Lupus (2015) 24, 613–620 http://lup.sagepub.com
PEDIATRIC LUPUS
Subclinical right ventricle systolic dysfunction in childhood-onset systemic lupus erythematosus: insights from two-dimensional speckle-tracking echocardiography GN Leal1, KF Silva1, CMP Franc¸a2, AC Lianza1, JL Andrade3, LMA Campos2, E Bonfa´4 and CA Silva2 1
Radiology Unit, Instituto da Crianc¸a, Hospital das Clı´ nicas da Faculdade de Medicina da Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil; 2 Pediatric Rheumatology Unit, Instituto da Crianc¸a, Hospital das Clı´ nicas da Faculdade de Medicina da Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil; 3Department of Radiology, Faculdade de Medicina da Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil; and 4Department of Rheumatology, Faculdade de Medicina da Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil
Objective: The objective of this article is to evaluate right ventricle strain imaging by two-dimensional speckle-tracking (2DST) in childhood-onset systemic lupus erythematosus (c-SLE). Methods: Thirty-five c-SLE patients with no signs or symptoms of heart failure and 33 healthy volunteers were evaluated by standard echocardiogram and 2DST. Conventional parameters included tricuspid annular plane systolic excursion (TAPSE), RV tissue-Dopplerderived Tei index and systolic pulmonary artery pressure. Global peak longitudinal systolic strain (PLSS) and strain rate (PLSSR) of RV were obtained by 2DST. Demographic/clinical features, SLEDAI-2K/SLICC/ACR-DI and treatment were also assessed. Results: The median current age was similar in patients and controls (14.75 vs. 14.88 years, p ¼ 0.62). RV PLSS was significantly reduced in c-SLE (24.5 5.09 vs. 27.62 3.02%, p ¼ 0.003). Similar findings were observed after excluding patients with pulmonary hypertension (24.62 4.87% vs. 27.62 3.02%, p ¼ 0.0041). RV PLSS was positively correlated with TAPSE (r ¼ þ0.49, p ¼ 0.0027) and negatively correlated with Tei index (r ¼ 0.34, p ¼ 0.04) in c-SLE. RV PLSSR was not different comparing patients and controls (0.65 s1 0.47 vs. 1.87 0.49 s1, p ¼ 0.07). Further analysis of c-SLE patients revealed higher frequencies of neuropsychiatric manifestations (39% vs. 0%, p ¼ 0.007) and antiphospholipid antibodies (55% vs. 18%, p ¼ 0.035) in those with RV PLSS 23.7% vs >23.7%. No differences were evidenced in demographic data, disease activity/damage or treatments (p > 0.05). Conclusions: The present study, using a new and more sensitive technique, revealed subclinical RV systolic dysfunction in c-SLE patients that may have future prognostic implications. The novel association of asymptomatic RV dysfunction with neuropsychiatric manifestations and antiphospholipid antibodies may suggest common physiopathological pathways. Lupus (2015) 24, 613–620. Key words: Childhood-onset systemic lupus erythematosus; right ventricle systolic function; speckle-tracking echocardiography; antiphospholipid antibodies; neuropsychiatric manifestations
Introduction Systemic lupus erythematosus (SLE) is a chronic and systemic autoimmune disorder that may compromise cardiovascular structures, including the right ventricle (RV).1 Although RV performance is an important determinant of prognosis in a Correspondence to: Clovis Artur Silva, Rua Araioses, 152/81, Vila Madalena, Sa˜o Paulo – SP, CEP 05442-010, Brazil. Email: [email protected] Received 24 September 2014; accepted 15 November 2014
variety of cardiovascular conditions2 and directly affects exercise tolerance in adult SLE patients,3 little is known about RV systolic function in childhood-onset systemic lupus erythematosus (c-SLE). Recent literature has documented not only improved survival over the past 15 years, but also more aggressive disease compared with adults. Detection of myocardial involvement in SLE is difficult, since it begins in a stealth mode with no symptoms or warning signs.4 Moreover, given that the RV is a complex, crescent-shaped structure, traditional echocardiographic methods that rely
! The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at OAKLAND UNIV on June 8, 2015
10.1177/0961203314563135
Right ventricle systolic dysfunction in c-SLE GN Leal et al.
614
on geometric model assumptions to estimate systolic function are often imprecise.5 The RV architecture comprises superficial oblique and deep longitudinal layers, but deformation of longitudinal myofibers provides the major contribution to stroke volume during systole.6 Two-dimensional speckle-tracking-derived strain (2DST) is an angle-independent method for echocardiographic assessment of that longitudinal myocardial deformation and was recently proven to have a better accuracy in detecting subtle RV dysfunction in children with congenital heart diseases.7 However, there are no data using this new diagnostic tool in the c-SLE population. The primary aim of this study was to evaluate RV strain imaging by 2DST in c-SLE patients and healthy controls, as well as to assess possible associations of RV subclinical dysfunction with demographic data, clinical manifestations, laboratory and treatment. A secondary aim was to investigate the correlation between RV systolic strain and conventional echocardiographic parameters of RV systolic function and left ventricle (LV) systolic strain.
Methods Study design and patients From September to October 2012, 48 consecutive c-SLE patients were initially selected at the Pediatric Rheumatology Unit of Hospital das Clı´ nicas da Faculdade de Medicina da Universidade de Sa˜o Paulo. All patients fulfilled the American College of Rheumatology (ACR) criteria for c-SLE.8 The exclusion criteria were the presence of heart failure, congenital heart diseases, moderate/severe pericardial effusion, history of infectious myocarditis or pulmonary obstructive diseases, poor-quality echocardiographic imaging and unwillingness to participate in the study. Five were excluded because of moderate/severe pericardial effusion, one because of heart failure and seven owing to unwillingness to participate. The control group included 35 healthy control volunteers recruited from primary care clinics using the same exclusion criteria, and two were discarded because of poor quality of echocardiographic imaging. Therefore, the crosssectional study was conducted in 35 c-SLE patients and 33 controls. The local ethics committee of our university hospital approved this study and written informed consent was obtained from all participants or legal guardians.
Standard and 2DST echocardiography were performed at study entry, blinded to disease parameters. Patient’s medical records were carefully reviewed for clinical, laboratorial and therapeutic data, by the attendant physician (CPF). Demographic information assessed included age at diagnosis, current age, disease duration and gender. Weight and height were obtained for each patient and control, in order to calculate body surface area (BSA) by Haycock formula.9 Standard echocardiography Patients and controls were evaluated by the same pediatric cardiologist (GNL). Standard transthoracic echocardiogram was performed according to the recommendations of the American Society of Echocardiography and included M-mode, twodimensional, conventional and tissue Doppler evaluation.10 The equipment used was a MyLab 60 echo machine (Esaote, Florence, Italy), with multi-frequency transducers (2.5–3.5 MHz and 5–7.5 MHz). Cardiac chamber dimensions were obtained using M-mode and LV and ejection fraction was calculated by Teichholz’s formula.11 All values obtained were indexed for BSA. LV mass was estimated using Devereaux’s formula according to Penn convention12 and indexed for height powered to 2.7. Pulmonary arterial hypertension was diagnosed whenever peak velocity of the tricuspid regurgitation jet was greater than 2.5 m/s. Tricuspid annular plane systolic excursion (TAPSE), systolic wave velocity (S) and Tei index were used to evaluate RV systolic function. TAPSE was measured in apical four-chamber view, using M-mode. S-wave velocity and Tei index of the RV were assessed by tissue-Doppler profile, obtained at the tricuspid annulus.13 2DST echocardiography The main principle of 2DST is that each segment of myocardial tissue displays a specific pattern of gray values in the ultrasound image, commonly referred to as a speckle pattern. Tracking this acoustic pattern during the cardiac cycle enables the observer to follow myocardial motion and to directly assess ventricular deformation.5 Two-dimensional harmonic image cine-loops recordings of RV focused on apical four-chamber views, with good-quality electrocardiogram signal and a frame rate between 60 and 80/s, were acquired and stored for off-line analysis. Off-line computer-based analyses of the exams stored on the Esaote MyLab 60 were performed using
Lupus Downloaded from lup.sagepub.com at OAKLAND UNIV on June 8, 2015
Right ventricle systolic dysfunction in c-SLE GN Leal et al.
615 TM
XStrain software (Esaote, Florence, Italy), installed on a WindowsTM-based computer workstation. For all individuals examined, three video clips containing three consecutive cardiac cycles each were digitally stored. The clip with best RV endocardial borders was chosen and processed as follows: The endocardial borders, drawn by the operator on an arbitrary single frame, were identified as a sequence of points. The automated software program calculated the frame-to-frame displacements of speckle pattern within the region of interest, throughout the cardiac cycle. Clips with one or more ventricular segments inadequately tracked owing to poor image quality were considered unsatisfactory and discarded. Only individuals with at least one satisfactory clip were included in the study.14 Longitudinal strain and strain rate curves were obtained for six RV segments: the basal, mid and apical segments of the septum and of the RV free wall. The extent of myocardial deformation, defined as the longitudinal systolic strain, was expressed as a percentage of the longitudinal shortening in systole compared with diastole, for each segment of interest. The systolic strain rate, defined as the rate of change in strain,15 was expressed as s–1. Global RV peak longitudinal systolic strain (PLSS) and strain rate (PLSSR) were calculated as the average of the regional values obtained. The computed values for PLSS and PLSSR corresponded to the average of the three consecutive cardiac cycles contained in the clip. Longitudinal strain and strain rate curves of the LV were obtained by repeating the same analysis. Intraobserver and interobserver reproducibility was tested concerning 2DST echocardiography. The first examiner (GNL) repeated analysis of 20 c-SLE patients and 20 healthy controls randomly selected, four months after having acquired images. A second observer (KFS), unaware of previous results, has also performed off-line analysis of the same individuals. Clinical, laboratory and treatment evaluation of c-SLE patients SLE clinical manifestations were defined as: cutaneous lesions (malar or discoid rash, oral ulcers or photosensitivity), articular involvement (non-erosive arthritis), serositis (pleuritis or pericarditis), nephritis (proteinuria 0.5 g/24 hours, presence of cellular casts, and/or persistent hematuria 10 red blood cells per high-power field), hematologic
abnormalities (hemolytic anemia, leukopenia with a white blood cell count
PEDIATRIC LUPUS
Subclinical right ventricle systolic dysfunction in childhood-onset systemic lupus erythematosus: insights from two-dimensional speckle-tracking echocardiography GN Leal1, KF Silva1, CMP Franc¸a2, AC Lianza1, JL Andrade3, LMA Campos2, E Bonfa´4 and CA Silva2 1
Radiology Unit, Instituto da Crianc¸a, Hospital das Clı´ nicas da Faculdade de Medicina da Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil; 2 Pediatric Rheumatology Unit, Instituto da Crianc¸a, Hospital das Clı´ nicas da Faculdade de Medicina da Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil; 3Department of Radiology, Faculdade de Medicina da Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil; and 4Department of Rheumatology, Faculdade de Medicina da Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil
Objective: The objective of this article is to evaluate right ventricle strain imaging by two-dimensional speckle-tracking (2DST) in childhood-onset systemic lupus erythematosus (c-SLE). Methods: Thirty-five c-SLE patients with no signs or symptoms of heart failure and 33 healthy volunteers were evaluated by standard echocardiogram and 2DST. Conventional parameters included tricuspid annular plane systolic excursion (TAPSE), RV tissue-Dopplerderived Tei index and systolic pulmonary artery pressure. Global peak longitudinal systolic strain (PLSS) and strain rate (PLSSR) of RV were obtained by 2DST. Demographic/clinical features, SLEDAI-2K/SLICC/ACR-DI and treatment were also assessed. Results: The median current age was similar in patients and controls (14.75 vs. 14.88 years, p ¼ 0.62). RV PLSS was significantly reduced in c-SLE (24.5 5.09 vs. 27.62 3.02%, p ¼ 0.003). Similar findings were observed after excluding patients with pulmonary hypertension (24.62 4.87% vs. 27.62 3.02%, p ¼ 0.0041). RV PLSS was positively correlated with TAPSE (r ¼ þ0.49, p ¼ 0.0027) and negatively correlated with Tei index (r ¼ 0.34, p ¼ 0.04) in c-SLE. RV PLSSR was not different comparing patients and controls (0.65 s1 0.47 vs. 1.87 0.49 s1, p ¼ 0.07). Further analysis of c-SLE patients revealed higher frequencies of neuropsychiatric manifestations (39% vs. 0%, p ¼ 0.007) and antiphospholipid antibodies (55% vs. 18%, p ¼ 0.035) in those with RV PLSS 23.7% vs >23.7%. No differences were evidenced in demographic data, disease activity/damage or treatments (p > 0.05). Conclusions: The present study, using a new and more sensitive technique, revealed subclinical RV systolic dysfunction in c-SLE patients that may have future prognostic implications. The novel association of asymptomatic RV dysfunction with neuropsychiatric manifestations and antiphospholipid antibodies may suggest common physiopathological pathways. Lupus (2015) 24, 613–620. Key words: Childhood-onset systemic lupus erythematosus; right ventricle systolic function; speckle-tracking echocardiography; antiphospholipid antibodies; neuropsychiatric manifestations
Introduction Systemic lupus erythematosus (SLE) is a chronic and systemic autoimmune disorder that may compromise cardiovascular structures, including the right ventricle (RV).1 Although RV performance is an important determinant of prognosis in a Correspondence to: Clovis Artur Silva, Rua Araioses, 152/81, Vila Madalena, Sa˜o Paulo – SP, CEP 05442-010, Brazil. Email: [email protected] Received 24 September 2014; accepted 15 November 2014
variety of cardiovascular conditions2 and directly affects exercise tolerance in adult SLE patients,3 little is known about RV systolic function in childhood-onset systemic lupus erythematosus (c-SLE). Recent literature has documented not only improved survival over the past 15 years, but also more aggressive disease compared with adults. Detection of myocardial involvement in SLE is difficult, since it begins in a stealth mode with no symptoms or warning signs.4 Moreover, given that the RV is a complex, crescent-shaped structure, traditional echocardiographic methods that rely
! The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at OAKLAND UNIV on June 8, 2015
10.1177/0961203314563135
Right ventricle systolic dysfunction in c-SLE GN Leal et al.
614
on geometric model assumptions to estimate systolic function are often imprecise.5 The RV architecture comprises superficial oblique and deep longitudinal layers, but deformation of longitudinal myofibers provides the major contribution to stroke volume during systole.6 Two-dimensional speckle-tracking-derived strain (2DST) is an angle-independent method for echocardiographic assessment of that longitudinal myocardial deformation and was recently proven to have a better accuracy in detecting subtle RV dysfunction in children with congenital heart diseases.7 However, there are no data using this new diagnostic tool in the c-SLE population. The primary aim of this study was to evaluate RV strain imaging by 2DST in c-SLE patients and healthy controls, as well as to assess possible associations of RV subclinical dysfunction with demographic data, clinical manifestations, laboratory and treatment. A secondary aim was to investigate the correlation between RV systolic strain and conventional echocardiographic parameters of RV systolic function and left ventricle (LV) systolic strain.
Methods Study design and patients From September to October 2012, 48 consecutive c-SLE patients were initially selected at the Pediatric Rheumatology Unit of Hospital das Clı´ nicas da Faculdade de Medicina da Universidade de Sa˜o Paulo. All patients fulfilled the American College of Rheumatology (ACR) criteria for c-SLE.8 The exclusion criteria were the presence of heart failure, congenital heart diseases, moderate/severe pericardial effusion, history of infectious myocarditis or pulmonary obstructive diseases, poor-quality echocardiographic imaging and unwillingness to participate in the study. Five were excluded because of moderate/severe pericardial effusion, one because of heart failure and seven owing to unwillingness to participate. The control group included 35 healthy control volunteers recruited from primary care clinics using the same exclusion criteria, and two were discarded because of poor quality of echocardiographic imaging. Therefore, the crosssectional study was conducted in 35 c-SLE patients and 33 controls. The local ethics committee of our university hospital approved this study and written informed consent was obtained from all participants or legal guardians.
Standard and 2DST echocardiography were performed at study entry, blinded to disease parameters. Patient’s medical records were carefully reviewed for clinical, laboratorial and therapeutic data, by the attendant physician (CPF). Demographic information assessed included age at diagnosis, current age, disease duration and gender. Weight and height were obtained for each patient and control, in order to calculate body surface area (BSA) by Haycock formula.9 Standard echocardiography Patients and controls were evaluated by the same pediatric cardiologist (GNL). Standard transthoracic echocardiogram was performed according to the recommendations of the American Society of Echocardiography and included M-mode, twodimensional, conventional and tissue Doppler evaluation.10 The equipment used was a MyLab 60 echo machine (Esaote, Florence, Italy), with multi-frequency transducers (2.5–3.5 MHz and 5–7.5 MHz). Cardiac chamber dimensions were obtained using M-mode and LV and ejection fraction was calculated by Teichholz’s formula.11 All values obtained were indexed for BSA. LV mass was estimated using Devereaux’s formula according to Penn convention12 and indexed for height powered to 2.7. Pulmonary arterial hypertension was diagnosed whenever peak velocity of the tricuspid regurgitation jet was greater than 2.5 m/s. Tricuspid annular plane systolic excursion (TAPSE), systolic wave velocity (S) and Tei index were used to evaluate RV systolic function. TAPSE was measured in apical four-chamber view, using M-mode. S-wave velocity and Tei index of the RV were assessed by tissue-Doppler profile, obtained at the tricuspid annulus.13 2DST echocardiography The main principle of 2DST is that each segment of myocardial tissue displays a specific pattern of gray values in the ultrasound image, commonly referred to as a speckle pattern. Tracking this acoustic pattern during the cardiac cycle enables the observer to follow myocardial motion and to directly assess ventricular deformation.5 Two-dimensional harmonic image cine-loops recordings of RV focused on apical four-chamber views, with good-quality electrocardiogram signal and a frame rate between 60 and 80/s, were acquired and stored for off-line analysis. Off-line computer-based analyses of the exams stored on the Esaote MyLab 60 were performed using
Lupus Downloaded from lup.sagepub.com at OAKLAND UNIV on June 8, 2015
Right ventricle systolic dysfunction in c-SLE GN Leal et al.
615 TM
XStrain software (Esaote, Florence, Italy), installed on a WindowsTM-based computer workstation. For all individuals examined, three video clips containing three consecutive cardiac cycles each were digitally stored. The clip with best RV endocardial borders was chosen and processed as follows: The endocardial borders, drawn by the operator on an arbitrary single frame, were identified as a sequence of points. The automated software program calculated the frame-to-frame displacements of speckle pattern within the region of interest, throughout the cardiac cycle. Clips with one or more ventricular segments inadequately tracked owing to poor image quality were considered unsatisfactory and discarded. Only individuals with at least one satisfactory clip were included in the study.14 Longitudinal strain and strain rate curves were obtained for six RV segments: the basal, mid and apical segments of the septum and of the RV free wall. The extent of myocardial deformation, defined as the longitudinal systolic strain, was expressed as a percentage of the longitudinal shortening in systole compared with diastole, for each segment of interest. The systolic strain rate, defined as the rate of change in strain,15 was expressed as s–1. Global RV peak longitudinal systolic strain (PLSS) and strain rate (PLSSR) were calculated as the average of the regional values obtained. The computed values for PLSS and PLSSR corresponded to the average of the three consecutive cardiac cycles contained in the clip. Longitudinal strain and strain rate curves of the LV were obtained by repeating the same analysis. Intraobserver and interobserver reproducibility was tested concerning 2DST echocardiography. The first examiner (GNL) repeated analysis of 20 c-SLE patients and 20 healthy controls randomly selected, four months after having acquired images. A second observer (KFS), unaware of previous results, has also performed off-line analysis of the same individuals. Clinical, laboratory and treatment evaluation of c-SLE patients SLE clinical manifestations were defined as: cutaneous lesions (malar or discoid rash, oral ulcers or photosensitivity), articular involvement (non-erosive arthritis), serositis (pleuritis or pericarditis), nephritis (proteinuria 0.5 g/24 hours, presence of cellular casts, and/or persistent hematuria 10 red blood cells per high-power field), hematologic
abnormalities (hemolytic anemia, leukopenia with a white blood cell count
