Abstract
Background Rheumatoid arthritis (RA) is associated with increased mortality and morbidity because of accelerated atherosclerosis. The study assessed the prevalence of left and right ventricle diastolic and systolic dysfunction in outpatients with RA.
Methods The study included 93 outpatients with RA. In all patients and control group, echocardiographic conventional and tissue Doppler (TDI) studies were conducted.
Results In the group of RA patients, we found high prevalence of left ventricular systolic and diastolic dysfunction and right diastolic dysfunction compared with controls (13.5% vs 5.5 %, 76.3% vs 48.8% and 41.9% vs 6.6%, respectively; P < 0.001).
Rheumatoid arthritis patients and controls showed significant differences about mitral, tricuspid, and pulmonary flow velocity curves; tissue Doppler curves of the lateral and the septal myocardial walls of the left ventricle; and basal myocardial free wall of the right ventricle. There were not any correlations between inflammatory and functional disease parameters and variables of systolic and diastolic function.
Conclusions Our study shows a high prevalence of left ventricular systolic and diastolic dysfunction in a population of outpatients affected by rheumatoid arthritis.
Cardiovascular disease is considered the leading cause of mortality in patients with rheumatoid arthritis (RA), responsible for approximately half of the deaths observed in RA cohorts.1
Some studies reported an increased risk of developing heart failure (HF) in RA,2estimated as two-fold higher, when compared with subjects without RA. This excess risk is not explained only by traditional cardiovascular risk factors and/or ischemic heart diseases.3
Recently, an increased prevalence of left ventricular (LV) systolic dysfunction was described among patients with RA in comparison to the general population, based on echocardiographic evaluation of LV ejection fraction4; however, the exact mechanism of the high prevalence of LV systolic dysfunction in subjects with rheumatoid disease is still uncertain.
Rheumatoid arthritis patients reflect subclinical myocardial damage, perhaps reflected by small vessel disease or fibrosis, in addition to that accrued from hypertension, age, and other cardiovascular risk factors.
Moreover, an increased diastolic dysfunction without clinically evident cardiac disease is reported in patients with RA,5–8correlated with the disease duration and suggesting a subclinical myocardial involvement. Left ventricular diastolic dysfunction is usually attributable to common structural abnormalities, such as hypertrophy, interstitial fibrosis, or impaired myocyte relaxation resulting from ischemia.7,8
However, these studies, including a limited number of patients, were conducted on patients with different duration of the disease and have had substantial methodological differences.
Little is known about the exact prevalence of left and right systolic and diastolic dysfunction in outpatients with RA, in particular in those cases without symptoms.
The aim of this study was to assess the prevalence of diastolic and systolic dysfunction of the left ventricle (LV) and right ventricle (RV) in asymptomatic outpatients with RA compared with a control group matched for sex, age, and cardiovascular risk factors. We search for possible correlations between systolic and diastolic heart indices and disease activity parameters.
MATERIALS AND METHODS
We enrolled 93 consecutive nonselected outpatients attending the Rheumatology Unit that had signed informed consent, according to the institutional review board–approved protocol.
The diagnosis of RA was achieved according to ACR criteria.9All the patients underwent a complete joint count and had their erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) dosages been measured, to calculate disease activity index (DAS44). A clinical remission and a low disease activity are defined when DAS44 is lower than 1.6 and 2.4, respectively. The patients underwent clinical assessment, 12-lead electrocardiography, and echocardiography. Each one was individually matched to a control subject based on age, sex, race, and cardiovascular risk factors for LV dysfunction such as hypertension, diabetes, coronary artery disease, smoke, and dyslipidemia.
Electrocardiography
Major abnormalities were defined as pathologic Q waves, left bundle branch block, left ventricular hypertrophy, atrial fibrillation, or flutter. Other abnormalities were considered minor.
Echocardiography
Patients underwent 2-dimensional and Doppler transthoracic echocardiography. Echocardiograms were performed using Vivid 7 (GE) with a 3.5 MHz transducer. The subjects were examined in the left lateral decubitus position according to the standardization of the American Society of Echocardiography.10
Left ventricular dimensions and ejection fraction (LVEF) were estimated according to LV volumes evaluated by biplane Simpson’s method; LV systolic dysfunction was defined as LV ejection fraction (EF) less than 50% measured by 2-dimensional echocardiography.10
Mitral and tricuspid valve regurgitation grade were assessed semiquantitatively according to the current guidelines and classified as mild, moderate, and severe.11By placing the 2-mm PWD at the mitral inflow, velocities were traced, and the early diastolic (E) and atrial (A) velocities were measured, and the E/A ratio was calculated. The deceleration time (DT) was measured according to the recommendations of the American Society of Echocardiography.12Pulmonary venous flow velocities were obtained by placing the 2-mm PWD sample volume 1 cm within the orifice of the right superior pulmonary vein with the guidance of color Doppler imaging.
Myocardial systolic and diastolic velocities were recorded using the PW TDI. Systolic (S’), early (E’), and late (A’) diastolic waves velocities were measured by placing the sample volume, underneath the mitral annulus, on the lateral and on the septal myocardial wall of the LV from the apical 4-chamber view and on tricuspid lateral annulus. The E/E’ ratio was also obtained; we used the average E´ velocity obtained from the septal and lateral sides of the mitral annulus for the prediction of LV filling pressures.13
According to the recommendations of The American Society of Echocardiography,13LV diastolic dysfunction was defined as septal E’ less than 8 and/or lateral E’ less than 10; different rates of diastolic dysfunction were classified in mild or grade I (impaired relaxation pattern), moderate or grade II (pseudonormal filling pattern), and severe (restrictive filling pattern) or grade III. In patients with mild diastolic dysfunction, the mitral E/A ratio was less than 0.8 and decreases by less than 50% during the Valsalva maneuver, DT was greater than 200 ms and average (from septal and lateral mitral annular velocities) E/E’ ratio is less than 8. In patients with moderate diastolic dysfunction (grade II), the mitral E/A ratio varies from 0.8 to 1.5 and decreases by greater than 50% during the Valsalva maneuver, DT was from 160 to 200 ms, the E/E’ (average) ratio was from 9 to 12. Patients with severe diastolic dysfunction (grade III) had an E/A ratio greater than 2 and decreases by greater than 50% during the Valsalva maneuver, DT less than 160 ms, IVRT less than 160 ms, and average E/e’ ratio greater than 13.13The Valsalva maneuver can be used to decrease preload and unmask the seemingly normal pattern of pseudonormal filling to reveal a pattern characteristic of relaxation abnormality.
Right ventricular systolic dysfunction was assessed by measuring tricuspidal annular plane systolic excursion (TAPSE) by M-Mode less than 16 mm and by systolic velocity (s’) of lateral tricuspid annulus with pulse wave tissue Doppler imaging (TDI) less than 10 cm/s.14According to the American Society of Cardiology,14measurement of RV diastolic function were done as follows with the same parameters as those used to assess the left side: tricuspid E/A ratio less than 0.8 suggests impaired relaxation, a tricuspid E/A ratio of 0.8 to 2.1 with an E/e lateral ’ ratio greater than 6 or diastolic flow predominance in the hepatic venis suggests pseudonormal filling, and a tricuspid E/A ratio greater than 2.1 with a DT less than 120 ms suggests restrictive filling (as does late diastolic antegrade flow in the pulmonary artery).14
Left ventricular and RV myocardial performance indexes (MPIs) were derived using conventional PW echocardiography, as previously described by Tei and colleagues.15We consider values of the LV MPI less than 0.4015and RV MPI less than 0.3016as normal. Higher index values correspond to more pathological states with overall cardiac dysfunction.
Statistical Analysis
All data were expressed as an average ± SD. Differences between continual variables were evaluated using the Student t test or Mann-Whitney test, whereas the test chi-square was used to analyze the categorical variables. A P < 0.05 value was considered as statistically significant.
RESULTS
We analyzed 93 patients affected by RA, with a mean age at the time of the clinical cardiac assessment of 60.4 ± 12.2 years and a mean RA duration of 10.6 ± 7 years. Thirty-six patients showed an elevation of CRP, whereas an overall positivity for rheumatoid factor and anti-CCP antibodies was detected in 62% and 43% of the patients, respectively. The mean DAS44 index of these patients was quite low (mean, 2.1 ± 1.2). The clinical characteristics of the cohort were shown in Table 1.
When compared with the control group, RA patients showed a significantly higher prevalence of LV systolic and diastolic dysfunction (13.5% vs 5.5 %, and 76.3% vs 48.8%, respectively; P < 0.001), in addition to an higher rate of RV diastolic dysfunction (41.9% vs 6.6%; P < 0.001), as shown in Table 2. The diastolic dysfunction is distributed in the following way: 65% impaired relaxation pattern, 25% pseudonormal filling pattern, and 10% restrictive filling pattern.
In fact, RA patients and controls showed significant differences about mitral and tricuspid flow velocity curves, tissue Doppler curves of mitral (lateral and septal) and tricuspid annulus, and pulmonary venous velocity tissue curves. Moreover, no difference was found about other RV functional parameters (ie, systolic pulmonary pressure, degree of tricuspid insufficiency, TAPSE, or peak systolic velocity at tricuspid lateral annulus) and degree of valves’ disease or electrocardiographic abnormalities between RA patients and controls (Table 2).
Systolic dysfunction (defined as LV EF, <50%) was found in 13 RA subjects. We compared clinical characteristics and echocardiographic data of these patients with the 80 RA cases with LV EF of 50% or greater. No differences were recorded between the 2 groups regarding RA duration, age at onset, and serological or inflammatory markers of disease.
We evaluated possible correlations between clinical and laboratory characteristics of the patients and echocardiographic indexes of diastolic dysfunction: we found a correlation between CAD and E/A ratio, and age and DT.
Regarding systolic dysfunction, we found that CAD and history of hypertension were significantly correlated with LVEF at univariate analysis, whereas only CAD was related with LVEF at multivariable regression analysis. However, LVEF values were evenly distributed among cases and controls; therefore, LVEF is related with CAD itself, independent from RA.
We observed that patients with LV systolic dysfunction have higher dimension of the left atrium, higher degree of significant mitral regurgitation, higher values of pulmonary hypertension, and more degree of significant tricuspid regurgitation than patients without LV systolic dysfunction (Table 3); in addition, there were significant differences about RA treatment: only 33.3% and 66.7% of patients with systolic dysfunction were assuming, respectively, methotrexate and corticosteroids in comparison to 72.7% and 83.1% of patients with EF of 50% or greater (P = 0.02 and P < 0.001).
In our study population, we show a high incidence of RV diastolic dysfunction (41.9% vs 6.6%; P < 0.001) in RA patients, although there were any differences in terms of TAPSE or systolic artery pulmonary pressure. The prevalent grade of diastolic dysfunction was the impaired relaxation (80%), followed by the pseudonormal (10%) and from the restrictive one (10%).
However, LV systolic dysfunction was more frequent in hypertensive patients and in whom with a history of coronary artery disease.
DISCUSSION
We evaluated left and right systolic and diastolic function in RA outpatients compared with a control group matched for age, sex, and cardiovascular risk factors. Our study provides evidence that RA patients had a high prevalence of left (but not right) systolic dysfunction and biventricular diastolic dysfunction.
In our study, 13 RA patients showed LV systolic dysfunction. We could not find any correlation between inflammatory parameters, disease activity score index, and variables of systolic function in RA patients with and without LV dysfunction. These patients show higher dimension of left atrium, higher significant degree (more than moderate) of mitral and tricuspid regurgitation, higher systolic pulmonary artery pressure when compared with others without left ventricular systolic dysfunction.
Overall, these results are consistent with some previous studies that have demonstrated an increased risk of heart failure (HF) in RA patients compared with the general population,2,3,17,18but the underlying pathophysiology is uncertain, and only about half of the excess risk of heart failure in RA patients can be attributed to traditional cardiovascular risk factors.
The increase of HF among RA patients may be associated with increased inflammatory activity, probably resulting in premature atherosclerosis. Some plausible explanations involve endothelial dysfunction, because of lipid abnormalities, atherogenic lipoprotein factors, adhesion molecules, and proinflammatory cytokines, including interleukin-1 and TNF alpha,19,20leading to endothelial injury and accelerated atherosclerosis.21Moreover, clinical markers of inflammation have been associated with cardiovascular mortality and morbidity in these patients.22A chronic immune activation and inflammatory mechanisms participate in the development and progression of HF, including the induction of myocardial hypertrophy, fibrosis, and contractile dysfunction.23Patients with RA and elevated levels of inflammatory mediators would therefore be at particularly high risk of heart failure progression and, consequently, of higher mortality.24Our patients, although with low inflammatory status at the moment of cardiologic assessment, showed a higher biventricular diastolic and LV systolic disfunction when compared with controls. This finding could be due to the long duration of the disease.
The increased risk of heart failure in patients with RA is not explained by traditional cardiovascular risk factors or solely by the presence of ischemic heart disease. Our results emphasize a need for greater understanding of the dynamics of myocardial dysfunction in RA Interestingly, a recent cardiac MRI study reported lower myocardial mass in patients with RA compared with age-matched controls,25suggesting chronic myocardial injury or myocyte loss as an underlying problem in RA.
Some studies report an increased diastolic dysfunction in patients with long-standing RA without clinically evident heart disease.5,6In our population, LV diastolic dysfunction was detected in 76.3% of RA, whereas in the control group it was present in 48.8% (P < 0.001); this is in line with our previous results.26Besides, our study showed that patients with RA show also impaired right ventricular diastolic function. However, this high prevalence of diastolic dysfunction is not all explained only by cardiovascular risk factors. Several mechanisms have been held responsible for diastolic impairment: fibrous scarring of the heart muscle, nodular granulomatous, myocarditis or arteritis, amyloidosis, focal inflammation, and vasculitis and cardiotoxic therapies used for the treatment of RA.23,27
We postulate that chronic low-grade myocardial inflammation resulting in fibrosis may predispose patients with RA to diastolic dysfunction This finding might be clinically very important because diastolic dysfunction has been recognized as a primary cause of congestive heart failure.
In literature, there were many data about direct correlation between RA pharmacological therapy and cardiac function, and opinions remain undivided as to whether anti-inflammatory therapy in particular steroids can influence the heart.
Corticosteroids can promote hypertension, diabetes, and dyslipidemia as a risk factor for atherosclerosis.28,29However, other different studies suggest that anti-inflammatory effects of corticosteroids may be beneficial in RA patients and others show that disease-modifying antirheumatic drugs does not seem to have adverse effect on cardiac function.19,30,31
A recent experimental study on rats suggests that low-dose methotrexate has the ability to regulate inflammatory responses and improves cardiac function and, hence, contributes to prevent the development of postmyocarditis dilated cardiomyopathy32; this hypothesis could explain the association between LV systolic function and methotrexate assumption.
However, further studies with larger population are needed to determine the effects of aggressive anti-inflammatory therapy on cardiac dysfunction in RA patients.
Based on our results, we think that echocardiographic assessment should be considered as part of the instrumental assessment of the RA patients. However, further research is needed to understand the possible relationship of our findings and the increased cardiovascular mortality in this kind of patients. Finally, the knowledge of presence and type of unrecognized cardiac abnormalities in asymptomatic patients might be important for the correct management of RA patients.
CONCLUSIONS
We demonstrate a high prevalence of LV systolic and diastolic dysfunction in RA. These data strongly suggest that RA patients need an increased vigilance for the signs and symptoms of HF. A strict collaboration between cardiologists and rheumatologist could induce a tight control of cardiovascular risk factors, and an improved control of RA disease maybe using therapeutic strategies tailored on the single case, to offer the best chance of improving cardiovascular outcomes for RA patients. Future studies evaluate the potential utility of screening RA patients with echocardiography to identify early asymptomatic ventricular dysfunction.