Introduction

Rheumatoid arthritis (RA) is a chronic and systemic articular inflammatory disease [1, 2], often associated with cardiac manifestations [3]. Among many other extra-articular features, several forms of cardiac involvement have been described in RA, most commonly pericarditis and pericardial effusion [4]. The rate of mortality due to cardiovascular disease and ischaemic heart disease in both sexes is higher in RA [5]. Autopsy studies have shown high incidences of pericardial, myocardial, and endocardial involvement in RA patients [6, 7]. These lesions may cause conduction defects, myocardiopathy, structural abnormalities, and cardiac dysfunction. Cardiac failure is the result of systolic or diastolic dysfunction or both [8]. Systolic dysfunction and cardiac failure are often preceded by alterations in left ventricular diastolic function, which may be clinically silent for years or even decades [9].

Doppler echocardiography is a sensitive and noninvasive method for detecting cardiac abnormalities and systolic and/or diastolic dysfunction. Although easy to use, this conventional method has several limiting factors, such as the effects of changes in preload-afterload and arrhythmia on the method.

Recently, a myocardial performance index (MPI) was suggested for evaluating ventricular function. The MPI gives information about the global function of a ventricle by assessing systolic and diastolic phases of the cardiac cycles simultaneously [10]. Since it is a ratio of time intervals, it reflects the systodiastolic rather than solely systolic or diastolic dysfunction [11]. It was also shown to be independent of changes in preload and afterload, heart rate, and tricuspid regurgitation during the assessment of ventricular myocardial performance [12].

The aim of the present study was to evaluate cardiac involvement in patients with active RA by standard pulsed-wave Doppler echocardiography and MPI.

Patients and methods

The study was carried out on 40 outpatients (eight men and 32 women) and 44 age- and sex-matched healthy controls (35 women, nine men). All of them fulfilled the 1987 revised criteria of the American College of Rheumatology for RA [13]. The disease was considered to be active if the patient had at least two of the following features [9]:

  1. 1.

    Six or more tender joints

  2. 2.

    Three or more swollen joints

  3. 3.

    Morning stiffness lasting more than 45 min

  4. 4.

    Erythrocyte sedimentation rate (ESR) higher than 25 mm

Patients with histories of rheumatic fever, systemic arterial hypertension, diabetes mellitus, primary cardiomyopathy, congenital heart disease, chronic lung disease, coronary artery disease, or arrhythmia and those with small echo window and poor image quality were excluded from the study. None of the subjects were on any pharmaceutical treatment (beta blockers, Ca channel blockers, etc.) except for antirheumatic drugs. All patients were evaluated for the numbers of tender and swollen joints and submitted to laboratory analyses including ESR, C-reactive protein (CRP), complete blood count (CBC), serum protein electrophoresis, serum creatinine, serum transaminases, and rheumatoid factor (latex agglutination test) measurement.

All patients were in stage 1–4 of the disease according to Steinbrocker's criteria [14]. The joints were scored for tenderness on a 0–3 scale according to the Ritchie Articular Index [15]. Total Ritchie Index, which is the number of tender and swollen joints, was also calculated. Each patient filled in a health assessment questionnaire (HAQ) [16] for assessment of functional impairment. All patients were treated with second-line drugs (hydroxychloroquine, methotrexate, sulphasalazine) and steroids.

Echocardiography

In all subjects, two-dimensional, M-mode, pulsed Doppler, and color flow Doppler echocardiography examinations (ATL 5000, 2–4 MHz phased array transducer) were performed by the same examiner. The ejection fraction of the left ventricle was obtained using Simpson's biplane methods in two-dimensional echocardiography [17]. The left atrial and ventricular dimensions were measured with M-mode echocardiography using a parasternal window. Fractional shortening was calculated using the equation: (end diastolic diameter minus end systolic diameter)×100/end diastolic diameter. The pulsed Doppler recordings of mitral and tricuspid flow velocities were obtained from the apical 4-chamber view by placing the sample volume between the tips of the mitral and tricuspid leaflets. The peak early diastolic flow (E) and peak atrial flow (A) velocities, E wave deceleration time, time-velocity integrals of early diastolic flow velocity curve (E-VTI), time-velocity integrals of the atrial contraction velocity curve (A-VTI), and time-velocity integrals of the total diastolic velocity curve (T-VTI) were recorded. The E/A and E-VTI/A-VTI ratios and left atrial filling fractions (AFF=A-VTI/T-VTI) were calculated.

Myocardial performance index measurements:

The Doppler time intervals were measured using atrioventricular (mitral and tricuspid valves) inflow and left and right ventricular outflow tract velocities. Left ventricle outflow velocities were obtained from the apical 5-chamber view by placing the sample volume in the outflow tract below the aortic valves. Right ventricle outflow velocities were obtained from the parasternal short-axis view by placing the sample volume in the outflow tract below the pulmonary valves.

The MPI is defined as the sum of isovolumic contraction time (ICT) and isovolumic relaxation time (IRT) divided by the ventricular ejection time (ET): (ICT+IRT)/ET. To derive the sum of ICT and IRT, the ejection time was subtracted from the interval between cessation and onset of atrioventricular valve inflow. Measured intervals are depicted in Fig. 1. The interval between cessation and onset of mitral valve inflow was measured from the end of the Doppler A wave of the mitral inflow signal to the beginning of the next E wave. Similarly, the interval between cessation and onset of tricuspid valve inflow was measured from the pulsed Doppler signal of tricuspid inflow. Ejection times of the left and right ventricles were measured from the onset to the end of the ventricular outflow Doppler velocity profile. The pre-ejection period was measured from the onset of the QRS complex to the onset of ventricular ejection flow. To minimise variations due to heart rate, the average values of five consecutive beats were used for the measurement of each interval.

Fig. 1.
figure 1

Myocardial performance index. Myocardial performance index = (a−b)/b. a Time interval from cessation to onset of atrioventricular inflow, b Ventricular outflow tract ejection time. ICT isovolumic contraction time, IRT isovolumic relaxation time

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Diastolic dysfunction was suspected when E velocity decreased, A velocity increased, the E/A ratio was <1, and deceleration time (DT) and IRT were prolonged (>150 ms and >100 ms, respectively) [18]. The normal MPI value was formerly reported as 0.39±0.05 for the left ventricle and 0.28±0.04 for the right ventricle [19].

Statistical analysis

The independent samples t-test and Pearson's correlation analysis were used for statistical analysis. Values of P<0.05 were considered to be statistically significant.

Results

Demographic and clinical characteristics of the patients and controls are shown in Table 1. The mean ages were 48.50±11.80 years for patients and 46.1±12.7 years for the control group. There were no significant differences between age, heart rate, and systolic and diastolic blood pressure between RA patients and controls. The end systolic diameter of the left atrium, end diastolic diameter of the left ventricle, end systolic diameter of the left ventricle, ejection fraction, and fractional shortening were not statistically significantly different between the groups (Table 2).

Table 1. Characteristics of the RA patients
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Table 2. Clinical and baseline echocardiographic measurement. EDD end diastolic diameter, ESD end systolic diameter, EF ejection fraction, FS fractional shortening, LA left atrial diameter
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Doppler echocardiography measurements of the left ventricle

Peak E velocity and E/A and E-VTI/A-VTI ratios were significantly lower than those of controls (P<0.05). Peak A velocity, A-VTI, and AFF were significantly higher (P<0.05). The mean IRT value was significantly longer than in controls (96.07±14.7 vs 73.72±9.5), and the IRT/ET ratio was significantly higher. We found no significant difference between the groups in other echocardiographic indices of left ventricle performance (Table 3). The mean value of left ventricular MPI was 0.52±0.12 in patients, which was also significantly higher than that of controls (0.43±0.06, P<0.05).

Table 3. Left ventricle Doppler echocardiographic variables in patients and control subjects. E mitral peak early flow velocity, A mitral peak atrial flow velocity, VTI velocity time integral, AFF atrial filling fraction, DT E wave deceleration time, IRT isovolumic relaxation time, ICT isovolumic contraction time, ET ejection time, MPI myocardial performance index, NS not significant
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Doppler echocardiography measurements of the right ventricle

Mean A-VTI values were significantly higher in all patients than in healthy controls (P<0.05). The E/A and E-VTI/A-VTI ratios were also significantly lower in all the patients. In both groups, ET, ICT, and IRT intervals and ICT/ET and IRT/ET ratios did not differ (Table 4). The mean right ventricular MPI in RA patients (0.30±0.08) was not significantly different from that of controls (0.30±0.04) (P<0.05).

Table 4. Right ventricle Doppler echocardiographic variables in patients and control subjects. E mitral peak early flow velocity, A mitral peak atrial flow velocity, VTI velocity time integral, AFF atrial filling fraction, DT E wave deceleration time, IRT isovolumic relaxation time, ICT isovolumic contraction time, ET ejection time, MPI myocardial performance index, NS not significant
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A significant correlation did not emerge between cardiac parameters and age, number of tender joints, Ritchie index, or HAQ score. No correlation was found between the Steinbrocker index stage and pulsed Doppler echo parameters (P>0.05). A correlation was present between the duration of illness and E/A ratio and IRT (P<0.05). There was no statistically significant correlation between other echocardiographic parameters and disease parameters (Table 5).

Table 5. Correlation coefficients between the demographic and inflammatory parameters and values of cardiac variables (left ventricle). E/A E/A ratio, IRT isovolumetric relaxation time, MPI myocardial performance index
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Discussion

Previous studies reported high mortality rates for RA [20, 21, 22, 23, 24, 25, 26, 27]. Researchers also noted that the rate of mortality in RA patients was dependent on concurrent heart disease [28]; however, many of these patients did not experience clinical cardiac symptoms [29]. Cardiac disease is often clinically silent in patients affected by RA.

The aim of our study was to evaluate cardiac function in patients affected by active RA but without clinical evidence of heart disease and to compare them with a control group matched for sex and age. We found diastolic dysfunction of right and left ventricles in patients with RA. In patients, we also found abnormal left ventricular MPI, which shows global ventricular function status.

Some studies report increased systolic and diastolic dysfunction in patients with RA [4, 20, 30, 31, 32, 33]. We found diastolic dysfunction in them. Abnormalities were detected in certain variables of both left ventricle diastolic dysfunctions such as E, A, E/A, A-VTI, AFF, and IRT and in right ventricle diastolic dysfunctions such as E/A, A-VTI, and E-VTI/A-VTI ratio in our study.

In accordance with the findings of previous studies [9, 31, 34], we could not find any correlation between inflammatory and functional disease parameters and variables of diastolic function. Also, no correlation was found between Steinbrocker index stage and pulsed Doppler echo parameters.

We found a statistically significant correlation between duration of disease and the alteration of left ventricle diastolic function expressed by E/A ratio and IRT. This result is in accordance with recent reports [9, 31, 34] showing a correlation between disease duration and an index of left ventricular function parameters. Other studies failed to find such a correlation [30, 32].

Until now, ventricular performance in RA has not been evaluated by measuring MPI, either. This index reflects both systolic and diastolic performance of the ventricles. The findings from this study showed that left ventricular MPI of the patients was significantly higher than that of controls. Right ventricular MPI class was preserved despite abnormal left ventricular MPI scores. We can only speculate that higher systemic pressures on the left ventricle and lower pulmonary pressures on the right ventricle might have been responsible for this observation.

A mechanistic explanation for the increase in cardiovascular disease (CVD)-related morbidity and mortality in this population remains elusive. The pathogenesis of CVD in the setting of RA is multifactorial [35]. There is increasing evidence that inflammatory mediators intrinsic to the disease represent major culprits in the development of CVD [36]. Inflammation, characteristic of active RA, likely plays a major role in CVD. Therefore, one can speculate that chronic cytokine release may lead to the deposition of connective tissue in the myocardium [9].

It has been suggested that subclinical vasculitis, speculated to be common in RA, leads to endothelial injury and accelerated atherosclerosis [37]. Myocardial fibrosis and inflammation have been reported in about 20% of the patients in autopsy studies [38, 39].

The earliest deterioration in cardiac disease is in diastolic function. Such abnormalities have been reported in a number of conditions such as arterial hypertension, coronary artery disease, and in elderly subjects. We selected patients with no evidence of hypertension or known cardiac disease. Impaired ventricular function was observed at all ages in RA patients but not in control subjects, which suggests the deterioration of diastolic function in active RA at any age.

The inflammation may accelerate the development of atherogenesis, thrombosis, and congestive heart disease [35]. Medications aimed at combatting inflammation may also adversely affect a patient's CVD risk factor profile [40, 41, 42, 43]. For instance, chloroquine has cardiotoxic side effects [44, 45]. D-penicillamine and gold salts are known to be capable of causing vasculitis, which may lead to myocardial dysfunction [46]. Sulphasalazine, methotrexate, nonsteroidal anti-inflammatory drugs, and steroids do not have known direct cardiotoxic side effects. Our patients were treated with second-line drugs (chloroquine, sulphasalazine, methotrexate) following the diagnosis of RA. None were treated with gold salts or D-penicillamine. In this study, the actual duration of antirheumatic therapy and the agents used varied in each patient. Therefore, we can not attribute our findings to the side effects of antirheumatic drug therapy. However, it is not clear whether the above mentioned parameters are effective in RA and whether they affect prognosis. We can not comment on the exact mechanism of ventricular dysfunction, because the present study was not planned to clarify its aetiopathogenesis.

In conclusion, this study showed impaired diastolic function in both ventricles of patients with active RA. The findings indicate a direct relationship between some parameters of left ventricular diastolic function (E/A ratio and IRT) and disease duration. They also suggest a subclinical myocardial involvement during the course of the disease. Being aware of unrecognised cardiac abnormalities can be very important for the correct assessment and management of RA patients. In addition to standard pulsed-wave Doppler echocardiography, MPI may be used for the evaluation of ventricular function in RA.