ATRIAL fibrillation is one of the most common cardiac arrhythmias and has

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1 Distinct Increase in Hematocrit Associated with Paroxysm of Atrial Fibrillation Shigeru OKUNO, MD*, Terunao ASHIDA, MD, Aya EBIHARA, MD, Takao SUGIYAMA, MD, and Jun FUJII, MD SUMMARY In a previous study we found that hemoconcentration, which was identified by an increase in hematocrit, occured during a paroxysm of atrial fibrillation. In the present study we investigated the changes in hematocrit from sinus rhythm to paroxysm in 10 patients who had multiple paroxysms of atrial fibrillation in order to assess the ranges of the changes in hematocrit among the paroxysms. In these patients hematocrit was measured simultaneously with electrocardiographic recording during 3 or more paroxysms and sinus rhythm just before each paroxysm. The changes in hematocrit varied among the paroxysms. The maximum increase in hematocrit in each patient ranged from 3.5 to 8.0 points with an average of 5.1 points. Such a distinct increase in hematocrit which abruptly develops with a paroxysm of atrial fibrillation may be a potential risk for thrombus formation. (Jpn Heart J 2000; 41: ) Key words: Atrial natriuretic peptide, Hematocrit, Hemoconcentration, Stroke, Thromboembolism ATRIAL fibrillation is one of the most common cardiac arrhythmias and has drawn increasing attention as a risk factor for stroke. 1,2) Paroxysmal atrial fibrillation is also considered to be a stroke risk factor similar to chronic atrial fibrillation. 3,4) Another aspect of this arrhythmia is characterized by accompanying body fluid changes. Polyuria has been observed during a paroxysm of this arrhythmia since the first description of Wood. 5) Polyuria results in hemoconcentration, which is identified by an increase in hematocrit. Imataka, et al. 6) of our institute confirmed that hematocrit levels were higher during a paroxysm than during the corresponding sinus rhythm in almost all patients with an average increase of 2.0 points. Hematocrit was also increased by about 2 points with transition to chronic atrial fibrillation from sinus rhythm and it remained high at least throughout the first 4 years. 7,8) From the Institute for Adult Diseases Asahi Life Foundation, Tokyo, Japan. *Visiting Scientist from the Second Department of Internal Medicine, Gunma University. Present address: Second Department of Internal Medicine, Gunma University, Maebashi, Japan. Address for correspondence: Jun Fujii, MD, the Institute for Adult Diseases Asahi Life Foundation, , Nishi-Shinjuku, Shinjuku-ku, Tokyo , Japan. Received for publication April 12, Revised and accepted June 9,

2 618 OKUNO, ET AL Jpn Heart J September 2000 As described in our previous study 6) the changes in hematocrit associated with paroxysm of atrial fibrillation varied among patients. There were patients who showed marked increases in hematocrit which were over 5 points. It is probable but has not been confirmed that the changes in hematocrit vary among paroxysms in an individual patient. In this study we investigated the changes in hematocrit from sinus rhythm to paroxysm in patients who had multiple paroxysms of atrial fibrillation in order to assess the ranges of the changes in hematocrit and the maximum changes in hematocrit in individual patients. SUBJECTS AND METHODS Since our previous study 6) demonstrated that hemoconcentration occurred during a paroxysm of atrial fibrillation, we have measured blood hematocrit simultaneously with electrocardiographic recording as much as possible in patients who had paroxysms of atrial fibrillation. Before hematocrit measurement all patients were informed that hemoconcentration could occur during their paroxysms and they expressed their consent about the hematocrit measurement. By the end of 1998 we had collected 10 patients including one patient with paroxysmal atrial flutter (7 males and 3 females) in whom blood hematocrit was measured simultaneously with electrocardiographic recording during 3 or more paroxysms and during sinus rhythm just before each paroxysm. The average age at their first paroxysm was 65.9 years and underlying diseases were hypertension in 5, diabetes mellitus on diet treatment in 2, and lone atrial fibrillation in 3 patients. All of the patients had normal or slightly dilated left atria and left ventricles with normal or near normal ejection fractions which were estimated with conventional echocardiographic measurements. Echocardiograms were recorded at sinus rhythm in 9 patients and at atrial fibrillation in one patient (No. 8). Patients who took diuretics and those who were in the acute stage of myocardial infarction or stroke were not included. One patient (No. 6) suffered from reversible left side hemiparesis probably caused by cardiogenic embolism after the close of this study. The paroxysms returned to sinus rhythm spontaneously or with antiarrhythmic agents that included quinidine, disopyramide and pilsicainide. Differences in hematocrit and heart rate between paroxysm and sinus rhythm just before each paroxysm were calculated and averaged. The maximum and minimum differences in hematocrit were identified in each patient and were also averaged in all patients. Data are expressed as the

3 Vol 41 No 5 HEMATOCRIT INCREASE WITH ATRIAL FIBRILLATION 619 Figure. Time course of hematocrit changes in a 58 year old patient with four paroxysms of atrial fibrillation. mean ± standard deviation and the statistical significance was analysed by the t-test. RESULTS The Figure illustrates a time course of changes in hematocrit in a 58 year old male patient in whom blood hematocrit was measured simultaneously with electrocardiographic recording during 4 paroxysms of atrial fibrillation in the period from August, 1997 to December, He noticed a sudden onset of palpitations which was followed by polyuria at the beginning of his paroxysms. As shown in the Figure the hematocrit levels were higher at a paroxysm than at the a preceding sinus rhythm in all 4 paroxysms. However, the increases in hematocrit from a preceding sinus rhythm to a paroxysm varied among the 4 paroxysms. The maximum increase was 8.0 and the minimum was 5.1 points. The Table shows the maximum and minimum increases in hematocrit and the corresponding increases in heart rate. Left atrial dimension and ejection fraction values are presented in the Table. The maximum increases in hematocrit ranged from 3.5 to 8.0 points with an average of 5.05 points, and they were over 7 points in 3 of 10 patients. The average increase in hematocrit was 2.93 points for all paroxysms in 10 patients. The average increase in heart rate corresponding to the maximum

4 620 OKUNO, ET AL Jpn Heart J September 2000 Table. Maximum and Minimum Increases in Hematocrit (Hct) and Corresponding Increases in Heart Rate (HR) Associated with Paroxysms of Atrial Fibrillation. Patient, age, and gender LAD (mm) EF (%) Maximum increase in Hct (Increase in HR) Minimum increase in Hct (Increase in HR) Mean increase in Hct (Number of Paroxysms) 1 ( ) 53y M 2 ( ) 74y M 3 ( ) 57y M 4 ( ) 72y M* 5 ( ) 63y M 6 ( ) 65y M 7 ( ) 58y M 8 ( ) 56y F 9 ( ) 82y F 10 ( ) 79y F Mean 65.9y # ± # ± (51) 5.1 (31) 3.5 (67) 7.4 (21) 7.6 (20) 3.7 (17) 8.0 (50) 3.6 (36) 3.7 (21) 4.0 (24) 5.05 ± 1.87 (33.8 ± 16.9) -0.4 (5) -2.9 (5) -0.6 (-4) 3.2 (38) 0.2 (27) 2.2 (10) 5.1 (43) -0.1 (60) 0.0 (28) 1.4 (11) 0.81 ± 2.25 (22.3 ± 20.3) 1.45 ( 6 ) 2.84 ( 9 ) 1.93 ( 3 ) 5.08 ( 4 ) 2.55 ( 4 ) 3.13 ( 3 ) 6.28 ( 4 ) 2.23 ( 3 ) 1.48 ( 5 ) 2.34 ( 5 ) 2.93 ± 1.56 (4.6 ± 1.8) (Values are expressed as means ± SD) LAD = left atrial dimension; EF = ejection fraction; * = atrial flutter; # = values measured at atrial fibrillation. increases in hematocrit was greater than that corresponding to the minimum increase in hematocrit, but the difference was statistically not significant (p > 0.05). DISCUSSION In the present study we investigated the changes in hematocrit from sinus rhythm to atrial fibrillation in 10 patients who had multiple paroxysms of atrial fibrillation. The changes in hematocrit varied among paroxysms and the maximum increases in hematocrit in individual patients were an average of 5.05 points. The increase in hematocrit associated with a paroxysm of atrial fibrillation was initially considered as a result of polyuria which was occasionally observed during the paroxysm. 6) The polyuria is believed to be induced by atrial natriuretic peptide (ANP), because plasma ANP levels were reported to be elevated during paroxysms of atrial fibrillation. 9,10) However, polyuria is not always observed during the paroxysms. Earlier studies reported that clinically detectable polyuria was observed only in 20 to 50% of patients with paroxysmal atrial fibrillation. 5,11) In a previous study 6) we reported there were no patients who complained of recognizable polyuria, although they showed a significant increase in hematocrit during the paroxysm. Another possibility is that the increase in hematocrit is induced by a fluid shift from the intravascular to extravascular space, because ANP has been reported to promote vascu-

5 Vol 41 No 5 HEMATOCRIT INCREASE WITH ATRIAL FIBRILLATION 621 lar permeation which results in the fluid shift. 12,13) We did not measure plasma ANP levels in this series of patients. However, we could assume that ANP release during paroxysm of atrial fibrillation remained intact in these patients who had normal or slightly dilated atria with almost normal left ventricular ejection, although plasma ANP levels were reported to be reduced in patients who had atrial fibrillation of long duration associated with congestive heart failure. 14) The present study showed that the changes in hematocrit from sinus rhythm to atrial fibrillation were variable among paroxysms in patients who had multiple paroxysms. The variation may be attributable to differences in the duration of paroxysm and the amounts of ANP released during the paroxysms. In addition, the timing of the hematocrit measurements may be one of the determinants for the hematocrit levels. It is not conceivable that the hematocrit level remains unchanged throughout the paroxysm, although the time course of hematocrit level during the paroxysm has not been studied. In the present study we did not record the intervals between the start of paroxysm and the hematocrit measurements. An increase of 5 points in hematocrit induces a hemoconcentration which corresponds to about a 10% increase in plasma concentration of macromolecular substances including hemostatic factors. The hemoconcentration develops probably within hours after the onset of a paroxysm. Such an abrupt development of distinct hemoconcentration may promote intracardiac thrombus formation, because regional blood stasis has been observed in the left atrial appendage during atrial fibrillation 15) and the activation of platelets and coagulation were reported to occur in a time dependent manner after the start of atrial fibrillation. 16) REFERENCES 1. Kuramoto K, Matsushita S, Yamanouchi H. Atrial fibrillation as a cause of myocardial and cerebral infarctions. Jpn Circ J 1984; 48: Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: The Framingham Study. Stroke 1991; 22: Aboaf AP, Wolf PS. Paroxysmal atrial fibrillation. A common but neglected entity. Arch Intern Med 1996; 156: Hart RG, Pearce LA, Rothbart RM, McAnulty JH, Asinger RW, Halperin JL. Stroke with intermittent atrial fibrillation: Incidence and predictors during aspirin therapy. J Am Coll Cardiol 2000; 35: Wood P. Polyuria in paroxysmal tachycardia and paroxysmal atrial flutter and fibrillation. Br Heart J 1963; 25: Imataka K, Nakaoka H, Kitahara Y, Fujii J, Ishibashi M, Yamaji T. Blood hematocrit changes during paroxysmal atrial fibrillation. Am J Cardiol 1987; 59:

6 622 OKUNO, ET AL Jpn Heart J September Yamada H, Sugiyama T, Ashida T, Fujii J. Sustained hemoconcentration in patients with chronic atrial fibrillation, a potential risk for stroke and thromboembolitic complications. A retrospective study. Jpn Heart J 1998; 39: Irita A, Serita T, Ueyama C, et al. Effects of atrial fibrillation on stroke risk factors. 10-year longitudinal observations before and after development of atrial fibrillation. Jpn Circ J 1999; 63(Suppl 1): 239(Abstr). 9. Schiffrin EL, Gutkowska J, Kuchel O, Cantin M, Genest J. Plasma concentration of atrial natriuretic factor in a patient with paroxysmal atrial tachycardia. N Engl J Med 1985; 312: Yamaji T, Ishibashi M, Nakaoka H, Imataka K, Amano A, Fujii J. Possible role for atrial natriuretic peptide in polyuria associated with paroxysmal atrial arrhythmias. Lancet 1985; 1: Luria MH. Selected clinical features of paroxysmal tachycardia. A prospective study in 120 patients. Br Heart J 1971; 33: Williamson JR, Holmberg SW, Chang K, Marvel J, Sutera SP, Needleman P. Mechanisms underlying atriopeptin-induced increases in hematocrit and vascular permeation in rats. Circ Res 1989; 64: Flückiger JP, Waeber B, Matsueda G, Delaloye B, Nussberger J, Brunner HR. Effect of atriopeptin III on hematocrit and volemia of nephrectomized rats. Am J Physiol 1986; 251: H Van Den Berg MP, Crijns HJGM, Van Veldhuisen DJ, Van Gelder IC, De Kam PJ, Lie KI: Atrial natriuretic peptide in patients with heart failure and chronic atrial fibrillation: Role of duration of atrial fibrillation. Am Heart J 1998; 135: Shively BK, Gelgand EA, Crawford MH. Regional left atrial stasis during atrial fibrillation and flutter: Determinants and relation to stroke. J Am Coll Cardiol 1996; 27: Sohara H, Amitani S, Kurose M, Miyahara K. Atrial fibrillation activates platelets and coagulation in a timedependent manner: A study in patients with paroxysmal atrial fibrillation. J Am Coll Cardiol 1997; 29: