apparently result cause it. from coincident causes. In arteriosclerotic heart disease atria1 fibrillation alone does not give rise to sufficient stasis for mural clotting in the atria unless congestive failure is also present. Even then, with both atria fibrillating, thrombosis characteristically occurs only in the right atrium which is the site of endothelial damage. Rheumatic heart disease is the only disease in which atria1 fibrillation can be correlated with a greater frequency of cardiac mural thrombi, and the left atrium is the only chamber in which clots are more frequent in fibrillation. What effect has restoration of normal rhythm Hechtig meason effective atria1 contraction? APRIL
1962
ured left heart pressure by catheterization in patients with mitral stenosis and atria1 fibrillation; he calculated by the laws of fluid dynamics that restoration of atria1 contraction could not appreciably augment atrioventricular flow. The left atrium observed at cardiotomy for mitral stenosis has no discernible effective contraction regardless of rhythm, nor has there been any report of significant contraction on fortuitous restoration of normal rhythm during this operation. Postoperative roentgen studies disclose no significant reduction in size of the left atrium except that due to removal of the auricle.20 Studies by Rowe and his co-workers,21 and Selzerz2 indicate that after restoration of normal rhythm even though the ventricular rate remains the same, the flow per minute increases. This increase is generally ascribed to greater atria1 contraction, but it can better be ascribed to the related improvement in left ventricular contractility with a longer effective diastolic filling time. In rheumatic mitral stenosis which has progressed to atria1 fibrillation, the average volume of the left atrium is estimated as 230 cc. (normal, 50 cc.).23 If this volume is not significantly reduced after commissurotomy, the improvement in atrioventricular flow per second can only reduce a residual volume slightly which may be more than four times normal. Therefore, localized left atria1 stasis remains a significant thrombotic factor, as shown by the continued occurrence of systemic arterial embolism after commissurotomy.24 If opening of the narrow fixed mitral valve fails to relieve atria1 stasis sufficiently to prevent thrombosis, it is difficult to believe restoration of faint contraction to At the dilated atrium can be of greater value. present, such improvement is an assumption that cannot be accepted without proof.
Editorial CESSATION OF EMBOLIW FOLLOWING RESTORATION OF NORMAL RHYTHM If quinidine conversion of atria1 fibrillation does not reduce atria1 stasis, what accounts for that cessation of clinically recognized embolism which is attributed to restoration of normal rhythm? The explanation lies in the natural history of thromboembolism, which in the case of mitral stenosis is fairly well documented. In one group of 47 patients with systemic arterial embolism due to mitral stenosi~,~r 12 died from the first cfinically recognized embolus. Of the 35 who survived the first episode, only 16 had a second recognized embolus, which in 8 cases did not occur until a year or more after the first. In another group,25 the first clinically recognized systemic arterial embolism was fatal in 18 of 75 cases, but only 28 of the surviving 57 had another recognized embolus. Although there was no prophylactic antithrombotic drug treatment in either of these series, more than half the patients who survived a recognized embolism clid not have another. Even in patients with rapidly recurring embolism, a cessation of six munths or more may not be significant, 26 for the clinical recognition of an embolism depends largely on the point of impact. Towbin”? has shown that small cerebral emboli from left ventricular thrombi may be frequent but unrecognized in patients with old myocardial infarction. MacFarlanez8 has reported one case in which repeated embolism (six episodes in two months) required repeated embolectomy, and in which embolism ceased without treatment. Before any prophylactic therapy can be judged effective, it must be observed as long and as widely as the natural course of the disease deFurthermore, as Mainlandzg emphamands. sizes, follow-up observations must be made at regular intervals from the start of therapy in treated patients and controls. By these criteria, a period of six months without recurrence, even after repeated embolism, is probably not In arteriosclerotic heart disease significant. the formation of left ventricular thrombi has not been statistically associated with atria1 fibrillation; accordingly, cessation of systemic arterial emboli following conversion cannot be demonIf a significant period strated as significant. without embolism does occur after conversion, it is probably due to relief of congestive failure, which has been correlated with ventricular thrombosis. Pulmonary embolism from the right atrium is likewise associated with conges-
tive failure but not with atria1 fibrillation; furthermore, it must not be overlooked that the pulmonary emboli may have been derived from peripheral venous thrombi and not from the right atrium. With these qualifications, the evidence for cessation of embolism through restoration of normal rhythm is not convincing. DISCUSSION The efficacy of any antithrombotic measure must at present be judged against that of anticoagulant drugs, whose value has been established by long and broad experience. Since embolism may occur at any time following an episode, the prophylactic effect must be both prompt and sustained. Antithrombotic drugs in proper combination give an immediate effect which continues as long as such therapy Most clinicians agree that this continues. method, unless seriously contraindicated, is the prime measure to be used after a single embolism, though they differ on the length of time it shouid be continued. In rheumatic heart disease with mitral stenosis, some would continue indefinitely, but others would reevaluate the need after six weeks.30 As long as this therapy is continued, there is no need to convert atria1 fibrillation as a measure to inhibit further embolism.“’ Collective data on survivors of the first systemic arterial embolism in rheumatic heart disease indicate that the average interval between embolic episodes was seven months before treatment and seven years during treatment3’ By comparison, conversion of atria1 fibrillation in rheumatic heart disease is neither as reliable nor as effective. Conversion can be obtained in, at most, 80 per cent of cases, and only after one to several days; maintenance of normal rhythm is difficult and unpredictable. The prophylactic value of conversion is often obscured by the fact that most investigators favor a course of antithrombotic drug therapy for ten to fourteen days before conversion. Freedom from embolism, therefore, can better be credited to the antithrombotic drug therapy, as Freeman and Wexler3’ observe. Even if antithrombotic drugs are discontinued after six weeks, and normal rhythm has been restored, continued freedom from embolism can still be ascribed as logically to the natural course of the disease as to maintenance of normal rhythm. In arteriosclerotic heart disease embolism is characteristically in the right atrium and left ventricle, and the correlation is with endoTHE
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Editorial The cardial damage and congestive failure. only thrombotic effect of atria1 fibrillation is Occasionally to increase congestive failure. conversion of atria1 fibrillation may be desirable to help relieve congestive failure, and decrease Since antithrombotic the thrombotic tendency. drugs are usually given for such embolism, the beneficial effect of returning normal rhythm is probably negligible. In either condition, the danger is that concern with conversion of atria1 fibrillation may detract attention from reliable and effective antithrombotic drug therapy. ACKNOWLEDGMENT The author wishes to express his appreciation to Sol Bernstein, M.D., Oscar Magidson, M.D., F.R.CP. and John M. Weiner, PH.D. for their assistance in the preparation of this paper. JOHN MARTIN
ASKEY, M.D.
Department of Medicine University of Southern California School of Medicine Los Angeles, California REFERENCES 1. WRIGHT, I. S. and FOLEY, W. T. Use of anticoagulants in treatment of heart disease. Am. J. Med., 3: 718, 1947. 2. LEWIS, T. The value of quinidine in cases of auricular fibrillation. Am. J. M. SC., 163: 781, 1922. 3. KOHN, C. N. and LEVINE, S. A. An evaluation of the use of quinidine sulphate in persistant auricular fibrillation. Ann. Znt. Med., 8: 923, 1935. 4. BECKWITH, J. R., IBARRA, J. A. and WOOD, J. E. The problem of established atria1 fibrillation. Am. J. M. SC., 231 : 519, 1956. 5. FLEISCHMANN,C. A. The use of quinidine in auricular fibrillation. Am. J. M. SC., 225: 617, 1953. The management of chronic 6. GOLDMAN, M. J. Indication for and methods of atria1 fibrillation. conversion to sinus rhythm. Progr. Cardiov. Dir., 2: 465, 1960. 7. MCMILLAN, R. L. and WELFARE, C. R. Chronic auricular fibrillation. J.A.M.A., 135: 1132, 1947. Quinidine in the treatment of 8. SOKOLOW, M. benign auricular fibrillation with repeated emboli. Am. Heart J., 18: 494, 1939. 9. YOUNT, E. H., ROSENBLUM,M. and MCMILLAN, R. L. Use of quinidine in the treatment of Arch. Znt. Med., 89 : chronic auricular fibrillation. 63, 1952. 10. Recommendations of National Research Council J.A.M.A., 124: 239, restricting use of quinidine. 1944. 11. PEARL, R. Introduction to Medical Biometry and Statistics, p. 435, 3rd ed. Philadelphia, 1940. W. B. Saunders.
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12. SODERSTROM,N. Myocardial infarction and mural thrombosis in the atria of the heart. Acta. med. scandinau. supp. 132: 217, 1948. 13. GRAHAM, G. K., TAYLOR, J. A., ELLIS, L. B., GREENBERG, D. J. and ROBBINS,S. L. Studies in mitral stenosis; correlations of post-mortem findings with clinical course of disease in 101 cases. Arch. Znt. Med., 88: 532, 1951. 14. JORDAN, R. A., MILLER, R. D., EDWARDS, J. E. and PARKER, R. L. Intracardiac mural thrombosis, thromboembolism in acute and healed myocardial infarction. Circulation, 6 : 1, 1952. 15. GARVIN, C. F. Mural thrombi in the heart. Am. Heart J., 21: 713, 1941. 16. BEAN, W. B. Infarction of the heart. III. Clinical course and morphological findings. Ann. Znt. Med., 12: 71, 1938. 17. BEER, D. T. and GHITMAN, B. Embolization from the atria in arteriosclerotic heart disease. J.A.M.A., 177: 287, 1961. 18. ZINSSER, H. F., JR. and JOHNSON,J. The use of angiocardiography in the selection of patients for mitral valvular surgery. Ann. Znt. Med., 39: 1200, 1353. 19. HECIXT, H. The hemodynamic consequences of atria1 fibrillation. Mod. Conqbts Cardiouas. Dir., 25 : 351, 1956. 20. GARY, J. E. Late follow-up of radiologic changes after mitral valvuloplasty. iVew England J. Med., 254: 831, 1956. 21. ROWE, J. C., BLAND, E. F., SPRAGUE, H. B. and WHITE, P. D. The course of mitral stenosis without surgery: ten and twenty year perspectives. Ann. Znt. Med., 52: 741, 1960. 22. SELZER, A. Effect of atria1 fibrillation upon the cirAm. culation in patients with mitral stenosis. Heart J., 59: 518, 1960. 23. ARVIDSSON,H. Angiocardiographic observations in mitral disease. Acta Radial. supp. 158, Stockholm, 1958. 24. KELLOGG, F., CHI KONG Lm and FISHMAN, W. Systemic and pulmonary emboli before and after mitral commissurotomy. Circulation, 24: 263,1961_ 25. OLESEN, K. H. Mitral Stenosis, p. 143. Copenhagen, 1955. Ejnar Munksgaards Forlag. 26. DALEY, R., MATTINGLY, T. W., HOLT, C. L., BLAND, E. F. and WHITE, P. D. Systemic arterial embolism in rheumatic heart disease. Am. Heart J., 42: 566, 1951. 27. TOWBIN, A. Recurrent cerebral embolism. Arch. Neural. & Psychiat., 73: 173, 1955. 28. MACFARLANE, J. A. Multiple emboli treated surgically. Brit. Med. J., 1 : 971, 1940. 29. MAINLAND, D. Notes on the planning and evaluation of research, with examples from cardioPart III. Am. Heart J., vascular investigation. 55: 838, 1958. 30. CARTER, S. A., MCDEVITT, E., GATJE, B. W. and WRIGHT, I. S. Analysis of factors affecting the recurrence of thromboembolism off and on anticoagulant therapy. Am. J. Med., 25: 43, 1958. 31. ASKEY, J. M. Systemic Arterial Embolism, p. 102. Grune and Stratton. New York, 1957. 32. FREEMAN,I. and WEXLER, J. Quinidine in chronic atria1 fibrillation. Am. J. M. SC., 239: 181, 1960.