Atrial Ejection Force in Systemic Autoimmune Diseases

Transcription

1 Noninvasive and Diagnostic Cardiology Cardiology 1999;92: Received: May 15, 1999 Accepted after revision: October 11, 1999 Atrial Ejection Force in Systemic Autoimmune Diseases Roland Jahns a Johji Naito b Hans-Peter Tony a Gerhard Inselmann a a Department of Internal Medicine, Medizinische Poliklinik, University of Würzburg, Germany; b Osaka National Hospital, Osaka, Japan Key Words Systemic autoimmune disease W Systemic lupus erythematosus W Rheumatoid arthritis W Atrial ejection force W Cardiac diastolic filling abnormalities Abstract Systemic autoimmune disorders may affect several organs, including the heart. We analyzed two-dimensional and pulsed Doppler echocardiograms of patients (n = 37) with systemic lupus erythematosus (SLE, n = 24) or rheumatoid arthritis (RA, n = 13) to determine whether atrial ejection force (AEF) could represent a suitable parameter for detecting left ventricular filling abnormalities in SLE and RA. In both patient subgroups, AEF was significantly higher than in healthy controls (n = 40) matched for gender and age (14.0 B 5.4 vs B 3.5 kdyn, p! 0.01). Because conventional echocardiographic parameters of left ventricular function failed to detect such a difference, AEF might serve as an additional sensitive parameter for detecting left ventricular diastolic filling abnormalities early in the course of a systemic autoimmune disease. Copyright 2000 S. Karger AG, Basel Introduction In a large number of patients suffering from connective tissue disorders or rheumatoid arthritis (RA) the inflammatory process and/or antibody- and complement-mediated immune reactions may also affect the heart. In patients with systemic lupus erythematosus (SLE), several clinical and autopsy studies revealed a high incidence of cardiovascular manifestations involving the peri-, myo-, and endocardium, the coronary arteries, and, most notably, the cardiac valves [1 4]. The prevalence of valvular lesions was strongly associated with the presence of anticardiolipin antibodies, suggesting a causal link between high levels of such antibodies and cardiac damage [3, 4]. However, more recently a latent impairment in left ventricular function has been described in patients suffering from early-stage connective tissue disorders without any obvious signs of cardiac disease and independent of the actual anticardiolipin antibody levels [5 7]. Thus, it has been suggested that cardiovascular mortality in systemic autoimmune disease might more often be related to congestive heart failure secondary to (chronic) autoimmuneinduced myocardial damage than to valvular heart disease, coronary artery disease, or hypertension [8, 9]. In a majority of the patients, left ventricular diastolic filling abnormalities have been found to precede the impairment in left ventricular systolic function [3, 5 7]. Hence, precise determination of cardiac diastolic function (or dysfunction, respectively) should allow for early detection ABC Fax karger@karger.ch S. Karger AG, Basel /99/ $17.50/0 Accessible online at: Dr. Gerhard Inselmann Medizinische Poliklinik der Universität Würzburg Klinikstrasse 6 8 D Würzburg (Germany) Tel , Fax

2 Table 1. Clinical characteristics and conventional two-dimensional and Doppler echocardiographic parameters of patients and corresponding healthy controls Parameters SLE subgroup patients (n = 24) controls (n = 25) RA subgroup patients (n = 13) controls (n = 15) Clinical parameters Gender, female/male 17/7 18/7 12/1 14/1 Age, years 40B13 40B15 62B11 62B10 Heart rate, b.p.m. 69B8 69B8 71B8 70B9 Two-dimensional echocardiography Ao, mm 29B4 28B4 29B4 30B3 LA, mm 30B5 30B5 31B5 33B4 IVSth, mm 10B1 10B1 10B1 10B1 PWth, mm 9B1 9B1 10B1 10B1 LVDd, mm 49B4 49B3 49B2 48B3 LVDs, mm 33B3 33B2 32B2 32B3 FS, % 34B3 33B2 34B2 33B2 MOA, mm 2 5.2B B B B0.7 Pulsed Doppler echocardiography E, cm Ws 1 73B13 73B12 68B16 62B13 A, cm Ws 1 69B12 64B11 77B14 70B10 E/A, ratio 1.08B B B B0.23 DT, m 143B15 149B18 151B17 141B21 IVRT, ms 63B5 63B4 64B6 65B3 All values are given as means B SD. No significant differences were found for any of the parameters analyzed. Ao = Aorta; LA = left atrium; IVSth = interventricular septum (wall thickness); PWth = posterior wall (thickness); LVDd/s = left ventricular diameter at end diastole/systole; FS = fractional shortening; MAO = mitral orifice area; E = peak early diastolic left ventricular inflow velocity; A = peak left ventricular inflow velocity at atrial contraction; E/A = ratio of (left ventricular) peak early diastolic inflow velocity to peak inflow velocity at atrial contraction. of myocardial alteration in systemic autoimmune diseases, and thus be helpful in the well-timed treatment and prevention of congestive heart failure in a large number of patients. A recent echocardiographic study on 29 patients who successfully underwent cardioversion from atrial fibrillation has provided evidence that the determination of left atrial systolic function by measuring atrial ejection force (AEF) at left ventricular relaxation enables to assess atrial contribution to the filling of the left ventricle [10]. Thus, AEF serves equally as an indirect parameter of left ventricular diastolic function (i.e. to assess left ventricular relaxation). The purpose of our study was to analyze whether AEF represents a sensitive and reliable parameter for the detection of cardiac alteration particularly in patients with SLE or RA. Patients and Methods Patients and Healthy Control Groups The study population consisted of 37 patients with systemic autoimmune disorders (29 females and 8 males, mean age 48 B 16 years) and 40 healthy control subjects matched for gender and age (32 females and 8 males, mean age 48 B 18 years). After informed consent was obtained, the patients were divided into two subgroups according to the type of the underlying autoimmune disease (table 1). (i) Twenty-four patients had SLE (17 females and 7 males, mean age 40 B 13 years) with disease duration ranging from 10 months to 26 years (mean 7.2 B 6.6 years). Six patients (25%, 4 females and 2 males) had detectable anticardiolipin antibodies with low-to-moderate IgG levels (from 20 up to 80 ELISA units, mean value 49 B 29). However, none of them had a clinically proven antiphospholipid syndrome, which is characterized by an elevated level of anticardiolipin antibodies associated with recurrent venous and/or arterial thromboses, thrombocytopenia, and cutaneous vascular abnormalities. Moreover, none of these patients had evidence of concomitant valvular lesions, which might generally serve as one of the most obvious 270 Cardiology 1999;92: Jahns/Naito/Tony/Inselmann

3 clinical features of cardiac damage associated with high anticardiolipin IgG levels [3, 4]. Because of their restricted number and their relatively low anticardiolipin levels, in the frame of the present study these 6 patients were assigned to the SLE group without further subgroup analysis. (ii) The other subgroup included 13 patients with RA (12 females and 1 male, mean age 62 B 11 years), and disease duration ranged from 6 months to 47 years (mean 6.5 B 12.7 years). Because of clear differences in the clinical baseline characteristics of our study population (mean age, gender, table 1) for each of the two patient subgroups a corresponding control collective was selected: 25 healthy subjects (18 females and 7 males, mean age 40 B 15 years) were compared with the SLE patients, and another 15 healthy individuals (14 females and 1 male, mean age 62 B 10 years) served as controls for the RA subgroup. All the SLE and RA patients were in clinical remission at the time of our study. None of the patients or control subjects had evidence of congenital heart disease, valvular heart disease, renal vascular disease, left ventricular hypertrophy (indicating concomitant hypertension), heart failure, or prior myocardial infarction in clinical history. All individuals included in our study had normal blood pressure, and none of them had a clinical history of hypertension and/or antihypertensive treatment. Moreover, no electrocardiographic abnormalities were found at rest or during exercise stress test in any of the subjects analyzed. Echocardiographic Examinations The study was performed utilizing a Hewlett-Packard Sonos 2500 with a 2.5-MHz transducer. Two-dimensional and pulsed Doppler echocardiograms were obtained at rest with the patient placed in the left lateral position. Left ventricular chamber size, wall thickness, and wall motion were measured by two-dimensional and M-mode echocardiography according to a standard procedure [11]. Pulsed Doppler (transmitral) left ventricular inflow velocities were obtained from an apical four-chamber view, placing the Doppler sample volume exactly between the tips of the mitral leaflets. In this position, peak left ventricular inflow velocities during early diastole and upon atrial contraction were measured and recorded at a paper speed of 100 mm Ws 1 for further analysis. Deceleration time (DT) was calculated by computer-aided regression analysis of the transmitral inflow velocities from peak velocity in early diastole [E, (m Ws 1 )] to the baseline (deceleration rate, fig. 1, time interval E-DT). Isovolumetric relaxation time (IVRT) was defined as the period between the closure of the aortic valve and the onset of transmitral inflow (fig. 1, time interval AVCA-IVRT). On the Doppler recordings, closure of the aortic valve is generally indicated by the typical (aortic) valve closure artifact (fig. 1) [12]. Atrial Ejection Force AEF was determined as previously described [10], using the equation AEF = 0.5! Ú! mitral orifice area! (peak A velocity) 2, with Ú corresponding to the density of blood (Ú = 1.06 WgWcm 3 ), and peak A velocity to the highest (in-)flow velocity recorded at atrial contraction (A, [m Ws 1 ]). Mitral annulus diameter (d) was obtained from an apical fourchamber view, and mitral orifice area was calculated as apple Wd 2 /4, assuming the shape of the annulus to be circular. The unit of the force is dynes (or g Wcm/s 2 ). Fig. 1. Transmitral left ventricular inflow velocity pattern obtained by pulsed Doppler echocardiography. Parameters derived are: E = Peak early diastolic left ventricular inflow velocity; A = left ventricular inflow velocity at atrial contraction; DT = deceleration (by extrapolation of E to the baseline); IVRT = isovolumetric relaxation time; AVCA = aortic valve closure artifact. Reproducibility of Measurements To estimate the accuracy of our measurements, the intra- and interobserver variability was calculated for all echocardiographic parameters obtained from 15 randomly selected patients and 15 healthy control subjects (two-dimensional as well as pulsed Doppler echocardiograms). In our study, intraobserver variability was less than 4.5%, and interobserver variability less than 7.5%. Biochemical Analysis Serum of the SLE patients was isolated from routinely obtained venous blood samples (within 24 h before/after the echocardiographic study). Titers of IgG and IgM anticardiolipin antibodies were measured by an enzyme-linked immunosorbent assay (ELISA) as described elsewhere [13], and are expressed in arbitrary ELISA units (normal mean values: 9 units for IgG, 8 units of IgM, normal range: mean B 2 SD; increased IgG antibody levels: mild: units, moderate: units, high: 1100 units). Tests for the lupus anticoagulant or false-positive VDRL reactions were not routinely performed. Statistical Analysis All data are presented as means B SD. Values for patients and controls were tested for significance by ANOVA, and for the subgroup analysis by Scheffé s F test [14]. Cardiac Alterations in Autoimmune Diseases Cardiology 1999;92:

4 trol groups (n = 25 or 15, respectively), a statistically significantly elevated AEF was obtained for these two types of systemic autoimmune disease (SLE subgroup: AEF = 13.3 B 4.2 vs B 4.0 kdyn, p! 0.05; RA subgroup: AEF = 15.2 B 7.0 vs B 2.1 kdyn, p! 0.05; fig. 2). Only a minor fraction (25%, n = 6; 4 females and 2 males) of SLE patients had detectable low-to-moderate levels of anticardiolipin IgG antibodies without clinical signs of an antiphospholipid syndrome (APS) or evidence for concomitant valvular lesions. Discussion Fig. 2. Mean values of echocardiographically determined AEF from patients with systemic autoimmune diseases (hatched columns) and the corresponding healthy controls, matched for gender and age (open columns). Error bars indicate the SD of the respective mean values. * p! 0.05; ** p! Results Clinical Characteristics and Conventional Parameters of Echocardiography No significant differences were obtained between healthy subjects and patients suffering from SLE or RA with respect to heart rate, echocardiographically determined cardiac diameters, and/or the structure and function of the cardiac valves. None of the patients or healthy controls presented left ventricular hypertrophy (suggesting concomitant hypertension), regional cardiac wall motion abnormalities or significant pericardial effusion. In addition, there were virtually no differences between patients and controls in the following (dynamic) echocardiographic parameters: fractional shortening, ratio of peak early diastolic filling velocity to peak filling velocity at atrial contraction (E/A ratio), DT and IVRT (table 1). Atrial Ejection Force Overall, AEF was significantly higher in the patients with systemic autoimmune disorders than in the healthy controls (AEF = 14.0 B 5.4 vs B 3.5 kdyn, p! 0.01; fig. 2). Even when comparing the SLE (n = 24) or RA subgroups (n = 13) separately with their corresponding con- Assessment of Cardiac Alteration in Systemic Autoimmune Disorders Several morphological and/or functional studies have demonstrated cardiac alterations in a substantial fraction of patients suffering from systemic autoimmune disorders [1 7]. From these studies it was concluded that abnormalities in the diastolic filling pattern of the left ventricle represent one of the earliest indicators of cardiac involvement in systemic autoimmune disease: in most of the patients analyzed, an alteration in left ventricular diastolic function was apparent before the onset of systolic dysfunction and/or the development of structural and morphological cardiac abnormalities [3, 5 7, 9]. Some earlier echocardiographic studies utilized the pulsed Doppler transmitral flow pattern to estimate the degree of left ventricular diastolic dysfunction in patients with systemic autoimmune disorders. Parameters determined in the frame of these studies included the peak left ventricular inflow velocity in early diastole (E-wave), the left ventricular inflow velocity at atrial contraction (A-wave), and/or IVRT [6, 7]. However, in our study, no significant differences could be detected between healthy subjects and patients suffering from SLE or RA by using these parameters. By contrast, AEF differed significantly between patients and healthy control subjects. Thus, our results confirm the usefulness of echocardiographic determination of left AEF to noninvasively assess atrial contribution to left ventricular diastolic performance, as recently proposed by Manning et al. [10]. In addition, our data demonstrate that AEF represents a highly sensitive and suitable marker for early detection of left ventricular diastolic filling abnormalities in patients with SLE or RA. It has been commonly considered that cardiac involvement may be clinically silent in a large number of patients suffering from systemic autoimmune disorders, which contrasts sharply to the high incidence of cardiac manifestations in 272 Cardiology 1999;92: Jahns/Naito/Tony/Inselmann

5 autopsy studies [2, 15, 16]. From our data it seems advisable to routinely determine AEF in addition to the other established echocardiographic parameters of left ventricular diastolic function in order to permit an earlier and more sensitive detection of cardiac abnormalities in the clinical course of patients suffering from SLE or RA. APS or amyloidosis sometimes complicates SLE or RA. These manifestations are frequently associated with cardiac abnormalities [3, 4, 17, 18]. However, in our study none of the patients suffered from amyloidosis, and although 25% of the patients (n = 6) from the SLE subgroup had detectable low-to-moderate anticardiolipin IgG levels, none of them had valvular lesions, pericardial effusion, or a clinically proven APS. Thus, we assume that the abnormal left ventricular diastolic filling pattern seen in our patients was neither related to amyloidosis nor to APS. Usefulness and Limitations of AEF as an Indirect Marker of Left Ventricular Diastolic Function Some previous reports indicated that AEF should allow for a correct assessment of atrial contractility, because the peak velocity of transmitral (in-)flow at atrial contraction has been shown to be virtually independent of left ventricular pre- and afterload [10, 19], whereas the loading conditions have a major impact on the early diastolic peak (in-)flow velocities at left ventricular relaxation [20 22]. The ventricular filling pattern at atrial contraction has now generally been accepted as a valid parameter to estimate left ventricular diastolic function [6, 7, 10, 12, 21]. Accordingly, in the present study we focussed on measuring AEF, a parameter that has recently been proposed as a physiological indicator of atrial systolic performance [10]. A separate analysis of either (i) peak inflow velocity at atrial contraction, or (ii) the calculated mitral orifice area revealed no significant differences between healthy individuals and patients with SLE or RA. Because AEF is solely influenced by these two parameters of the equation, we believe that the square of the peak inflow velocity at atrial contraction has produced a significant difference in AEF between the subgroups analyzed and thus, finally accounts for the high sensitivity of this marker for detecting left ventricular diastolic filling abnormalities in systemic autoimmune diseases. However, some limitations of this method have to be mentioned. First, mitral orifice is not a constant diameter during the cardiac cycle; moreover, in men the orifice is nearly elliptic, while it was considered to be circular for calculating the AEF according to Manning et al. [10]. On the other hand it has been reported that the mitral orifice area does not significantly change during atrial systole [23]. Since our measurements were obtained by the same method for all of the individuals analyzed, this limitation should not substantially affect our results. Second, when left ventricular hypertrophy is evident from two-dimensional echocardiography or expected from clinical history (suggesting coincidence of systemic autoimmune disease and hypertension, which was not the case in our study), left ventricular diastolic filling abnormalities should be considered as (typical) indicators of hypertensive heart disease rather than indicators of cardiac alteration in the course of a systemic autoimmune disease. However, the diagnosis of left ventricular hypertrophy does not exclude concomitant systemic autoimmune disorders. Finally, AEF cannot be correctly determined in patients with atrial arrhythmia, such as atrial fibrillation, and/or in patients with conduction disturbances at the sinuatrial or atrioventricular level [10], since the determination of AEF is based on the analysis of the peak left ventricular inflow velocity at regular (physiological) atrial contraction (A-wave). In such cases (arrhythmia, conduction disturbance) the loading conditions of the left ventricle may differ considerably, and the lack of a coordinated contraction of the left ventricle and atrium [regularly occurring after the early diastolic left ventricular filling period (E-wave)] leads to a misinterpretation of AEF. Conclusion and Perspectives We explored whether AEF could represent an additional sensitive and suitable marker for noninvasively diagnosing cardiac manifestation in the course of systemic autoimmune disorders. In autoimmune diseases, impaired left ventricular diastolic function is now generally accepted as an early indicator of accompanying cardiac alteration [3, 5 7, 9]. Our data indicate that AEF appears to be a more sensitive parameter for the detection of left ventricular diastolic filling abnormalities in patients suffering from SLE or RA than other established echocardiographic parameters of cardiac diastolic function. Therefore, a broad (additional) application of this noninvasive and highly sensitive method might influence early treatment and thereby contribute to prevent congestive heart failure in a number of patients suffering from systemic autoimmune disorders. A longitudinal follow-up study with this aim is currently under way. Cardiac Alterations in Autoimmune Diseases Cardiology 1999;92:

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