Lupus (2015) 24, 263–272 http://lup.sagepub.com
PAPER
Subclinical deterioration of left ventricular function in patients with juvenile-onset systemic lupus erythematosus H-T Chung1, Y-L Huang2,3, K-W Yeh4 and J-L Huang3,4 1
Division of Cardiology, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; 2Department of Pediatrics, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan; 3Graduate Institute of Clinical Medical Science, Chang Gung University, Taoyuan, Taiwan; and 4Division of Asthma, Allergy, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
Objectives: Patients with systemic lupus erythematosus (SLE) have a higher risk of myocardial involvement, which can result in ventricular dysfunction. Little is known about the chronic influence of SLE on heart function in children and adolescents. This is the first study to demonstrate long-term changes in left ventricular function in patients with juvenile-onset SLE. Methods: This was a longitudinal study of 92 patients with juvenile-onset SLE. Twodimensional echocardiography was performed by a single pediatric cardiologist at baseline, with follow-up at six-month intervals. Clinical and laboratory parameters, disease activity, treatment, nailfold capillaroscopy, and the traditional risk factors for atherosclerosis were evaluated. The baseline comparison of ventricular function was performed against 50 agematched controls, and the follow-up results were analyzed using generalized estimating equations. Results: The patients’ mean age at baseline was 15.9 4.3 years, the mean disease duration was 3.6 3.2 years, and the mean follow-up duration was 4.5 1.6 years. At baseline, the mean left ventricular ejection fraction (LVEF) was 74.7 5.6% and the mean E/A ratio of left ventricular diastolic filling was 1.7 0.3 (E: the peak velocity at rapid left ventricular filling; A: the peak velocity during left atrial contraction). The LVEF of the SLE patients was similar to the healthy controls and it did not change during the follow-up period. In contrast, the E/A ratio was lower in the SLE patients than in the healthy controls (1.7 0.3 versus 1.88 0.37; p ¼ 0.002), and it decreased significantly with time (B SE, 0.013 0.006, p ¼ 0.023). In multiple analyses, abnormal microvasculature in nailfold capillaroscopy had a negative effect on LVEF progression (p ¼ 0.039). Disease duration of SLE and proteinuria were risk factors associated with the descent of E/A ratio (p ¼ 0.014 and p ¼ 0.015, respectively). Conclusion: In patients with juvenile-onset SLE who were free of cardiac symptoms, there was evidence of declining ventricular diastolic function with time. Abnormal nailfold microvasculature, proteinuria and longer disease duration were the main risk factors for worsening of ventricular function. Lupus (2015) 24, 263–272. Key words: Ventricular function; systemic lupus erythematosus; pediatric rheumatology; cardiovascular disease
Introduction Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by multiple organ inflammatory processes and vasculitis. Correspondence to: Jing-Long Huang, Division of Allergy, Asthma and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, #5 Fu-Hsin Street, Kweishan, Taoyuan, Taiwan. Email: [email protected] H.T.C. and Y.L.H. contributed equally to this work. Received 20 March 2014; revised: 1 September 2014; accepted 10 September 2014
Cardiovascular complications, infections, and renal disorders are the leading causes of morbidity and mortality,1,2 and cardiac involvement has been reported to have a direct impact on morbidity and mortality.3 Pathohistological studies in autopsy series of SLE patients have revealed a prevalence of myocarditis ranging from 40% to 78%.4–6 However, such a high prevalence is not observed in clinical practice, suggesting that the process of myocardial inflammation in SLE patients is insidious and slow paced. In the absence of cardiac symptoms, the deterioration of left ventricular (LV) function
! The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at UNIV OF FLORIDA on February 16, 2015
10.1177/0961203314554249
Ventricular function in juvenile-onset SLE H-T Chung et al.
264
progresses subclinically.7–13 Once clinical myocarditis occurs, it has a great impact on the survival of patients with SLE.3 Ventricular dysfunction often commences from diastolic dysfunction rather than systolic dysfunction. Thus, diastolic dysfunction is regarded to be an early indicator of myocardial involvement, and it is often detected in patients with SLE.14–16 Studies have shown that a longer disease duration is associated with poor diastolic function; however, no longitudinal study has shown the extent to which heart function worsens.17,18 Patients with juvenile-onset SLE are clinically different from those with adult-onset SLE. They have greater renal and central nervous system involvement and higher disease activity score at onset, and are more likely to develop significant organ damage than adults with SLE.19,20 Only a few studies have addressed the impairment of heart function in juvenile-onset SLE.8,10,11 Their findings suggested that asymptomatic diastolic and systolic dysfunction is common in children and adolescents with SLE. Short of long-term observational data, however, it is unknown how ventricular dysfunction progresses and what the risk factors are. To the best of our knowledge, this is the first longitudinal study of heart function in patients with juvenile-onset SLE. The aim of this study was to demonstrate the long-term changes in ventricular function and to identify the possible risk factors contributing to the deterioration of ventricular function.
Materials and methods Study population From June 2002 to May 2011, patients diagnosed with SLE according to the 1997 American College of Rheumatology (ACR) revised criteria21 with disease onset age 10% of the total loops longer than normal; tortuous, branched, bushy, enlarged, giant, and disarranged loops; and the presence of hemorrhages. Disease activity was assessed using the SLE Disease Activity Index (SLEDAI)27 and was recorded as SLEDAI score. Information on steroid usage (current dose in mg/kg/day), hydroxychloroquine, cyclophosphamide, and immunosuppressants including azathioprine, cyclosporine, methotrexate and mycophenolate mofetil was obtained and recorded by chart review. The renal disease, SLEDAI score, disease activity, and major organ involvement of each SLE patient were evaluated by the same pediatric rheumatologist throughout the study. Statistical analysis Descriptive statistics were shown as the mean standard deviation (SD) for continuous variables and as percentages for categorical variables. Differences in quantitative data between groups were evaluated using the two-tailed Student t test. Categorical variables were analyzed with Fisher’s exact test and the chi-square test when appropriate. The correlations between baseline LV function and risk factors were evaluated by stepwise linear regression. Age-adjusted analysis using generalized estimating equations (GEE) was used to determine the association between baseline risk factors and repeated LV function assessments, with
LVEF or E/A ratio as the dependent variable. Associated variables with p < 0.05 were selected to build the final GEE model. The Quasi-likelihood under Independence Model Criterion (QIC) was used in selecting the appropriate correlation structure. All of the possible combinations of the chosen factors were evaluated. The correlation structure with the lowest QIC score was determined to be the best model.28 All statistical analyses were performed using the SPSS/Windows software package version 15.0 (SPSS Inc, Chicago, IL, USA).
Results Ninety-two patients with SLE and 50 control individuals were evaluated. None of the study participants in either group had cardiac symptoms. Forty-seven patients (51%) were newly diagnosed after June 2002, and 49 patients (53%) were recruited within the first three years of disease. The clinical and echocardiographic characteristics of the two study groups are summarized in Table 1. The two study groups did not differ significantly with respect to age, sex, height, weight, and body mass index. The proportion of hypertension was higher in the patient group than in the control group (31.5% versus 16%; p ¼ 0.044). The mean (SD) number of traditional risk factors was higher in the SLE patient group than in the control group (1.29 0.67 versus 0.2 0.45; p < 0.001). Analysis of lipid profiles and dyslipidemia The mean (SD) levels of high-density lipoprotein cholesterol, total cholesterol, and triglycerides were 49.63 23.53 mg/dl, 188.54 71.29 mg/dl, and 188.29 129.78 mg/dl, respectively. The patients with abnormal findings on lipid analysis were defined as having dyslipidemia, which was present in 82 of the 92 SLE patients (89.1%). SLE-related characteristics The mean (SD) age at diagnosis of SLE was 12.38 2.87 years, and the mean (SD) disease duration was 3.56 3.21 years at baseline. At baseline, the mean (SD) SLEDAI score was 6.88 5.48, and most patients (n ¼ 91, 98.9%) were treated with prednisolone, of whom 35 (38.5%) had a prednisolone dose greater than 0.2 mg/kg/day. Thirty-nine patients (42.4%) were taking immunosuppressants at baseline, 34 of whom (87.1%) were treated with azathioprine. Cyclophosphamide was used in 47 patients (51.1%) before baseline or Lupus
Downloaded from lup.sagepub.com at UNIV OF FLORIDA on February 16, 2015
Ventricular function in juvenile-onset SLE H-T Chung et al.
266
Table 1 Baseline demographic features and baseline ventricular function in patients with juvenile-onset SLE and in control participants
Age, mean SD years No. (%) female Height, mean SD cm Weight, mean SD kg BMI, mean SD kg/m2 No. (%) with hypertension Systolic BP, mean SD mm Hg Diastolic BP, mean SD mm Hg Mean arterial pressure, mean SD mm Hg No. (%) of Chinese ethnicity No. (%) with family history of premature CHD No. of traditional risk factors, mean SD LVEF at baseline, mean SD % Peak E (cm/s), mean SD Peak A (cm/s), mean SD E/A ratio, mean SD
SLE (n ¼ 92)
Control participants (n ¼ 50)
p
15.94 4.32 79 (85.9) 152.62 12.87 47.99 12.45 20.33 3.59 29 (31.5) 116.01 15.99 70.14 12.13 85.45 11.93 92 (100) 5 (5.4) 1.29 0.67 74.76 5.6 90.7 16.8 54.7 12.8 1.7 0.3
15.67 3.86 39 (78) 154.14 12.12 47.88 12.86 19.82 3.76 8 (16) 112.48 11.9 69.16 9.09 83.54 9.03 50 (100) 2 (4) 0.2 0.45 74.82 4.12 92.3 12.6 50.2 7.9 1.88 0.37
0.717 0.232 0.495 0.961 0.435 0.044 0.139 0.587 0.287 – 1.0 0.2 mg/kg/day), and major abnormalities in capillaroscopy had harmful effects (p ¼ 0.046, p ¼ 0.028, and p ¼ 0.022, respectively). Variables with a significant association (p < 0.05) on initial GEE analysis were selected as potential risk factors to build the multiple regression models. The correlation structure with the lowest QIC score among all possible combinations of these factors was determined to build the final regression model. In multiple analyses, the disease duration of SLE and proteinuria were risk factors associated with a worsening E/A ratio (B SE ¼ 0.014 0.006 and 0.1 0.042; p ¼ 0.014 and p ¼ 0.015, respectively) (Table 3). With regards to multiple analysis of the LVEF, only major abnormalities in capillaroscopy showed a significant negative effect on LVEF progression (B SE, 1.257 0.607, p ¼ 0.039) (Tables 4 and 5).
Lupus Downloaded from lup.sagepub.com at UNIV OF FLORIDA on February 16, 2015
Ventricular function in juvenile-onset SLE H-T Chung et al.
267
Table 2 Baseline features, major organ involvement, medications and comorbid conditions of the study subjects with juvenile-onset SLE Age at diagnosis, mean SD years SLE duration, mean SD years Major organ system involvement, no. (%) Hematologic Renal Cutaneous CNS Musculoskeletal Pulmonary Serologic abnormality, no. (%) ANA Anti-dsDNA Anti-cardiolipin antibody Anti-RNP Anti-Sm Anti-SSA Anti-SSB SLEDAI score, mean SD Medications, no. (%) Steroid Prednisolone >0.2 mg/kg/day Cyclophosphamide Immunosuppressants Hydroxychloroquine Azathioprine Mycophenolate mofetil Cyclosporine Methotrexate Comorbid conditions, no. (%) Cardiovascular event Raynaud’s phenomenon Major abnormalities in capillaroscopy
12.38 2.87 3.56 3.21 78 58 69 21 44 10
(84.8) (63) (75) (22.8) (47.8) (10.9)
74 (80.4) 69 (75) 11 (12) 23 (25) 6 (6.5) 46 (50) 19 (20.7) 6.88 5.48 91 (98.9) 35 (38) 47 (51.1) 39 (42.4) 16 (17.4) 34 (37) 3 (3.3) 1 (1.1) 1 (1.1) 10 (10.9) 22 (23.9) 32 (34.8)
SLE: systemic lupus erythematosus; SD: standard deviation; CNS: central nervous system; ANA: antinuclear antibodies; Anti-dsDNA: anti-double-stranded DNA antibodies; Anti-RNP: antiribonucleoprotein antibody; SLEDAI: SLE Disease Activity Index.
Discussion SLE patients are at high risk of cardiovascular disease. Although cardiovascular complications in childhood SLE are rare,2 more attention to the care of patients with juvenile-onset SLE is justified, as the prognosis of juvenile-onset SLE has improved considerably in recent decades.29 A high prevalence of heart dysfunction has been reported in patients with juvenile-onset SLE;8,10,11 however, no longitudinal follow-up data have been previously reported. In the current longitudinal observation study, we showed the long-term changes in LV functions and identified some risk factors contributing to the deterioration in ventricular functions. Over the observation period in our study, we found that the E/A ratio, an indicator of diastolic function, fell dramatically year by year in the first
five years after disease onset. At baseline, the SLE patients with an average disease duration of 3.56 years had a significantly higher peak velocity of atrial contraction (peak A) and a lower E/A ratio than the age- and sex-matched healthy volunteers. Analysis of repeated E/A ratio measurements using GEE identified two major risk factors for the worsening of diastolic function: the disease duration of SLE and proteinuria. Previous studies have reported similar findings of diastolic dysfunction in cross-sectional settings;7,9,14–16,18,30–36 however, only a few identified the possible causes. Winslow et al. followed 28 adult SLE patients for five years, and found increasing systolic and diastolic LV dysfunction with time that was related to hypertension and coronary artery disease.33 Wislowska et al. found that diastolic dysfunction was related not to disease activity but to long (>10 years) disease duration in 32 adult SLE patients.18 A high degree of similarity between these studies implies that diastolic dysfunction is a time-dependent process of SLE itself. However, the extent to which diastolic dysfunction would worsen was unknown until the current study. The repeated measurements of E/A ratio in our juvenile-onset SLE patients demonstrated a dramatic drop of diastolic function in the first five years after disease onset, and then remained at its nadir in the following years. Although a previous study has observed that E/A ratio did decrease from adolescence to young adulthood,37 the decreasing rate of E/A ratio in our study (0.0862 per year; p < 0.001) was far faster than normal individuals in the similar age group (0.02153 per year). Sixty-three percent of the patients in our study presented with renal involvement at the diagnosis of SLE. Among them, proteinuria was a frequent finding and present in 50 of 58 patients (86%). Proteinuria is a frequent presentation of lupus nephritis, which is also related to hyperlipidemia, and it increases the risk of coronary artery disease and the potential for thrombosis. A recent report showed that patients with lupus nephritis, especially those with a young age at onset, were at high risk for morbidity from ischemic heart disease.38 In non-lupus studies, proteinuria has been showed to be associated with diastolic dysfunction in type 1 and type 2 diabetes.39,40 There is also supportive evidence that mild renal insufficiency in rats results in cardiac fibrosis and impaired diastolic function.41 Our study revealed an association between proteinuria and a decreasing E/A ratio over time. This finding implies that the patients with an initial presentation of proteinuria require close monitoring of diastolic heart function and Lupus
Downloaded from lup.sagepub.com at UNIV OF FLORIDA on February 16, 2015
Ventricular function in juvenile-onset SLE H-T Chung et al.
268
Figure 1 (a) Representative Doppler echocardiographic measurement of left ventricular diastolic function. The E/A ratio in mitral inflow patterns from Doppler echocardiography. Peak early diastolic velocity (E-wave) and peak late diastolic velocity (A-wave) were measured to determine the E/A ratio. (b) Representative M-mode echocardiographic measurement of left ventricular systolic function. Left ventricular internal dimension at end diastole (LVIDd) and left ventricular internal dimension at end systole (LVIDs) were measured and left ventricular ejection fraction (LVEF) was automatically calculated by the Teichholz method.23
Lupus Downloaded from lup.sagepub.com at UNIV OF FLORIDA on February 16, 2015
Ventricular function in juvenile-onset SLE H-T Chung et al.
269
Figure 2 Mean E/A ratio and left ventricular ejection fraction (LVEF) over disease duration of systemic lupus erythematosus (SLE). Values are the mean and standard error of the mean. *p < 0.05, **p < 0.01, and ***p < 0.001 versus the value at diagnosis of SLE (year 0). E/A ratio: peak of early diastolic (E) to late diastolic (A) flow velocity.
Table 3 Multiple regression analysis of longitudinal E/A ratio progression and risk factors E/A ratio progression
Age at diagnosis, years SLE duration, years (Proteinuria)
B SE
p value
0.00067 0.00756 0.01357 0.00554 0.10087 0.04153
0.929 0.014 0.015
E/A ratio: peak of early diastolic (E) to late diastolic (A) flow velocity ratio; SE: standard error; SLE: systemic lupus erythematosus. Generalized estimating equations models with the E/A ratio as the dependent variable. Factors in parentheses were categorical factors.
periodic evaluations, since the initial manifestation of diastolic dysfunction is usually silent. With regards to systolic function of the left ventricle, we did not find any significant differences in systolic heart function in the SLE patients compared to the healthy volunteers, even over time. This finding is similar to previous studies;7,17,18,31,34,42 however, in contrast to others.10–12,14,33,36,43 In our cohort, which was characterized by juvenile-onset SLE, a relatively large number of patients, and a longer observation period, this finding at least showed that systolic heart function is well preserved in patients with juvenile-onset SLE throughout the first several years of disease. Few studies have demonstrated the risk factors related to systolic ventricular impairment. Yip et al.12 reported that SLE patients with subclinical ventricular systolic dysfunction were older, and had a higher prevalence of
hypertension, higher disease activity score and end-organ damage index. Winslow et al.33 found that both systolic and diastolic LV dysfunction were present in SLE patients, that it progressed over time, and that it was related to the presence of hypertension and coronary artery disease. Murai et al.36 observed that anti-DNA antibody titers were related to systolic and diastolic ventricular dysfunction. In the analysis of the risk factors related to systolic ventricular function in the current study, major abnormalities in capillaroscopy was a significant risk for LVEF progression in multiple regression analysis. Nailfold capillaroscopy has been widely used to evaluate the peripheral microvasculature, and it has been proven to be a useful noninvasive and reproducible technique to assess the microvasculature in patients with SLE.44 Capillaroscopic abnormalities have been shown to be related to disease activity in patients with juvenile-onset SLE.45 Major abnormal and scleroderma patterns in nailfold capillaroscopy suggest the systemic involvement of the microvasculature in SLE patients. Microvascular heart involvement may increase the stiffness in elastic arteries thereby imposing a greater workload on the heart and an increased risk of LV dysfunction. Our results showed that abnormal nailfold capillaroscopy was a predictor of systolic LV dysfunction, suggesting it plays a role in indirect monitoring of heart microvascular involvement in patients with SLE. Although the LV systolic function was similar to the healthy controls and was well maintained throughout the years of the study, a subtle decline in systolic function after repeated observations was associated with a fatal outcome (Table 4). Our results suggest that the impairment of systolic LV function seems to be multifactorial, and thus such patients should be closely observed. Regular monitoring of heart function is mandatory in patients with major abnormalities in nailfold capillaroscopy. In a normal mitral inflow pattern, the early diastolic mitral velocity (E-wave) is higher than the late velocity (A-wave) with atrial contraction, so that the E/A ratio is >1. With impaired relaxation, the magnitude of the E-wave will decrease. As less volume is transported into the left ventricle during early filling, more blood is present in atrial contraction. Hence atrial contraction will eject more blood into the left ventricle, and the A-wave will be larger than normal and will typically also be larger than the E-wave (E/A ratio 5 mg/l) AntidsDNA per 100 IU/ml (Positive ANA) (Anticardiolipin antibody) (Anti-RNP positivity) (Anti-Sm positivity) (Anti-SSA positivity) (Anti-SSB positivity) SLEDAI score (Cyclophosphamide use) Prednisolone, mg/kg/day (Prednisolone >0.2 mg/kg/day) (Immunosuppressant use) (Antihypertensive drug use) (Raynaud’s phenomenon) (Major abnormalities in capillaroscopy) (Mortality)
E/A ratio progression
B SE
p value
B SE
p value
0.01097 0.05011 0.00758 0.10626 0.01279 0.06394 1.0186 0.81072 0.10744 0.06047 0.70199 0.67433 0.46199 1.48561 0.13268 0.39908 0.00283 0.00438 0.00049 0.00293 0.45792 0.84048 1.64908 1.39088 0.03346 0.55791 0.01589 0.54155 0.17383 0.53897 0.59523 0.29795 0.023 0.04435 0.14305 0.79629 0.9496 0.59195 0.41432 0.59676 0.5258 1.0073 0.02575 0.55018 0.45432 0.62393 0.0213 0.04183 0.22521 0.54758 0.98729 1.27434 1.21153 0.55121 0.46045 0.57029 1.62573 0.96438 0.52786 0.68278 1.28672 0.56258 1.3307 0.37512
0.827 0.943 0.841 0.209 0.076 0.298 0.756 0.740 0.519 0.868 0.586 0.236 0.952 0.977 0.747 0.046 0.604 0.857 0.109 0.488 0.602 0.963 0.467 0.611 0.681 0.438 0.028 0.419 0.092 0.439 0.022 5 mg/l) (Prednisolone >0.2 mg/kg/day) (Major abnormalities in capillaroscopy)
B SE
p value
0.00383 0.04883 0.36177 0.70951 1.01002 0.56274 1.25679 0.60747
0.938 0.611 0.073 0.039
LVEF: left ventricular ejection fraction; SE: standard error; CRP: Creactive protein. Generalized estimating equations models with the LVEF as the dependent variable. Factors in parentheses were categorical factors.
Since diastolic dysfunction had not yet occurred, the profile of grade I diastolic dysfunction including low E, high A, and reversed E/A ratio was not observed in the SLE patients. Our results showed a lower E/A ratio and a higher A wave in the SLE patients than in the controls with no difference in E wave, which is consistent with previous studies.15,30,47 It may be presumed that the initial mechanism of ventricular diastolic function in SLE patients is different from that of typical diastolic heart failure. Further research is needed to clarify this issue. A reverse in E/A ratio from greater than 1.0 to less than 1.0 is sensitive for early diastolic dysfunction; however, pseudonormalization of E/A occurs
Lupus Downloaded from lup.sagepub.com at UNIV OF FLORIDA on February 16, 2015
Ventricular function in juvenile-onset SLE H-T Chung et al.
271
in patients with severe diastolic dysfunction. The E- and A-wave velocities are affected by blood volume, mitral valve anatomy, mitral valve function, and atrial fibrillation, making standard echocardiography less reliable in such instances. In these cases, tissue Doppler imaging (TDI) is useful for measuring mitral annular motion (a measure of transmitral flow that is independent of the aforementioned factors). Many recent studies have shown that new imaging modalities such as TDI and cardiovascular magnetic resonance imaging (CMR) are more sensitive to detect the early disruption of LV function in SLE patients. Teixeira et al.48 found no differences of LVEF and mitral E/A ratio between SLE patients and controls. Instead, LV diastolic dysfunction was identified by tissue Doppler of the mitral ring and by mitral flow propagation velocity. Buss et al.13 used TDI and strain imaging to identify SLE patients associated with impairment of systolic and diastolic LV function. In addition, Puntmann et al.49 detected subclinical myocardial and perimyocardial involvement in SLE patients using CMR imaging. The myocardial involvement is subtle in most SLE patients without cardiac symptoms and is barely detectable by traditional echocardiography. New imaging techniques provide sensitive methods to detect early ventricular dysfunction and myocardial inflammation and may overcome some of the limitation in our study. There are some limitations to this study. First, the confounding effects of steroid and immunosuppressive agents on ventricular function could not be ruled out, as it would have been unethical to stop treatment. Second, we did not perform myocardial perfusion scans to evaluate the coronary arterial involvement. Third, we did not perform follow-up measurements of echocardiography in the healthy controls. Fourth, mitral flow E/A ratio, when used alone, is less reliable in advanced diastolic dysfunction and some of the aforementioned situations. Finally, we did not divide the patients into subsets according to disease severity and disease duration because of the limitations of the statistical method used for analysis of repeat measurements (the number was too small in each groups).
Conclusions This is the first study to show the long-term changes in heart function in patients with juvenile-onset SLE. The patients in our cohort had a declining LV diastolic function over time, and disease
duration and proteinuria were the main risk factors contributing to its progression. Unlike the early deterioration of diastolic function, the LV systolic function was stable. Abnormal nailfold microvasculature was a risk factor for worsening LV systolic function, and the downward trend of systolic function was associated with mortality. We suggest thorough echocardiographic follow-up for SLE patients, particularly in those with abnormal nailfold microvasculature, renal involvement, and longer disease duration. This study has contributed to the few data available in patients with juvenileonset SLE; however, further research is required to build on this and explore further with other diagnostic and noninvasive modalities that can be used to detect subclinical changes.
Funding This study was supported by a Chang Gung Medical Research Progress Grant (CMRPG40004143) and a National Science Council Grant (NSC98-2314-B-182-002-MY3).
Conflict of interest statement The authors have no conflicts of interest to declare.
References 1 Huang JL, Lin CJ, Hung IJ, Luo SF. The morbidity and mortality associated with childhood onset systemic lupus erythematosus. Chang Gung Med J 1994; 17: 113–120. 2 Wei HY, Chung HT, Wu CT, Huang JL. Aortic dissection complicated with hemothorax in an adolescent patient with systemic lupus erythematosus: Case report and review of literature. Semin Arthritis Rheum 2011; 41: 12–18. 3 Apte M, McGwin G Jr, Vila´ LM, Kaslow RA, Alarco´n GS, Reveille JD. Associated factors and impact of myocarditis in patients with SLE from LUMINA, a multiethnic US cohort (LV). [corrected]. Rheumatology (Oxford) 2008; 47: 362–367. 4 Estes D, Christian CL. The natural history of systemic lupus erythematosus by prospective analysis. Medicine (Baltimore) 1971; 50: 85–95. 5 Doherty NE, Siegel RJ. Cardiovascular manifestations of systemic lupus erythematosus. Am Heart J 1985; 110: 1257–1265. 6 Mandell BF. Cardiovascular involvement in systemic lupus erythematosus. Semin Arthritis Rheum 1987; 17: 126–141. 7 Sasson Z, Rasooly Y, Chow CW, Marshall S, Urowitz MB. Impairment of left ventricular diastolic function in systemic lupus erythematosus. Am J Cardiol 1992; 69: 1629–1634. 8 Gazarian M, Feldman BM, Benson LN, Gilday DL, Laxer RM, Silverman ED. Assessment of myocardial perfusion and function in childhood systemic lupus erythematosus. J Pediatr 1998; 132: 109–116. 9 Paradiso M, Gabrielli F, Masala C, et al. Evaluation of myocardial involvement in systemic lupus erythematosus by signal-averaged electrocardiography and echocardiography. Acta Cardiol 2001; 56: 381–386. Lupus
Downloaded from lup.sagepub.com at UNIV OF FLORIDA on February 16, 2015
Ventricular function in juvenile-onset SLE H-T Chung et al.
272 10 Gu¨nal N, Kara N, Akko¨k N, Cakar N, Kahramanyol O, Akalin N. Cardiac abnormalities in children with systemic lupus erythematosus. Turk J Pediatr 2003; 45: 301–305. 11 Chow PC, Ho MH, Lee TL, Lau YL, Cheung YF. Relation of arterial stiffness to left ventricular structure and function in adolescents and young adults with pediatric-onset systemic lupus erythematosus. J Rheumatol 2007; 34: 1345–1352. 12 Yip GW, Shang Q, Tam LS, et al. Disease chronicity and activity predict subclinical left ventricular systolic dysfunction in patients with systemic lupus erythematosus. Heart 2009; 95: 980–987. 13 Buss SJ, Wolf D, Korosoglou G, et al. Myocardial left ventricular dysfunction in patients with systemic lupus erythematosus: New insights from tissue Doppler and strain imaging. J Rheumatol 2010; 37: 79–86. 14 Crozier IG, Li E, Milne MJ, Nicholls MG. Cardiac involvement in systemic lupus erythematosus detected by echocardiography. Am J Cardiol 1990; 65: 1145–1148. 15 Fujimoto S, Kagoshima T, Nakajima T, Dohi K. Doppler echocardiographic assessment of left ventricular diastolic function in patients with systemic lupus erythematosus. Cardiology 1994; 85: 267–272. 16 Astorri E, Fiorina P, Ridolo E, Contini GA, Albertini D, Dall’Aglio P. Doppler echocardiographic study of left ventricular function in patients with systemic lupus erythematosus [article in Italian]. Cardiologia 1997; 42: 1179–1183. 17 Giunta A, Picillo U, Maione S, et al. Spectrum of cardiac involvement in systemic lupus erythematosus: Echocardiographic, echoDoppler observations and immunological investigation. Acta Cardiol 1993; 48: 183–197. 18 Wislowska M, Deren D, Kochmanski M, Sypula S, Rozbicka J. Systolic and diastolic heart function in SLE patients. Rheumatol Int 2009; 29: 1469–1476. 19 Brunner HI, Gladman DD, Iban˜ez D, Urowitz MD, Silverman ED. Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus. Arthritis Rheum 2008; 58: 556–562. 20 Levy DM, Kamphuis S. Systemic lupus erythematosus in children and adolescents. Pediatr Clin North Am 2012; 59: 345–364. 21 Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725. 22 Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: Results of a survey of echocardiographic measurements. Circulation 1978; 58: 1072–1083. 23 Teichholz LE, Kreulen T, Herman MV, Gorlin R. Problems in echocardiographic volume determinations: Echocardiographicangiographic correlations in the presence of absence of asynergy. Am J Cardiol 1976; 37: 7–11. 24 Ashley EA, Niebauer J. Cardiology explained. London: Remedica, 2004. p. 40. 25 Huang YL, Chung HT, Chang CJ, Yeh KW, Chen LC, Huang JL. Lymphopenia is a risk factor in the progression of carotid intimamedia thickness in juvenile-onset systemic lupus erythematosus. Arthritis Rheum 2009; 60: 3766–3775. 26 Ingegnoli F, Zeni S, Gerloni V, Fantini F. Capillaroscopic observations in childhood rheumatic diseases and healthy controls. Clin Exp Rheumatol 2005; 23: 905–911. 27 Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 1992; 35: 630–640. 28 Pan W. Akaike’s information criterion in generalized estimating equations. Biometrics 2001; 57: 120–125. 29 Huang JL, Yeh KW, Yao TC, et al. Pediatric lupus in Asia. Lupus 2010; 19: 1414–1418. 30 Kalke S, Balakrishanan C, Mangat G, Mittal G, Kumar N, Joshi VR. Echocardiography in systemic lupus erythematosus. Lupus 1998; 7: 540–544.
31 Enomoto K, Kaji Y, Mayumi T, et al. Left ventricular function in patients with stable systemic lupus erythematosus. Jpn Heart J 1991; 32: 445–453. 32 Cujec B, Sibley J, Haga M. Cardiac abnormalities in patients with systemic lupus erythematosus. Can J Cardiol 1991; 7: 343–349. 33 Winslow TM, Ossipov MA, Fazio GP, Foster E, Simonson JS, Schiller NB. The left ventricle in systemic lupus erythematosus: Initial observations and a five-year follow-up in a university medical center population. Am Heart J 1993; 125: 1117–1122. 34 Wranicz JK, Cygankiewicz I, Zielinska M, Woz´niacka A, SysaJedrzejowska A. Non-invasive cardiac evaluation in patients with systemic lupus erythematosus. J Med 2001; 32: 195–206. 35 Driazhenkova IV. The diastolic dysfunction of the left ventricle in patients with systemic lupus erythematosus and system scleroderma [article in Russian]. Klin Med (Mosk) 2005; 83: 45–47. 36 Murai K, Oku H, Takeuchi K, Kanayama Y, Inoue T, Takeda T. Alterations in myocardial systolic and diastolic function in patients with active systemic lupus erythematosus. Am Heart J 1987; 113: 966–971. 37 Schmitz L, Koch H, Bein G, Brockmeier K. Left ventricular diastolic function in infants, children, and adolescents. Reference values and analysis of morphologic and physiologic determinants of echocardiographic Doppler flow signals during growth and maturation. J Am Coll Cardiol 1998; 32: 1441–1448. 38 Faurschou M, Mellemkjaer L, Starklint H, et al. High risk of ischemic heart disease in patients with lupus nephritis. J Rheumatol 2011; 38: 2400–2405. 39 Sampson MJ, Chambers JB, Sprigings DC, Drury PL. Abnormal diastolic function in patients with type 1 diabetes and early nephropathy. Br Heart J 1990; 64: 266–271. 40 Liu JE, Robbins DC, Palmieri V, et al. Association of albuminuria with systolic and diastolic left ventricular dysfunction in type 2 diabetes: The Strong Heart Study. J Am Coll Cardiol 2003; 41: 2022–2028. 41 Martin FL, McKie PM, Cataliotti A, et al. Experimental mild renal insufficiency mediates early cardiac apoptosis, fibrosis, and diastolic dysfunction: A kidney-heart connection. Am J Physiol Regul Integr Comp Physiol 2012; 302: R292–R299. 42 Sta˘nescu C, Dan GA. Myocardial involvement in systemic lupus erythematosus and systemic sclerosis—pulsed Doppler echocardiographic evaluation of left ventricular diastolic function. Rom J Intern Med 1992; 30: 243–248. 43 Strauer BE, Brune I, Schenk H, Knoll D, Perings E. Lupus cardiomyopathy: Cardiac mechanics, hemodynamics, and coronary blood flow in uncomplicated systemic lupus erythematosus. Am Heart J 1976; 92: 715–722. 44 Riccieri V, Spadaro A, Ceccarelli F, Scrivo R, Germano V, Valesini G. Nailfold capillaroscopy changes in systemic lupus erythematosus: Correlations with disease activity and autoantibody profile. Lupus 2005; 14: 521–525. 45 Ingegnoli F. Capillaroscopy abnormalities in relation to disease activity in juvenile systemic lupus erythematosus. Microvasc Res 2013; 87: 92–94. 46 Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 2009; 22: 107–133. 47 Roldan CA, Alomari IB, Awad K, et al. Aortic stiffness is associated with left ventricular diastolic dysfunction in systemic lupus erythematosus: A controlled transesophageal echocardiographic study. Clin Cardiol 2014; 37: 83–90. 48 Teixeira AC, Bonfa E, Herskowictz N, Barbato AJ, Borba EF. Early detection of global and regional left ventricular diastolic dysfunction in systemic lupus erythematosus: the role of the echocardiography. Rev Bras Reumatol 2010; 50 1: 16–30. 49 Puntmann VO, D’Cruz D, Smith Z, Pastor A, Choong P, Voigt T et al. Native myocardial T1 mapping by cardiovascular magnetic resonance imaging in subclinical cardiomyopathy in patients with systemic lupus erythematosus. Circulation Cardiovascular imaging 2013; 6 2: 295–301.
Lupus Downloaded from lup.sagepub.com at UNIV OF FLORIDA on February 16, 2015
PAPER
Subclinical deterioration of left ventricular function in patients with juvenile-onset systemic lupus erythematosus H-T Chung1, Y-L Huang2,3, K-W Yeh4 and J-L Huang3,4 1
Division of Cardiology, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; 2Department of Pediatrics, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan; 3Graduate Institute of Clinical Medical Science, Chang Gung University, Taoyuan, Taiwan; and 4Division of Asthma, Allergy, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
Objectives: Patients with systemic lupus erythematosus (SLE) have a higher risk of myocardial involvement, which can result in ventricular dysfunction. Little is known about the chronic influence of SLE on heart function in children and adolescents. This is the first study to demonstrate long-term changes in left ventricular function in patients with juvenile-onset SLE. Methods: This was a longitudinal study of 92 patients with juvenile-onset SLE. Twodimensional echocardiography was performed by a single pediatric cardiologist at baseline, with follow-up at six-month intervals. Clinical and laboratory parameters, disease activity, treatment, nailfold capillaroscopy, and the traditional risk factors for atherosclerosis were evaluated. The baseline comparison of ventricular function was performed against 50 agematched controls, and the follow-up results were analyzed using generalized estimating equations. Results: The patients’ mean age at baseline was 15.9 4.3 years, the mean disease duration was 3.6 3.2 years, and the mean follow-up duration was 4.5 1.6 years. At baseline, the mean left ventricular ejection fraction (LVEF) was 74.7 5.6% and the mean E/A ratio of left ventricular diastolic filling was 1.7 0.3 (E: the peak velocity at rapid left ventricular filling; A: the peak velocity during left atrial contraction). The LVEF of the SLE patients was similar to the healthy controls and it did not change during the follow-up period. In contrast, the E/A ratio was lower in the SLE patients than in the healthy controls (1.7 0.3 versus 1.88 0.37; p ¼ 0.002), and it decreased significantly with time (B SE, 0.013 0.006, p ¼ 0.023). In multiple analyses, abnormal microvasculature in nailfold capillaroscopy had a negative effect on LVEF progression (p ¼ 0.039). Disease duration of SLE and proteinuria were risk factors associated with the descent of E/A ratio (p ¼ 0.014 and p ¼ 0.015, respectively). Conclusion: In patients with juvenile-onset SLE who were free of cardiac symptoms, there was evidence of declining ventricular diastolic function with time. Abnormal nailfold microvasculature, proteinuria and longer disease duration were the main risk factors for worsening of ventricular function. Lupus (2015) 24, 263–272. Key words: Ventricular function; systemic lupus erythematosus; pediatric rheumatology; cardiovascular disease
Introduction Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by multiple organ inflammatory processes and vasculitis. Correspondence to: Jing-Long Huang, Division of Allergy, Asthma and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, #5 Fu-Hsin Street, Kweishan, Taoyuan, Taiwan. Email: [email protected] H.T.C. and Y.L.H. contributed equally to this work. Received 20 March 2014; revised: 1 September 2014; accepted 10 September 2014
Cardiovascular complications, infections, and renal disorders are the leading causes of morbidity and mortality,1,2 and cardiac involvement has been reported to have a direct impact on morbidity and mortality.3 Pathohistological studies in autopsy series of SLE patients have revealed a prevalence of myocarditis ranging from 40% to 78%.4–6 However, such a high prevalence is not observed in clinical practice, suggesting that the process of myocardial inflammation in SLE patients is insidious and slow paced. In the absence of cardiac symptoms, the deterioration of left ventricular (LV) function
! The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at UNIV OF FLORIDA on February 16, 2015
10.1177/0961203314554249
Ventricular function in juvenile-onset SLE H-T Chung et al.
264
progresses subclinically.7–13 Once clinical myocarditis occurs, it has a great impact on the survival of patients with SLE.3 Ventricular dysfunction often commences from diastolic dysfunction rather than systolic dysfunction. Thus, diastolic dysfunction is regarded to be an early indicator of myocardial involvement, and it is often detected in patients with SLE.14–16 Studies have shown that a longer disease duration is associated with poor diastolic function; however, no longitudinal study has shown the extent to which heart function worsens.17,18 Patients with juvenile-onset SLE are clinically different from those with adult-onset SLE. They have greater renal and central nervous system involvement and higher disease activity score at onset, and are more likely to develop significant organ damage than adults with SLE.19,20 Only a few studies have addressed the impairment of heart function in juvenile-onset SLE.8,10,11 Their findings suggested that asymptomatic diastolic and systolic dysfunction is common in children and adolescents with SLE. Short of long-term observational data, however, it is unknown how ventricular dysfunction progresses and what the risk factors are. To the best of our knowledge, this is the first longitudinal study of heart function in patients with juvenile-onset SLE. The aim of this study was to demonstrate the long-term changes in ventricular function and to identify the possible risk factors contributing to the deterioration of ventricular function.
Materials and methods Study population From June 2002 to May 2011, patients diagnosed with SLE according to the 1997 American College of Rheumatology (ACR) revised criteria21 with disease onset age 10% of the total loops longer than normal; tortuous, branched, bushy, enlarged, giant, and disarranged loops; and the presence of hemorrhages. Disease activity was assessed using the SLE Disease Activity Index (SLEDAI)27 and was recorded as SLEDAI score. Information on steroid usage (current dose in mg/kg/day), hydroxychloroquine, cyclophosphamide, and immunosuppressants including azathioprine, cyclosporine, methotrexate and mycophenolate mofetil was obtained and recorded by chart review. The renal disease, SLEDAI score, disease activity, and major organ involvement of each SLE patient were evaluated by the same pediatric rheumatologist throughout the study. Statistical analysis Descriptive statistics were shown as the mean standard deviation (SD) for continuous variables and as percentages for categorical variables. Differences in quantitative data between groups were evaluated using the two-tailed Student t test. Categorical variables were analyzed with Fisher’s exact test and the chi-square test when appropriate. The correlations between baseline LV function and risk factors were evaluated by stepwise linear regression. Age-adjusted analysis using generalized estimating equations (GEE) was used to determine the association between baseline risk factors and repeated LV function assessments, with
LVEF or E/A ratio as the dependent variable. Associated variables with p < 0.05 were selected to build the final GEE model. The Quasi-likelihood under Independence Model Criterion (QIC) was used in selecting the appropriate correlation structure. All of the possible combinations of the chosen factors were evaluated. The correlation structure with the lowest QIC score was determined to be the best model.28 All statistical analyses were performed using the SPSS/Windows software package version 15.0 (SPSS Inc, Chicago, IL, USA).
Results Ninety-two patients with SLE and 50 control individuals were evaluated. None of the study participants in either group had cardiac symptoms. Forty-seven patients (51%) were newly diagnosed after June 2002, and 49 patients (53%) were recruited within the first three years of disease. The clinical and echocardiographic characteristics of the two study groups are summarized in Table 1. The two study groups did not differ significantly with respect to age, sex, height, weight, and body mass index. The proportion of hypertension was higher in the patient group than in the control group (31.5% versus 16%; p ¼ 0.044). The mean (SD) number of traditional risk factors was higher in the SLE patient group than in the control group (1.29 0.67 versus 0.2 0.45; p < 0.001). Analysis of lipid profiles and dyslipidemia The mean (SD) levels of high-density lipoprotein cholesterol, total cholesterol, and triglycerides were 49.63 23.53 mg/dl, 188.54 71.29 mg/dl, and 188.29 129.78 mg/dl, respectively. The patients with abnormal findings on lipid analysis were defined as having dyslipidemia, which was present in 82 of the 92 SLE patients (89.1%). SLE-related characteristics The mean (SD) age at diagnosis of SLE was 12.38 2.87 years, and the mean (SD) disease duration was 3.56 3.21 years at baseline. At baseline, the mean (SD) SLEDAI score was 6.88 5.48, and most patients (n ¼ 91, 98.9%) were treated with prednisolone, of whom 35 (38.5%) had a prednisolone dose greater than 0.2 mg/kg/day. Thirty-nine patients (42.4%) were taking immunosuppressants at baseline, 34 of whom (87.1%) were treated with azathioprine. Cyclophosphamide was used in 47 patients (51.1%) before baseline or Lupus
Downloaded from lup.sagepub.com at UNIV OF FLORIDA on February 16, 2015
Ventricular function in juvenile-onset SLE H-T Chung et al.
266
Table 1 Baseline demographic features and baseline ventricular function in patients with juvenile-onset SLE and in control participants
Age, mean SD years No. (%) female Height, mean SD cm Weight, mean SD kg BMI, mean SD kg/m2 No. (%) with hypertension Systolic BP, mean SD mm Hg Diastolic BP, mean SD mm Hg Mean arterial pressure, mean SD mm Hg No. (%) of Chinese ethnicity No. (%) with family history of premature CHD No. of traditional risk factors, mean SD LVEF at baseline, mean SD % Peak E (cm/s), mean SD Peak A (cm/s), mean SD E/A ratio, mean SD
SLE (n ¼ 92)
Control participants (n ¼ 50)
p
15.94 4.32 79 (85.9) 152.62 12.87 47.99 12.45 20.33 3.59 29 (31.5) 116.01 15.99 70.14 12.13 85.45 11.93 92 (100) 5 (5.4) 1.29 0.67 74.76 5.6 90.7 16.8 54.7 12.8 1.7 0.3
15.67 3.86 39 (78) 154.14 12.12 47.88 12.86 19.82 3.76 8 (16) 112.48 11.9 69.16 9.09 83.54 9.03 50 (100) 2 (4) 0.2 0.45 74.82 4.12 92.3 12.6 50.2 7.9 1.88 0.37
0.717 0.232 0.495 0.961 0.435 0.044 0.139 0.587 0.287 – 1.0 0.2 mg/kg/day), and major abnormalities in capillaroscopy had harmful effects (p ¼ 0.046, p ¼ 0.028, and p ¼ 0.022, respectively). Variables with a significant association (p < 0.05) on initial GEE analysis were selected as potential risk factors to build the multiple regression models. The correlation structure with the lowest QIC score among all possible combinations of these factors was determined to build the final regression model. In multiple analyses, the disease duration of SLE and proteinuria were risk factors associated with a worsening E/A ratio (B SE ¼ 0.014 0.006 and 0.1 0.042; p ¼ 0.014 and p ¼ 0.015, respectively) (Table 3). With regards to multiple analysis of the LVEF, only major abnormalities in capillaroscopy showed a significant negative effect on LVEF progression (B SE, 1.257 0.607, p ¼ 0.039) (Tables 4 and 5).
Lupus Downloaded from lup.sagepub.com at UNIV OF FLORIDA on February 16, 2015
Ventricular function in juvenile-onset SLE H-T Chung et al.
267
Table 2 Baseline features, major organ involvement, medications and comorbid conditions of the study subjects with juvenile-onset SLE Age at diagnosis, mean SD years SLE duration, mean SD years Major organ system involvement, no. (%) Hematologic Renal Cutaneous CNS Musculoskeletal Pulmonary Serologic abnormality, no. (%) ANA Anti-dsDNA Anti-cardiolipin antibody Anti-RNP Anti-Sm Anti-SSA Anti-SSB SLEDAI score, mean SD Medications, no. (%) Steroid Prednisolone >0.2 mg/kg/day Cyclophosphamide Immunosuppressants Hydroxychloroquine Azathioprine Mycophenolate mofetil Cyclosporine Methotrexate Comorbid conditions, no. (%) Cardiovascular event Raynaud’s phenomenon Major abnormalities in capillaroscopy
12.38 2.87 3.56 3.21 78 58 69 21 44 10
(84.8) (63) (75) (22.8) (47.8) (10.9)
74 (80.4) 69 (75) 11 (12) 23 (25) 6 (6.5) 46 (50) 19 (20.7) 6.88 5.48 91 (98.9) 35 (38) 47 (51.1) 39 (42.4) 16 (17.4) 34 (37) 3 (3.3) 1 (1.1) 1 (1.1) 10 (10.9) 22 (23.9) 32 (34.8)
SLE: systemic lupus erythematosus; SD: standard deviation; CNS: central nervous system; ANA: antinuclear antibodies; Anti-dsDNA: anti-double-stranded DNA antibodies; Anti-RNP: antiribonucleoprotein antibody; SLEDAI: SLE Disease Activity Index.
Discussion SLE patients are at high risk of cardiovascular disease. Although cardiovascular complications in childhood SLE are rare,2 more attention to the care of patients with juvenile-onset SLE is justified, as the prognosis of juvenile-onset SLE has improved considerably in recent decades.29 A high prevalence of heart dysfunction has been reported in patients with juvenile-onset SLE;8,10,11 however, no longitudinal follow-up data have been previously reported. In the current longitudinal observation study, we showed the long-term changes in LV functions and identified some risk factors contributing to the deterioration in ventricular functions. Over the observation period in our study, we found that the E/A ratio, an indicator of diastolic function, fell dramatically year by year in the first
five years after disease onset. At baseline, the SLE patients with an average disease duration of 3.56 years had a significantly higher peak velocity of atrial contraction (peak A) and a lower E/A ratio than the age- and sex-matched healthy volunteers. Analysis of repeated E/A ratio measurements using GEE identified two major risk factors for the worsening of diastolic function: the disease duration of SLE and proteinuria. Previous studies have reported similar findings of diastolic dysfunction in cross-sectional settings;7,9,14–16,18,30–36 however, only a few identified the possible causes. Winslow et al. followed 28 adult SLE patients for five years, and found increasing systolic and diastolic LV dysfunction with time that was related to hypertension and coronary artery disease.33 Wislowska et al. found that diastolic dysfunction was related not to disease activity but to long (>10 years) disease duration in 32 adult SLE patients.18 A high degree of similarity between these studies implies that diastolic dysfunction is a time-dependent process of SLE itself. However, the extent to which diastolic dysfunction would worsen was unknown until the current study. The repeated measurements of E/A ratio in our juvenile-onset SLE patients demonstrated a dramatic drop of diastolic function in the first five years after disease onset, and then remained at its nadir in the following years. Although a previous study has observed that E/A ratio did decrease from adolescence to young adulthood,37 the decreasing rate of E/A ratio in our study (0.0862 per year; p < 0.001) was far faster than normal individuals in the similar age group (0.02153 per year). Sixty-three percent of the patients in our study presented with renal involvement at the diagnosis of SLE. Among them, proteinuria was a frequent finding and present in 50 of 58 patients (86%). Proteinuria is a frequent presentation of lupus nephritis, which is also related to hyperlipidemia, and it increases the risk of coronary artery disease and the potential for thrombosis. A recent report showed that patients with lupus nephritis, especially those with a young age at onset, were at high risk for morbidity from ischemic heart disease.38 In non-lupus studies, proteinuria has been showed to be associated with diastolic dysfunction in type 1 and type 2 diabetes.39,40 There is also supportive evidence that mild renal insufficiency in rats results in cardiac fibrosis and impaired diastolic function.41 Our study revealed an association between proteinuria and a decreasing E/A ratio over time. This finding implies that the patients with an initial presentation of proteinuria require close monitoring of diastolic heart function and Lupus
Downloaded from lup.sagepub.com at UNIV OF FLORIDA on February 16, 2015
Ventricular function in juvenile-onset SLE H-T Chung et al.
268
Figure 1 (a) Representative Doppler echocardiographic measurement of left ventricular diastolic function. The E/A ratio in mitral inflow patterns from Doppler echocardiography. Peak early diastolic velocity (E-wave) and peak late diastolic velocity (A-wave) were measured to determine the E/A ratio. (b) Representative M-mode echocardiographic measurement of left ventricular systolic function. Left ventricular internal dimension at end diastole (LVIDd) and left ventricular internal dimension at end systole (LVIDs) were measured and left ventricular ejection fraction (LVEF) was automatically calculated by the Teichholz method.23
Lupus Downloaded from lup.sagepub.com at UNIV OF FLORIDA on February 16, 2015
Ventricular function in juvenile-onset SLE H-T Chung et al.
269
Figure 2 Mean E/A ratio and left ventricular ejection fraction (LVEF) over disease duration of systemic lupus erythematosus (SLE). Values are the mean and standard error of the mean. *p < 0.05, **p < 0.01, and ***p < 0.001 versus the value at diagnosis of SLE (year 0). E/A ratio: peak of early diastolic (E) to late diastolic (A) flow velocity.
Table 3 Multiple regression analysis of longitudinal E/A ratio progression and risk factors E/A ratio progression
Age at diagnosis, years SLE duration, years (Proteinuria)
B SE
p value
0.00067 0.00756 0.01357 0.00554 0.10087 0.04153
0.929 0.014 0.015
E/A ratio: peak of early diastolic (E) to late diastolic (A) flow velocity ratio; SE: standard error; SLE: systemic lupus erythematosus. Generalized estimating equations models with the E/A ratio as the dependent variable. Factors in parentheses were categorical factors.
periodic evaluations, since the initial manifestation of diastolic dysfunction is usually silent. With regards to systolic function of the left ventricle, we did not find any significant differences in systolic heart function in the SLE patients compared to the healthy volunteers, even over time. This finding is similar to previous studies;7,17,18,31,34,42 however, in contrast to others.10–12,14,33,36,43 In our cohort, which was characterized by juvenile-onset SLE, a relatively large number of patients, and a longer observation period, this finding at least showed that systolic heart function is well preserved in patients with juvenile-onset SLE throughout the first several years of disease. Few studies have demonstrated the risk factors related to systolic ventricular impairment. Yip et al.12 reported that SLE patients with subclinical ventricular systolic dysfunction were older, and had a higher prevalence of
hypertension, higher disease activity score and end-organ damage index. Winslow et al.33 found that both systolic and diastolic LV dysfunction were present in SLE patients, that it progressed over time, and that it was related to the presence of hypertension and coronary artery disease. Murai et al.36 observed that anti-DNA antibody titers were related to systolic and diastolic ventricular dysfunction. In the analysis of the risk factors related to systolic ventricular function in the current study, major abnormalities in capillaroscopy was a significant risk for LVEF progression in multiple regression analysis. Nailfold capillaroscopy has been widely used to evaluate the peripheral microvasculature, and it has been proven to be a useful noninvasive and reproducible technique to assess the microvasculature in patients with SLE.44 Capillaroscopic abnormalities have been shown to be related to disease activity in patients with juvenile-onset SLE.45 Major abnormal and scleroderma patterns in nailfold capillaroscopy suggest the systemic involvement of the microvasculature in SLE patients. Microvascular heart involvement may increase the stiffness in elastic arteries thereby imposing a greater workload on the heart and an increased risk of LV dysfunction. Our results showed that abnormal nailfold capillaroscopy was a predictor of systolic LV dysfunction, suggesting it plays a role in indirect monitoring of heart microvascular involvement in patients with SLE. Although the LV systolic function was similar to the healthy controls and was well maintained throughout the years of the study, a subtle decline in systolic function after repeated observations was associated with a fatal outcome (Table 4). Our results suggest that the impairment of systolic LV function seems to be multifactorial, and thus such patients should be closely observed. Regular monitoring of heart function is mandatory in patients with major abnormalities in nailfold capillaroscopy. In a normal mitral inflow pattern, the early diastolic mitral velocity (E-wave) is higher than the late velocity (A-wave) with atrial contraction, so that the E/A ratio is >1. With impaired relaxation, the magnitude of the E-wave will decrease. As less volume is transported into the left ventricle during early filling, more blood is present in atrial contraction. Hence atrial contraction will eject more blood into the left ventricle, and the A-wave will be larger than normal and will typically also be larger than the E-wave (E/A ratio 5 mg/l) AntidsDNA per 100 IU/ml (Positive ANA) (Anticardiolipin antibody) (Anti-RNP positivity) (Anti-Sm positivity) (Anti-SSA positivity) (Anti-SSB positivity) SLEDAI score (Cyclophosphamide use) Prednisolone, mg/kg/day (Prednisolone >0.2 mg/kg/day) (Immunosuppressant use) (Antihypertensive drug use) (Raynaud’s phenomenon) (Major abnormalities in capillaroscopy) (Mortality)
E/A ratio progression
B SE
p value
B SE
p value
0.01097 0.05011 0.00758 0.10626 0.01279 0.06394 1.0186 0.81072 0.10744 0.06047 0.70199 0.67433 0.46199 1.48561 0.13268 0.39908 0.00283 0.00438 0.00049 0.00293 0.45792 0.84048 1.64908 1.39088 0.03346 0.55791 0.01589 0.54155 0.17383 0.53897 0.59523 0.29795 0.023 0.04435 0.14305 0.79629 0.9496 0.59195 0.41432 0.59676 0.5258 1.0073 0.02575 0.55018 0.45432 0.62393 0.0213 0.04183 0.22521 0.54758 0.98729 1.27434 1.21153 0.55121 0.46045 0.57029 1.62573 0.96438 0.52786 0.68278 1.28672 0.56258 1.3307 0.37512
0.827 0.943 0.841 0.209 0.076 0.298 0.756 0.740 0.519 0.868 0.586 0.236 0.952 0.977 0.747 0.046 0.604 0.857 0.109 0.488 0.602 0.963 0.467 0.611 0.681 0.438 0.028 0.419 0.092 0.439 0.022 5 mg/l) (Prednisolone >0.2 mg/kg/day) (Major abnormalities in capillaroscopy)
B SE
p value
0.00383 0.04883 0.36177 0.70951 1.01002 0.56274 1.25679 0.60747
0.938 0.611 0.073 0.039
LVEF: left ventricular ejection fraction; SE: standard error; CRP: Creactive protein. Generalized estimating equations models with the LVEF as the dependent variable. Factors in parentheses were categorical factors.
Since diastolic dysfunction had not yet occurred, the profile of grade I diastolic dysfunction including low E, high A, and reversed E/A ratio was not observed in the SLE patients. Our results showed a lower E/A ratio and a higher A wave in the SLE patients than in the controls with no difference in E wave, which is consistent with previous studies.15,30,47 It may be presumed that the initial mechanism of ventricular diastolic function in SLE patients is different from that of typical diastolic heart failure. Further research is needed to clarify this issue. A reverse in E/A ratio from greater than 1.0 to less than 1.0 is sensitive for early diastolic dysfunction; however, pseudonormalization of E/A occurs
Lupus Downloaded from lup.sagepub.com at UNIV OF FLORIDA on February 16, 2015
Ventricular function in juvenile-onset SLE H-T Chung et al.
271
in patients with severe diastolic dysfunction. The E- and A-wave velocities are affected by blood volume, mitral valve anatomy, mitral valve function, and atrial fibrillation, making standard echocardiography less reliable in such instances. In these cases, tissue Doppler imaging (TDI) is useful for measuring mitral annular motion (a measure of transmitral flow that is independent of the aforementioned factors). Many recent studies have shown that new imaging modalities such as TDI and cardiovascular magnetic resonance imaging (CMR) are more sensitive to detect the early disruption of LV function in SLE patients. Teixeira et al.48 found no differences of LVEF and mitral E/A ratio between SLE patients and controls. Instead, LV diastolic dysfunction was identified by tissue Doppler of the mitral ring and by mitral flow propagation velocity. Buss et al.13 used TDI and strain imaging to identify SLE patients associated with impairment of systolic and diastolic LV function. In addition, Puntmann et al.49 detected subclinical myocardial and perimyocardial involvement in SLE patients using CMR imaging. The myocardial involvement is subtle in most SLE patients without cardiac symptoms and is barely detectable by traditional echocardiography. New imaging techniques provide sensitive methods to detect early ventricular dysfunction and myocardial inflammation and may overcome some of the limitation in our study. There are some limitations to this study. First, the confounding effects of steroid and immunosuppressive agents on ventricular function could not be ruled out, as it would have been unethical to stop treatment. Second, we did not perform myocardial perfusion scans to evaluate the coronary arterial involvement. Third, we did not perform follow-up measurements of echocardiography in the healthy controls. Fourth, mitral flow E/A ratio, when used alone, is less reliable in advanced diastolic dysfunction and some of the aforementioned situations. Finally, we did not divide the patients into subsets according to disease severity and disease duration because of the limitations of the statistical method used for analysis of repeat measurements (the number was too small in each groups).
Conclusions This is the first study to show the long-term changes in heart function in patients with juvenile-onset SLE. The patients in our cohort had a declining LV diastolic function over time, and disease
duration and proteinuria were the main risk factors contributing to its progression. Unlike the early deterioration of diastolic function, the LV systolic function was stable. Abnormal nailfold microvasculature was a risk factor for worsening LV systolic function, and the downward trend of systolic function was associated with mortality. We suggest thorough echocardiographic follow-up for SLE patients, particularly in those with abnormal nailfold microvasculature, renal involvement, and longer disease duration. This study has contributed to the few data available in patients with juvenileonset SLE; however, further research is required to build on this and explore further with other diagnostic and noninvasive modalities that can be used to detect subclinical changes.
Funding This study was supported by a Chang Gung Medical Research Progress Grant (CMRPG40004143) and a National Science Council Grant (NSC98-2314-B-182-002-MY3).
Conflict of interest statement The authors have no conflicts of interest to declare.
References 1 Huang JL, Lin CJ, Hung IJ, Luo SF. The morbidity and mortality associated with childhood onset systemic lupus erythematosus. Chang Gung Med J 1994; 17: 113–120. 2 Wei HY, Chung HT, Wu CT, Huang JL. Aortic dissection complicated with hemothorax in an adolescent patient with systemic lupus erythematosus: Case report and review of literature. Semin Arthritis Rheum 2011; 41: 12–18. 3 Apte M, McGwin G Jr, Vila´ LM, Kaslow RA, Alarco´n GS, Reveille JD. Associated factors and impact of myocarditis in patients with SLE from LUMINA, a multiethnic US cohort (LV). [corrected]. Rheumatology (Oxford) 2008; 47: 362–367. 4 Estes D, Christian CL. The natural history of systemic lupus erythematosus by prospective analysis. Medicine (Baltimore) 1971; 50: 85–95. 5 Doherty NE, Siegel RJ. Cardiovascular manifestations of systemic lupus erythematosus. Am Heart J 1985; 110: 1257–1265. 6 Mandell BF. Cardiovascular involvement in systemic lupus erythematosus. Semin Arthritis Rheum 1987; 17: 126–141. 7 Sasson Z, Rasooly Y, Chow CW, Marshall S, Urowitz MB. Impairment of left ventricular diastolic function in systemic lupus erythematosus. Am J Cardiol 1992; 69: 1629–1634. 8 Gazarian M, Feldman BM, Benson LN, Gilday DL, Laxer RM, Silverman ED. Assessment of myocardial perfusion and function in childhood systemic lupus erythematosus. J Pediatr 1998; 132: 109–116. 9 Paradiso M, Gabrielli F, Masala C, et al. Evaluation of myocardial involvement in systemic lupus erythematosus by signal-averaged electrocardiography and echocardiography. Acta Cardiol 2001; 56: 381–386. Lupus
Downloaded from lup.sagepub.com at UNIV OF FLORIDA on February 16, 2015
Ventricular function in juvenile-onset SLE H-T Chung et al.
272 10 Gu¨nal N, Kara N, Akko¨k N, Cakar N, Kahramanyol O, Akalin N. Cardiac abnormalities in children with systemic lupus erythematosus. Turk J Pediatr 2003; 45: 301–305. 11 Chow PC, Ho MH, Lee TL, Lau YL, Cheung YF. Relation of arterial stiffness to left ventricular structure and function in adolescents and young adults with pediatric-onset systemic lupus erythematosus. J Rheumatol 2007; 34: 1345–1352. 12 Yip GW, Shang Q, Tam LS, et al. Disease chronicity and activity predict subclinical left ventricular systolic dysfunction in patients with systemic lupus erythematosus. Heart 2009; 95: 980–987. 13 Buss SJ, Wolf D, Korosoglou G, et al. Myocardial left ventricular dysfunction in patients with systemic lupus erythematosus: New insights from tissue Doppler and strain imaging. J Rheumatol 2010; 37: 79–86. 14 Crozier IG, Li E, Milne MJ, Nicholls MG. Cardiac involvement in systemic lupus erythematosus detected by echocardiography. Am J Cardiol 1990; 65: 1145–1148. 15 Fujimoto S, Kagoshima T, Nakajima T, Dohi K. Doppler echocardiographic assessment of left ventricular diastolic function in patients with systemic lupus erythematosus. Cardiology 1994; 85: 267–272. 16 Astorri E, Fiorina P, Ridolo E, Contini GA, Albertini D, Dall’Aglio P. Doppler echocardiographic study of left ventricular function in patients with systemic lupus erythematosus [article in Italian]. Cardiologia 1997; 42: 1179–1183. 17 Giunta A, Picillo U, Maione S, et al. Spectrum of cardiac involvement in systemic lupus erythematosus: Echocardiographic, echoDoppler observations and immunological investigation. Acta Cardiol 1993; 48: 183–197. 18 Wislowska M, Deren D, Kochmanski M, Sypula S, Rozbicka J. Systolic and diastolic heart function in SLE patients. Rheumatol Int 2009; 29: 1469–1476. 19 Brunner HI, Gladman DD, Iban˜ez D, Urowitz MD, Silverman ED. Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus. Arthritis Rheum 2008; 58: 556–562. 20 Levy DM, Kamphuis S. Systemic lupus erythematosus in children and adolescents. Pediatr Clin North Am 2012; 59: 345–364. 21 Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725. 22 Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: Results of a survey of echocardiographic measurements. Circulation 1978; 58: 1072–1083. 23 Teichholz LE, Kreulen T, Herman MV, Gorlin R. Problems in echocardiographic volume determinations: Echocardiographicangiographic correlations in the presence of absence of asynergy. Am J Cardiol 1976; 37: 7–11. 24 Ashley EA, Niebauer J. Cardiology explained. London: Remedica, 2004. p. 40. 25 Huang YL, Chung HT, Chang CJ, Yeh KW, Chen LC, Huang JL. Lymphopenia is a risk factor in the progression of carotid intimamedia thickness in juvenile-onset systemic lupus erythematosus. Arthritis Rheum 2009; 60: 3766–3775. 26 Ingegnoli F, Zeni S, Gerloni V, Fantini F. Capillaroscopic observations in childhood rheumatic diseases and healthy controls. Clin Exp Rheumatol 2005; 23: 905–911. 27 Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 1992; 35: 630–640. 28 Pan W. Akaike’s information criterion in generalized estimating equations. Biometrics 2001; 57: 120–125. 29 Huang JL, Yeh KW, Yao TC, et al. Pediatric lupus in Asia. Lupus 2010; 19: 1414–1418. 30 Kalke S, Balakrishanan C, Mangat G, Mittal G, Kumar N, Joshi VR. Echocardiography in systemic lupus erythematosus. Lupus 1998; 7: 540–544.
31 Enomoto K, Kaji Y, Mayumi T, et al. Left ventricular function in patients with stable systemic lupus erythematosus. Jpn Heart J 1991; 32: 445–453. 32 Cujec B, Sibley J, Haga M. Cardiac abnormalities in patients with systemic lupus erythematosus. Can J Cardiol 1991; 7: 343–349. 33 Winslow TM, Ossipov MA, Fazio GP, Foster E, Simonson JS, Schiller NB. The left ventricle in systemic lupus erythematosus: Initial observations and a five-year follow-up in a university medical center population. Am Heart J 1993; 125: 1117–1122. 34 Wranicz JK, Cygankiewicz I, Zielinska M, Woz´niacka A, SysaJedrzejowska A. Non-invasive cardiac evaluation in patients with systemic lupus erythematosus. J Med 2001; 32: 195–206. 35 Driazhenkova IV. The diastolic dysfunction of the left ventricle in patients with systemic lupus erythematosus and system scleroderma [article in Russian]. Klin Med (Mosk) 2005; 83: 45–47. 36 Murai K, Oku H, Takeuchi K, Kanayama Y, Inoue T, Takeda T. Alterations in myocardial systolic and diastolic function in patients with active systemic lupus erythematosus. Am Heart J 1987; 113: 966–971. 37 Schmitz L, Koch H, Bein G, Brockmeier K. Left ventricular diastolic function in infants, children, and adolescents. Reference values and analysis of morphologic and physiologic determinants of echocardiographic Doppler flow signals during growth and maturation. J Am Coll Cardiol 1998; 32: 1441–1448. 38 Faurschou M, Mellemkjaer L, Starklint H, et al. High risk of ischemic heart disease in patients with lupus nephritis. J Rheumatol 2011; 38: 2400–2405. 39 Sampson MJ, Chambers JB, Sprigings DC, Drury PL. Abnormal diastolic function in patients with type 1 diabetes and early nephropathy. Br Heart J 1990; 64: 266–271. 40 Liu JE, Robbins DC, Palmieri V, et al. Association of albuminuria with systolic and diastolic left ventricular dysfunction in type 2 diabetes: The Strong Heart Study. J Am Coll Cardiol 2003; 41: 2022–2028. 41 Martin FL, McKie PM, Cataliotti A, et al. Experimental mild renal insufficiency mediates early cardiac apoptosis, fibrosis, and diastolic dysfunction: A kidney-heart connection. Am J Physiol Regul Integr Comp Physiol 2012; 302: R292–R299. 42 Sta˘nescu C, Dan GA. Myocardial involvement in systemic lupus erythematosus and systemic sclerosis—pulsed Doppler echocardiographic evaluation of left ventricular diastolic function. Rom J Intern Med 1992; 30: 243–248. 43 Strauer BE, Brune I, Schenk H, Knoll D, Perings E. Lupus cardiomyopathy: Cardiac mechanics, hemodynamics, and coronary blood flow in uncomplicated systemic lupus erythematosus. Am Heart J 1976; 92: 715–722. 44 Riccieri V, Spadaro A, Ceccarelli F, Scrivo R, Germano V, Valesini G. Nailfold capillaroscopy changes in systemic lupus erythematosus: Correlations with disease activity and autoantibody profile. Lupus 2005; 14: 521–525. 45 Ingegnoli F. Capillaroscopy abnormalities in relation to disease activity in juvenile systemic lupus erythematosus. Microvasc Res 2013; 87: 92–94. 46 Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 2009; 22: 107–133. 47 Roldan CA, Alomari IB, Awad K, et al. Aortic stiffness is associated with left ventricular diastolic dysfunction in systemic lupus erythematosus: A controlled transesophageal echocardiographic study. Clin Cardiol 2014; 37: 83–90. 48 Teixeira AC, Bonfa E, Herskowictz N, Barbato AJ, Borba EF. Early detection of global and regional left ventricular diastolic dysfunction in systemic lupus erythematosus: the role of the echocardiography. Rev Bras Reumatol 2010; 50 1: 16–30. 49 Puntmann VO, D’Cruz D, Smith Z, Pastor A, Choong P, Voigt T et al. Native myocardial T1 mapping by cardiovascular magnetic resonance imaging in subclinical cardiomyopathy in patients with systemic lupus erythematosus. Circulation Cardiovascular imaging 2013; 6 2: 295–301.
Lupus Downloaded from lup.sagepub.com at UNIV OF FLORIDA on February 16, 2015
