The Egyptian Rheumatologist (2015) 37, S33–S41

HO ST E D BYEgyptian Society of Rheumatic Diseases

The Egyptian Rheumatologist

www.rheumatology.eg.netwww.elsevier.com/locate/ejr

ORIGINAL ARTICLE

Assessment of left ventricular function in systemic

lupus erythematosus patients by speckle tracking

echocardiography: Relation to circulating

endothelial progenitor cells

* Corresponding author at: 10th El-Hekma Street, El-Mariottiah,

Haram, Egypt. Tel.: +20 237624776, mobile: +20 1223616821.

E-mail address: mohamedelbasel@yahoo.com (M. El Basel).

Peer review under responsibility of Egyptian Society of Rheumatic

Diseases.

http://dx.doi.org/10.1016/j.ejr.2015.05.0021110-1164 � 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of Egyptian Society of Rheumatic Diseases.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Sameh W.G. Bakhoum a, Mohamed El Basel b,*, Alshaimaa R. Alnaggar b,

Mona S. Hamdyc, Hanan Hussein

d

a Cardiology Department, Faculty of Medicine, Cairo University, Egyptb Internal Medicine Department, Faculty of Medicine, Cairo University, Egyptc Clinical Pathology Department, Faculty of Medicine, Cairo University, Egyptd Rheumatology Department, Faculty of Medicine, Cairo University, Egypt

Received 5 May 2015; accepted 15 May 2015Available online 10 June 2015

KEYWORDS

Systemic lupus

erythematosus;

Endothelial progenitor cells;

Left ventricular function;

Speckle tracking

echocardiography

Abstract Background: Systemic lupus erythematosus is an autoimmune disease associated with

reduced number and impaired function of endothelial progenitor cells (EPCs) responsible for

vascular regeneration.

Aim of the work: to assess left ventricular (LV) function of SLE patients using relatively new

speckle tracking echocardiography (STE) and examine the relation of any detected abnormalities

with peripheral circulating EPC level.

Patients and methods: Fifty SLE patients and 25 healthy controls were subjected to quantifica-

tion of peripheral circulating Cluster of differentiation133+/vascular endothelial growth factor

receptor2+(CD133+/VEGFR2+) and CD34+/VEGFR2+ EPCs, transthoracic echocardiography

(TTE), tissue Doppler imaging (TDI) and STE.

Results: Patients showed a significantly lower CD133+/VEGFR2+ EPCs (p= 0.009) and

CD34+/VEGFR2+ EPC counts (p= 0.0001) compared to controls. TTE/TDI revealed a signifi-

cantly lower LV ejection fraction (EF) (p= 0.007), higher LV end systolic dimensions

(p= 0.02), myocardial performance index (MPI) (p= 0.0001) and mitral flow E/lateral annulus

E0 ratio (p= 0.002) in patients compared to controls. STE showed a significantly lower global

longitudinal strain (GLS) (p< 0.001), global circumferential strain (GCS) (p< 0.001) and global

S34 S.W.G. Bakhoum et al.

strain rate during isovolumic relaxation period (GSRivr) (p= 0.01) in patients compared to con-

trols. By multiple logistic regression analysis, the independent variables affecting GCS and

GSRivr were the prednisolone dose and the LVEF respectively. (95% CI = �0.46 to �0.03;p= 0.03 and 95% CI = 0.001–0.01; p= 0.021; respectively). There was no significant correlation

of the GLS, GCS or GSRivr with the EPCs.

Conclusion: STE detected subclinical systolic and diastolic abnormalities of LV function in SLE

patients. These abnormalities of LV function did not show however any relation with the signifi-

cantly lower EPC count detected in patients.

� 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of Egyptian Society of Rheumatic

Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/

licenses/by-nc-nd/4.0/).

1. Introduction

Systemic lupus erythematosus (SLE) is an autoimmune diseaseassociated with markedly increased atherosclerotic cardiovas-cular risk [1]. Young women with lupus are over 50 times morelikely to have a myocardial infarction compared to a

population-based sample of women of similar age [2].Endothelial dysfunction was found to significantly contributeto this accelerated atherosclerotic process, independently of

other classic risk factors of coronary artery disease (CAD) inSLE patients [3].

Anti-endothelial cell antibodies have been detected in

autoimmune diseases and were found to induce endothelial cell(EC) apoptosis [4,5]. Endothelial progenitor cells (EPCs) rep-resent a heterogeneous group of cells released from the bone

marrow into the circulation and are thought to contribute tovascular homeostasis and endothelial repair [6,7]. A study byEbner et al. [8], demonstrated that circulating mature EPCs(CD34+/VEGFR2+) in the peripheral blood of SLE patients

are reduced in number, together with increased apoptosis,impaired differentiation and a reduced migratory capacity.The diminished number and the altered functionality of these

mature EPCs reduce the ability to repair vascular damage.The number of EPCs was also found to be reduced, in heartfailure (HF) irrespective of its etiology [9]. Several abnormali-

ties of left ventricular (LV) systolic and diastolic function andincreased LV mass have been described in SLE patients[10–12]. Whether the inherent endothelial dysfunction andthe abnormalities of EPC mobilization in SLE contribute to

this LV dysfunction is uncertain.Speckle tracking echocardiography (STE) is a relatively

new technique that provides accurate quantitative evaluation

of regional and global LV function independent of the insona-tion angle and cardiac translational movements [13]. Theobjective of this study was to detect subclinical LV dysfunction

in SLE patients without clinically evident cardiovascular (CV)disease using STE and correlate possible LV function abnor-malities to circulating EPC count.

2. Patients and methods

In this prospective cross sectional study, a total of 50 SLE

patients out of 75 patients screened for the inclusion and exclu-sion criteria were recruited from the outpatient clinic or theinpatient section of the Internal Medicine and Rheumatologyand Rehabilitation Departments of Kasr Al-Ainy Cairo

University Hospitals. They were enrolled in the study between

July and September 2013. Inclusion criteria were patientsbetween 20 and 65 years of age with a diagnosis of SLE who

fulfilled at least 4 of the updated revised criteria of theAmerican College of Rheumatology for SLE diagnosis [14].Exclusion criteria were patients with hypertension defined as

a systolic blood pressure (BP)P 140 mmHg or diastolicBPP90 mmHg or on antihypertensive medication, diabetesmellitus defined as a fasting blood glucose P126 mg/dl or 2-

h post-load glucose P200 mg/dl [15], history of smoking, orsignificant valvular heart disease. Twenty-five healthy ageand gender matched subjects served as controls. The researchprotocol was approved by the ethics committee of Cairo

University Hospital. The study was conducted in accordancewith the Declaration of Helsinki. Written, informed consentwas obtained from each patient.

The disease activity was assessed using the SLE diseaseactivity index (SLEDAI) scoring system [16]. Information con-cerning disease duration and medications used was recorded.

A blood sample was collected from all patients and controlsfor EPC count estimation in addition to routine laboratoryworkup including complete blood count, high sensitivity C-

reactive protein (HsCRP) estimated by ELISA, erythrocytesedimentation rate (ESR), renal function tests, total choles-terol and triglyceride levels, fasting blood glucose, anti-nuclear antibodies (ANA), and anti-double stranded deoxyri-

bonucleic acid antibodies (Anti ds-DNA).

2.1. EPC identification and counting by flow cytometry (FC)analysis

Phycoerythrin (PE)-labeled monoclonal anti-CD34 & anti-CD133 (Cat. No. 130-081-002; Miltenyi Biotec, Germany),

fluorescein-labeled monoclonal anti-VEGFR2/KDR (Cat.No. FAB357F; R&D/UK) were used for the characterizationof circulating EPCs. Isotype and fluorochrome-matched con-

trol antibodies (Abs) (Mouse IgG1-FITC and IgG1-PE) wereused for setting fluorescence markers around negative popula-tion and detecting non-antigen specific antibody binding.EDTA venous blood collected from patients and controls

and kept at room temperature was analyzed within 24 h ofvenipuncture. For red blood cell lysis, peripheral blood sam-ples were diluted in 15 ml bicarbonate-buffered ammonium

chloride solution for 15 min at room temperature. The cellswere centrifuged and re-suspended in 2 ml FC staining buffer(Cat. No. FC001; R&D/UK). The number of cells was

adjusted to 1 · 106 cells/ml. The cells were then prepared intothree test tubes, containing 100 ll of cell suspension each,

Left ventricular function in systemic lupus erythematosus patients S35

together with 10 ll FcR blocking reagent (to prevent non-specific binding) and 10 ll 7-AAD (to exclude dead cells fromFC analysis). The first tube contained as well VEGFR2-

Fluorescein and CD133/1-PE monoclonal Abs; the secondtube contained as well VEGFR2-Fluorescein and CD34-PEmonoclonal Abs while the third tube contained as well 10 llof the matched isotypic control. Positive staining was definedas being greater than non-specific background staining. Allsamples were measured in duplicate. The lymphocyte fraction

was identified on a forward/side scatter, and a minimum of1 · 105 lymphocytes were counted. Cells positive forVEGFR2/CD133 were characterized as early EPCs, whereascells positive for VEGFR2/CD34 within the lymphocyte frac-

tion were characterized as mature EPCs. Results wereexpressed as the number of EPCs per 1 · 106 lymphocytes.

3. Echocardiography

3.1. Transthoracic echocardiography (TTE) and tissue Dopplerimaging (TDI)

TTE and TDI were performed to all patients and controls

using a commercially available echocardiography machine(ESAOTE MY LAB 60) equipped with broadbandS1-5 MHz transducer in the Cardiology Department of Kasr

Al-Ainy Cairo University Hospitals. After a 10-min rest, sub-jects were examined in the left lateral decubitus position toobtain adequate images in different standard views. Left atrial,

aortic diastolic, LV end-diastolic dimensions (LVEDD), andLV end-systolic dimensions (LVESD) were measured usingM-mode echocardiography. Left ventricular ejection fraction(LVEF) was obtained by the biplane Simpson’s method.

Trans-mitral pulsed wave Doppler velocities were recordedfrom the apical four-chamber (4-CH) view.

Early (E) and late (A) wave peak velocities, E/A ratio, E

deceleration time (E-DT) were measured. By placing theDoppler sample volume midway between the mitral inflowand aortic outflow tract, trans-mitral and trans-aortic

Doppler flows were recorded simultaneously. The ejectiontime (ET), isovolumic contraction time (ICT) and isovolumicrelaxation time (IVRT) were measured and myocardialperformance index (MPI) was calculated as the ratio:

IVRT + IVCT/ET. The myocardial systolic (S), early diastolic(E0), and late diastolic (A0) peak velocities were obtained at thelateral and septal corners of the mitral annulus in the

4-chamber (4-CH) view by pulsed wave tissue Doppler keepingthe angle between the beam and the wall motion direction<15�. The E/lateral annulus E0 (E/E0) ratio was subsequently

calculated. All the above measures were recorded as the aver-age of three consecutive cycles.

3.2. Speckle tracking echocardiography (STE)

Myocardial deformation measurements were obtained usingSTE. The analysis was performed on grayscale images ofthe LV obtained in the apical 4-CH, 2-chamber (2-CH)

and short-axis mid-ventricular views. Three consecutiveend-expiratory cardiac cycles using high frame rate >80 s�1

harmonic imaging in each echocardiographic view were

acquired. Data were analyzed off-line using dedicated software(ESAOTE MY LAB 60) on one cardiac cycle. The analysis is

initiated by defining manually in the apical views three endo-cardial landmarks at the lateral and medial corners of themitral annulus and the LV cardiac apex and in the mid ventric-

ular short axis views two landmarks at the inferior septum andthe lateral wall. Manual adjustment of the segments of interestwas performed when necessary. Thereafter, the software auto-

matically analyzed different segments of interest. From theapical 4-CH view, longitudinal strain was assessed throughbasal, mid apical septal, basal, mid and apical lateral wall seg-

ments. From the apical 2-CH view, longitudinal strain wasassessed through basal, mid, apical inferior, basal, mid, andapical anterior wall segments. The global longitudinal strain(GLS) was calculated as the average of the LS of the 12

myocardial segments of the 4-CH and 2-CH views. From theshort axis view at the level of the papillary muscles, the circum-ferential strain was assessed through the mid-segments of the

anteroseptal, anterior, anterolateral, inferolateral, inferior,and inferoseptal walls. The global circumferential strain(GCS) was calculated as the average of the CS of the 6 mid

myocardial segments of the ventricular short axis view. Theglobal longitudinal systolic strain rate (GSSR), global diastolicstrain rate during the IVR period (GSRivr), early diastole

(GSRe) and late diastole (GSRa) were calculated as the averageof the SR of the 12 myocardial segments of the 4-CH and the2-CH views.

Statistical analysis: Normally distributed continuous

variables were expressed as mean ± SD while continuousvariables with non-normal distribution were presented as med-ian values and interquartile range (IQR). Categorical data

were expressed as percentages. Differences between groupswere assessed by unpaired 2-tailed t test and the Mann–Whitney U test for continuous variables, according to whether

they were normally distributed or not. Categorical data andproportions were analyzed by the use of chi-square orFisher’s exact test when required. Pearson and Spearman’s

correlation were used to assess the correlation between differ-ent variables. Univariate and multivariate linear regressionanalyses were used to investigate possible associations betweenSTE LV deformation abnormalities and other studied vari-

ables. A significance level of p < 0.05 was used in all tests.All statistical procedures were carried out using SPSS version15 for Windows (SPSS Inc., Chicago, IL, USA).

4. Results

A total of 50 SLE patients were included in the study; 47

females and 3 males. The median disease duration was4.5 years with an IQR of 2–7.25 years. The mean SLEDAIscore was 5.9 ± 5.75 (range: 0–20). All patients were receiving

prednisolone with a median duration of 54 months (IQR: 24–96 months). The median prednisolone dose was 7.5 mg (IQR:5–15 mg). Twenty-five subjects with comparable age and gen-der were included. Patients had a significantly higher ESR

(p< 0.001), HsCRP (p = 0.005), total serum cholesterol(p= 0.001), serum triglycerides (p = 0.001) and alaninetransaminase (p= 0.01) compared to the control. The com-

parison of the demographic and laboratory data between thepatients and controls is shown in Table 1.

The CD133+/VEGFR2+ and CD34+/VEGFR2+ EPC

counts were significantly lower in patients compared to controls(p= 0.009 and p = 0.0001, respectively). No significant

Table 1 Demographic and laboratory data of systemic lupus

erythematosus patients and controls.

Variable Patients

(n = 50)

Controls

(n = 25)

p value

Demographic

Age (years) 28.5 ± 8.5 30.2 ± 10.2 0.45

Female/male 47/3 23/2 1

BMI 26.5 ± 2.3 24.7 ± 1.9 0.001

Laboratory

ESR (mm/h) 72.5 (35–110) 16 (11–24) <0.001

Hs CRP (mg/dl) 0.7 (0.31–1.52) 0.35 (0.23–0.79) 0.005

Hb (gm/dl) 10.3 ± 1.3 13.2 ± 1.5 0.001

WBCs (·103/mm3) 7 ± 3.8 7 ± 2.4 0.9

Platelets (·103/mm3) 234.7 ± 118.3 244.5 ± 105.9 0.7

Creatinine (mg/dl) 1 ± 0.4 0.9 ± 0.3 0.1

Albumin (g/dl) 3.7 ± 0.5 3.9 ± 0.9 0.09

Cholesterol (mg/dl) 210.1 ± 74.5 169.6 ± 26.7 0.001

Triglycerides (mg/dl) 163.2 ± 67.6 93.2 ± 21.6 0.001

AST (IU/l) 21.5 ± 7 19.2 ± 5.8 0.1

ALT (IU/l) 20.3 ± 6.1 16.5 ± 5.4 0.01

EPC (cells/106Ly)

CD133+/

VEGFR2+5 (3–12) 109 (3–429) 0.009

CD34+/VEGFR2+ 3.5 (2–9) 63 (5–104) 0.0001

BMI: body mass index; ESR: erythrocyte sedimentation rate; Hs

CRP: high sensitivity C-reactive protein; Hb: hemoglobin; WBC:

white blood cells; AST: aspartate transaminase; ALT: alanine

transaminase; VEGFR: vascular endothelial growth factor recep-

tor; EPCs: endothelial progenitor cells. Ly: lymphocytes. Results

are presented as mean ± SD or as median (Interquartile range).

Bold figures mean significant p value.

Table 2 Transthoracic Echocardiography (TTE) and tissue

Doppler imaging (TDI) data for the systemic lupus erythe-

matosus patients and controls.

TTE

measurements

Patients

(n= 50)

Controls

(n= 25)

p

value

LVSWT (mm) 8.1 ± 1.8 7.9 ± 1.6 0.6

LVEDD (mm) 49.6 ± 6.4 47.3 ± 5.4 0.1

LVPWT (mm) 7.8 ± 1.5 7.7 ± 1.3 0.8

LVESD (mm) 33.0 ± 6.1 29.6 ± 5.6 0.02

EF (%) 64.0 ± 6.7 68.8 ± 7.7 0.007

Ao (mm) 25.2 ± 2.9 24.6 ± 2.9 0.4

LA (mm) 33.6 ± 5.5 31.3 ± 4.3 0.08

Transmitral velocity

E wave (cm/s) 90 ± 20 80 ± 20 0.1

A wave (cm/s) 80 ± 20 60 ± 10 0.002

E/A ratio 1.3 ± 0.4 1.4 ± 0.4 0.2

E-DT (ms) 179.3 ± 37.8 170.4 ± 41.3 0.4

IVRT (ms) 75.7 ± 13.4 58.6 ± 6.1 0.01

MPI 0.62 ± 0.12 0.49 ± 0.05 0.0001

Tissue Doppler imaging

Med E0 (cm/s) 8.7 ± 2.9 11.4 ± 4 0.002

Med A0 (cm/s) 6.2 ± 2.5 5.3 ± 1.7 0.07

Med S0 (cm/s) 7.5 ± 1.6 7.5 ± 2.1 0.9

Lat E0 (cm/s) 9.0 ± 4.0 11.7 ± 3.4 0.01

Lat A0 (cm/s) 7.0 ± 3.8 6.4 ± 1.8 0.3

Lat S0 (cm/s) 8.3 ± 1.6 8.8 ± 2.2 0.4

Lat E/E0 11.1 ± 5 7.6 ± 2.2 0.002

TEE: Transthoracic Echocardiography; LVSWT: left ventricular

septal wall thickness; LVEDD: left ventricular end diastolic

dimension; LV PWT: left ventricular posterior wall thickness;

LVESD: left ventricular end systolic dimension; EF: ejection frac-

tion; Ao: aorta; LA: left atrium; MPI: myocardial performance

index; E-DT: E wave deceleration time; Lat: lateral; Med: medial;

IVRT: isovolumic relaxation time. Bold values mean significant p

value.

S36 S.W.G. Bakhoum et al.

correlation was detected between CD133+/VEGFR2+ or

CD34+/VEGFR2+ EPC count and age of patients (r = 0.21,p= 0.2 and r = 0.13; p= 0.4 respectively), disease duration(r = �0.08, p= 0.6 and r= �0.01; p = 1 respectively), pred-

nisolone dose (r= 0.02, p= 0.9 and r = 0.04; p = 0.8 respec-tively), prednisolone duration (r = �0.05, p = 0.7 andr= �0.03; p= 0.9 respectively), SLEDAI score (r = �0.19,p= 0.2 and r= �0.23; p = 0.1 respectively), BMI (r = 0.03,

p= 0.8 and r= 0.001; p = 1 respectively), Hs CRP(r = 0.26, p= 0.06 and r= 0.27; p = 0.06 respectively) orESR (r= 0.17, p = 0.3 and r= 0.26; p = 0.07 respectively).

4.1. Echocardiographic data

4.1.1. M-mode, two-dimensional Doppler measurements

The LVESD was significantly greater (p= 0.02) while theLVEF was significantly lower in patients (p= 0.007) com-

pared to controls. Trans-mitral flow A wave velocity was sig-nificantly higher (p = 0.002) and the IVRT significantlyprolonged (p= 0.01) in patients compared to controls. TheMPI was also significantly higher in patients (p = 0.0001).

4.1.2. Tissue Doppler imaging (TDI) measurements

The medial and lateral mitral annulus E0 wave velocities were

significantly lower in patients compared to controls (p = 0.002and p = 0.01, respectively). The lateral E/lateral E0 ratio wassignificantly higher in patients compared to controls

(p = 0.002). The detailed TTE and TDI measurements of thepatients and controls are shown in Table 2.

4.1.3. Speckle tracking echocardiography (STE) measurements

The GLS and GCS were significantly lower in patients com-pared to controls (p < 0.001 in both) (Fig. 1). The GSRivrwas significantly lower in patients compared to controls

(p = 0.01). The detailed STE measurements of patients andcontrols are listed in Table 3. Univariate logistic regressionwas used to investigate possible associations between the

GLS, GCS, GSRivr and the following variables: age ofpatients, duration of disease, prednisolone dose, prednisoloneintake duration, use of azathioprine vs. cyclophosphamide,

SLEDAI score, MPI, LVEF, CD133+/VEGFR2+ EPC countand CD34+/VEGFR2+ EPC count. There was no significantcorrelation between any of the studied variables and GLS

either by univariate or multivariate analysis. Using univariateanalysis, there was no significant correlation between studiedvariables and GCS except for prednisolone dose. After adjust-ment for all variables using multiple logistic regression model,

prednisolone dose remained the only independent variableaffecting GCS (adjusted regression coefficient = �0.24, 95%CI = �0.46 to �0.03; p = 0.03). As regards GSRivr, LVEF

was the only variable affecting it by both univariate andmultivariate logistic regression analyses (adjusted regression

Figure 1 Automatically generated left ventricular (LV) deformation curves by the software (my lab60). (A) LV circumferential strain in

the short axis view at the level of papillary muscles. (B) LV longitudinal strain in the four–chamber view. (C) LV longitudinal strain in the

two–chamber view. (D) LV strain rate in the two–chamber view. The curves in white represent the average (global) strain or strain rates of

different studied LV segments.

Left ventricular function in systemic lupus erythematosus patients S37

coefficient = 2.4, 95% CI = 0.001–0.01; p= 0.021). Thedetailed multivariate linear regression analysis of the different

factors affecting GLS, GCS and GSRivr is shown in Table 4.

5. Discussion

The current study demonstrated significantly reducedCD133+/VEGFR2+and CD34+/VEGFR2+ EPC count inSLE patients compared to controls. Experimental and clinical

studies have demonstrated the important role of EPCs in tissueregeneration including neoangiogenesis, reendothelialization,repair of injured arteries and improvement of LV function fol-lowing myocardial infarction [6,17–21]. The current study find-

ing of low EPCs in SLE patients is in agreement with theresults of several other studies. Denny et al. [22] reported a sig-nificant decrease of CD34+/CD133+ EPCs and myelomono-

cytic circulating angiogenic cells (CACs) and a significantcorrelation of EPC count with SLEDAI score but not withthe use of specific medications or daily corticosteroid doses.

However, even those individuals with no clinical or serologicdisease activity (SLEDAI = 0) had pronounced EPC decreasecompared with controls. Lee et al. [23] demonstrated a mark-

edly reduced level of EPC colony-forming units and the deple-tion of EPCs was more dramatic in SLE patients with elevatedlevels of IFN-I. The reduced EPC levels were not explained byuse of common medications including steroids, anti-malarials,

cytotoxic agents, or statins.In our study, we could not find any significant correlation

between EPC count and disease duration, SLEDAI score, pred-

nisolone dose or duration of intake, HsCRP or ESR. Thereduction of EPCs was even reported in SLE patients in an

inactive stage of disease, or in prolonged clinical remission[24,25]. Ebner et al. [8] reported an enhanced

VEGFR2+/CD133+ EPC number whereas the number ofVEGFR2+/CD34+ cells and the proliferation rate were signif-icantly decreased. In the current study, the levels of immature

VEGFR2+/CD133+ and mature VEGFR2+/CD34+ cellswere reduced. The decrease in the number of circulatingEPCs was also described in other diseases with vascular inflam-

matory components, for example, rheumatoid arthritis andchronic renal failure [26,27]. The low levels of circulatingEPCs in our study could be attributed to increased oxidativestress related to the inflammatory process associated with

SLE and which was shown to inhibit EPC differentiation,survival, and function [28]. An alternative explanation is thatcontinuous endothelial damage or dysfunction leads to an even-

tual depletion or exhaustion of a presumed finite supply of EPCsinvolved in vascular homeostasis and endothelial repair. SLEhas been shown to be an independent risk factor for endothelial

dysfunction [3]. In a recent study of 38 lupus women withoutdetectable myocardial ischemia on myocardial perfusion imag-ing, brachial artery flow mediated vasodilatation as a markerof endothelial function correlated strongly with E/E0 as a marker

of LV diastolic function independent of systolic blood pressure,age, or lupus clinical damage index [29].

The second important finding of the current study is the

echocardiographic abnormalities of both systolic and diastolicfunction in SLE patients with no clinically apparent CV dis-ease. Echocardiographic cardiac abnormalities were described

more than 3 decades ago in SLE [30–32]. To the best of ourknowledge, this the first study to investigate the correlationbetween LV deformation abnormalities as detected by STE

Table 3 Speckle tracking echocardiography (STE) data for the systemic lupus erythematosus patients and controls.

STE data Patients (n= 50) Control (n= 25) p value

4-Chamber view longitudinal strain (%)

Basal septal 14.3 ± 5.5 16.6 ± 2.6 0.01

Mid septal 16.2 ± 4.3 18.7 ± 2.3 0.002

Apical septal 18.3 ± 6.3 20.3 ± 3.7 0.2

Basal lateral 14.9 ± 3.7 19.8 ± 4.8 <0.001

Mid lateral 14.8 ± 3.8 19.1 ± 3.8 <0.001

Apical lateral 19.9 ± 26.7 18.2 ± 2.8 0.8

2-Chamber view longitudinal strain (%)

Basal inferior 11.1 ± 5.8 19.6 ± 4.3 <0.001

Mid inferior 13.5 ± 4.2 18.6 ± 2.9 <0.001

Apical inferior 14.9 ± 5.4 19.7 ± 4.1 <0.001

Basal anterior 13.2 ± 5.9 21.0 ± 5.2 <0.001

Mid anterior 13.1 ± 4.9 19.2 ± 5.0 <0.001

Apical anterior 12.7 ± 5.2 17.1 ± 4.1 <0.001

GLS (%) 14.5 ± 2.8 19.0 ± 1.3 <0.001

SAX view circumferential strain (%)

Mid anteroseptal 23.6 ± 11.0 30.3 ± 11.7 0.02

Mid anterior 20.5 ± 11.5 29.6 ± 11.5 0.002

Mid anterolateral 16.5 ± 7.4 24.6 ± 9.2 <0.001

Mid inferolateral 16.2 ± 6.0 22.7 ± 6.9 <0.001

Mid inferior 17.8 ± 6.5 24.3 ± 8.1 <0.001

Mid inferoseptal 21.0 ± 7.7 25.6 ± 9.1 0.04

GCS (%) 19.3 ± 6.8 26.2 ± 6.9 <0.001

GSR longitudinal systolic (1/s) 1.0 ± 0.2 1.1 ± 0.2 0.2

GSR longitudinal diastolic (1/s)

GSRivr 0.14 ± 0.09 0.2 ± 0.1 0.01

GSRe 1.2 ± 0.3 1.3 ± 0.2 0.1

GSRa 0.8 ± 0.3 0.7 ± 0.2 0.2

STE: speckle tracking echocardiography; SAX: GLS: global longitudinal strain; GCS: global circumferential strain; GSR: global strain rate; ivr:

isovolumic relaxation period; GSRe: global strain rate during early diastole; GSRa: global strain rate during atrial contraction; SAX: short axis.

Bold values mean significant p value.

Table 4 Factors affecting global longitudinal strain (GLS), global circumferential strain (GCS) and global strain rate (GSR) during

isovolumic relaxation period.

Variables GLS GCS GSRivr

ARC (95% CI) p ARC (95% CI) p ARC (95% CI) p

Age 0.07 (�0.06 to �0.19) 0.3 0.09 (�0.2 to �0.4) 0.5 1.1 (�0.002 to �0.01) 0.3

Disease duration 0.3 (�1.18 to �0.19) 0.7 0.68 (�2.6 to �4) 0.7 �0.1 (�0.05 to �0.05) 0.9

Steroid dose �0.007 (�0.10 to �0.09) 0.9 �0.24 (�0.5 to �0.03) 0.03 0.1 (�0.003 to �0.003) 0.9

Steroid duration �0.09 (�1.52 to �1.34) 0.9 �1.01 (�4.4 to �2.2) 0.5 0.5 (�0.04 to �0.06) 0.6

AZA/CYC 2.5 (�0.49 to �5.48) 0.1 1.63 (�5.2 to �8.4) 0.6 1.7 (�0.02 to �0.19) 0.09

SLEDAI score �0.04 (�0.2 to �0.12) 0.7 0.03 (�0.3 to �0.4) 0.9 �0.6 (�0.01 to �0.004) 0.6

MPI 1.4 (�5.64 to �7.51) 0.7 13.6 (�2.5 to �29.7) 0.1 1.3 (0.001 to 0.01) 0.2

LVEF �0.08 (�0.22 to �0.05) 0.2 0.08 (�0.2 to �0.4) 0.6 2.4 (0.001 to 0.01) 0.02

EPCs

VEGFR2+/CD133+ 0.002 (�0.01 to �0.02) 0.8 �0.01 (�0.04 to �0.02) 0.5 0.7 (0.00001 to 0.001) 0.5

VEGFR2+/CD34+ �0.006 (�0.06 to �0.05) 0.82 0.01 (�0.12 to �0.14) 0.9 �1.01 (�0.003 to �0.001) 0.3

GLS: global longitudinal strain; GCS: global circumferential strain; GSRivr: global strain rate during isovolumic relaxation period; ARC:

adjusted regression coefficient; CI: confidence interval; AZA/CYC: azathioprine/cyclophosphamide; SLEDAI: systemic lupus erythematosus

disease activity index; MPI: myocardial performance index; LVEF: left ventricular ejection fraction; EPCs: endothelial progenitor cells. Bold

values mean significant p value.

S38 S.W.G. Bakhoum et al.

and EPC count in the peripheral circulation of SLE patients.As regards conventional TTE and TDI findings, SLE patients

in the present study had a significantly higher LVESD com-pared to controls (p = 0.02). Although the LVEF of the

patients was in the normal range, it was significantly lowercompared to controls (p = 0.007) suggesting subclinical sys-

tolic dysfunction. The IVRT was significantly prolonged andthe MPI was significantly higher in patients compared to

Left ventricular function in systemic lupus erythematosus patients S39

controls denoting diastolic dysfunction as well. In agreementwith our results, a significantly lower LVEF was reported inSLE patients compared to controls (p< 0.001) in a study of

50 SLE patients. A significantly higher interventricular septum(IVS) and posterior wall (PW) dimensions, and Doppler mitralA/E ratio in patients compared to controls have been demon-

strated [33]. In our study, there was no statistically significantdifference in IVS, PW dimensions or trans-mitral flow DopplerE/A ratio between the patients and controls. A study compar-

ing patients with SLE to those with antiphospholipidsyndrome (APS), lupus patients had higher LVEDD andLVESD (p= 0.022 and 0.022, respectively), with a trendtoward a lower fractional shortening (p = 0.07) compared to

primary APS [10]. Cacciapuoti et al. [34] used TDI to calculateIVRT and MPI in 44 SLE patients without clinical signs ofheart disease, and found as well significantly higher IVRT

and MPI in patients compared to controls. The current studyalso demonstrated a significantly higher E/lateral E0 ratio inpatients compared to controls (p = 0.002) pointing again to

diastolic dysfunction. Similarly, Lee et al. [35] reported ahigher E/E0 in SLE patients compared to controls despite anormal Doppler flow E/A ratio (p < 0.01) This study also

described a lower E/E0 ratio and higher LVEF in SLE patientsreceiving angiotensin converting enzyme inhibitors (ACE-Is)or angiotensin receptor blockers (ARBs) compared to thosenot receiving these medications indicating their role in preserv-

ing LV diastolic and systolic functions. None of our patientswere receiving ACE-Is or ARBs because we excluded SLEhypertensive patients and the patients included were free of

clinically manifest CV disease.As regards STE findings, the current study revealed a signif-

icantly lower LV GLS (p< 0.001), LV GCS (p< 0.001) and

GSRivr (p= 0.01) in patients compared to controls. Therewas no significant correlation between any of the studied vari-ables and GLS. By multiple logistic regression analysis, the

independent variables affecting GCS and GSRivr were theprednisolone dose and the LVEF respectively. (p = 0.028and p = 0.021; respectively). These findings were in agreementwith some aspects of the study by Buss et al. [36] who used

TDI to calculate LV strain and strain rates in 67 young SLEpatients. This study not only demonstrated significantlyreduced GLS; a finding similar to our study but also detected

significantly reduced GSSR, GSRe, GSRa in patients com-pared to controls. Further, elevated SLEDAI score, resultedin significantly lower values for LV longitudinal function strain

and strain rate. In the current study, we could not find any sta-tistically significant difference in GSSR, GSRe, GSRa betweenpatients and controls. In a recent study using three-dimensional (3D) STE, although no difference in LV global

systolic function was noted by standard echocardiographybetween patients and controls, 3D LVEF, LV GLS, LVGCS,LV global area stain (GAS) and global radial strain (GRS)

were largely impaired in patients [37]. This study demonstratedalso that GLS, GAS, GRS but not GCS were significantlydecreased in those with severe disease activity than among

those with no or mild activity (all p< 0.05). GLS was alsoindependently correlated with SLEDAI score (p= 0.001).Yip et al. [12] showed that SLEDAI P1 was an independent

predictor of LV longitudinal systolic dysfunction in SLEpatients using TDI. In the present study, no correlation wasdetected between SLEDAI score and the different myocardialdeformation parameters. The lack of a significant correlation

between SLEDAI score and evident LV diastolic dysfunctionin SLE patients has been described before in previous studies[38,39]. In the present study, these LV subclinical abnormali-

ties cannot be explained by increased prevalence of traditionalCV risk factors such as smoking, HTN or DM becausepatients having them were excluded. The patients had however

significantly higher cholesterol and triglyceride levels com-pared to controls. This may be the result of prednisolonewhich was prescribed to all patients. It is generally perceived

that glucocorticoids have adverse effect on the lipid profilecausing increase in both total cholesterol and triglycerides[40,41]. This high level of cholesterol and triglycerides mayhave induced subclinical coronary atherosclerosis in our

patients. A high prevalence of myocardial perfusion abnormal-ities were detected in asymptomatic SLE patients without overtCV disease using single photon emission computed tomogra-

phy [42,43]. In a study by Doria et al. [44], subclinicalatherosclerosis has been shown to be more prevalent in SLEpatients. Patients with carotid abnormalities were significantly

older, had higher blood pressure and total serum cholesterollevels, and had taken a higher prednisone cumulative dosagethan those without any lesions. By multivariate analysis, the

cumulative prednisone dose remained associated with plaqueformation after adjusting it for the classical Framinghamatherosclerosis risk predictors. A significant associationbetween carotid plaque formation in SLE patients and cumu-

lative corticosteroid dosage as well as duration of treatmenthas been also reported by Manzi et al. [45]. In another studyon Egyptian SLE patients, an increased prevalence of subclin-

ical LV dysfunction was reported. SLE patients with positivetissue Doppler findings were of old age, had long disease dura-tion, high disease activity and nephritis [46]. In the current

study, the prednisolone dose was the only independent variableadversely affecting LV GCS (p= 0.028). In a study of diabeticpatients, those with coronary atherosclerosis as evidenced by

increased calcium score in multi-slice computerized tomogra-phy scanner showed an impaired LV GLS, even though theLVEF was still preserved compared to those with no evidenceof coronary atherosclerosis [47]. Hence, premature subclinical

atherosclerosis may be the underlying cause of these subtlechanges in LV function.

When we designed the current study, we hypothesized that

EPCs might have a relation to any possible detected systolic ordiastolic LV function abnormalities in SLE patients. Thesespeculations were based on the findings of previous studies

correlating EPC count to LV remodeling and function[9,21,48,49]. Peripheral blood CD34+ cells and EPC mobiliza-tion occurs in heart failure (HF) and shows a biphasicresponse, with elevation and depression in the early and

advanced phases, respectively [48]. In a study by Kissel et al.[9], the number of EPCs was found to be reduced, irrespectiveof the etiology of HF, whether ischemic or dilated cardiomy-

opathy. On the other hand, in a study by Leone et al. [49],the concentration of CD34+ bone marrow derived stem cellswas not only higher in acute myocardial infarction (AMI)

patients compared to patients with stable CAD but was alsoan independent predictor of global and regional improvementof LV function at the end of 1 year follow-up. In the

TOPCARE-AMI trial, intracoronary infusion of circulatingEPCs in patients with AMI resulted in an increased EF,reduced infarct size, and absence of reactive hypertrophy, sug-gesting functional regeneration of the infarcted ventricles at

S40 S.W.G. Bakhoum et al.

the end of 1 year follow-up. In the current study, the inabilityto detect a statistically significant correlation between the EPCcount and LV deformation abnormalities could be attributed

to their detection in a quite early stage using STE or becauseof the small number of patients studied.

The first limitation is the cross sectional design of the study.

The patients were not followed up to be able to examine theprogression of LV systolic and diastolic abnormalities detectedby STE or the effect of the low circulating EPCs on these

abnormalities over time. The second limitation is the relativelysmall number of patients. This can be explained by the rigor-ous exclusion criteria. We actually excluded patients with clas-sical risk factors such as smoking, HTN or DM which were

quite prevalent in lupus patients to avoid the impact of thesefactors on LV function.

In conclusion the relatively new STE can be used to diag-

nose subtle abnormalities in LV function in SLE patientswhich could not be detected by conventional TTE or TDI.The low count of circulating EPCs detected in these patients

was probably the result of the inflammatory process associatedwith SLE rather than early LV dysfunction which could onlybe detected by STE.

Conflict of interest

None.

References

[1] Urowitz MB, Bookman AA, Koehler BE, Gordon DA, Smythe

HA, Ogryzlo MA. The bimodal mortality pattern of systemic

lupus erythematosus. Am J Med 1976;60:221–5.

[2] Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger Jr TA,

Jansen-McWilliams L, et al. Age-specific incidence rates of

myocardial infarction and angina in women with systemic lupus

erythematosus: comparison with the Framingham Study. Am J

Epidemiol 1997;145:408–15.

[3] El-Magadmi M, Bodill H, Ahmad Y, Durrington PN, Mackness

M, Walker M, et al. Systemic lupus erythematosus: an indepen-

dent risk factor for endothelial dysfunction in women. Circulation

2004;110:399–404.

[4] Salojin KV, le Tonqueze M, Saraux A, Nassonov EL, Dueymes

M, Piette JC, et al. Antiendothelial cell antibodies: useful markers

of systemic sclerosis. Am J Med 1997;102:178–85.

[5] Jamin C, Dugue C, Alard JE, Jousse S, Saraux A, Guillevin L,

et al. Induction of endothelial cell apoptosis by the binding of

anti-endothelial cell antibodies to Hsp60 in vasculitis-associated

systemic autoimmune diseases. Arthritis Rheum 2005;52:4028–38.

[6] Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li

T, et al. Isolation of putative progenitor endothelial cells for

angiogenesis. Science 1997;275:964–7.

[7] Gehling UM, Ergun S, Schumacher U, Wagener C, Pantel K, Otte

M, et al. In vitro differentiation of endothelial cells from AC133-

positive progenitor cells. Blood 2000;95:3106–12.

[8] Ebner P, Picard F, Richter J, Darrelmann E, Schneider M, Strauer

BE, et al. Accumulation of VEGFR-2+/CD133+ cells and

decreased number and impaired functionality of CD34+/VEGFR-

2+ cells in patients with SLE. Rheumatology 2010;49:63–72.

[9] Kissel CK, Lehmann R, Assmus B, Aicher A, Honold J, Fischer-

Rasokat U, et al. Selective functional exhaustion of hematopoi-

etic progenitor cells in the bone marrow of patients with

postinfarction heart failure. J Am Coll Cardiol 2007;49:2341–9.

[10] Paran D, Caspi D, Levartovsky D, Elkayam O, Kaufman I,

Litinsky I, et al. Cardiac dysfunction in patients with systemic

lupus erythematosus and antiphospholipid syndrome. Ann

Rheum Dis 2007;66:506–10.

[11] Pieretti J, Roman MJ, Devereux RB, Lockshin MD, Crow MK,

Paget SA, et al. Systemic lupus erythematosus predicts increased

left ventricular mass. Circulation 2007;116:419–26.

[12] Yip G, Shang Q, Tam L, Zhang Q, Li EK, Fung JW, et al.

Disease chronicity and activity predict subclinical left ventricular

systolic dysfunction in patients with systemic lupus erythemato-

sus. Heart 2009;95:980–7.

[13] Geyer H, Caracciolo G, Abe H, Wilansky S, Carerj S, Gentile F,

et al. Assessment of myocardial mechanics using speckle tracking

echocardiography: fundamentals and clinical applications. J Am

Soc Echocardiogr 2010;23:351–69.

[14] Hochberg MC. Updating the American College of Rheumatology

revised criteria for the classification of systemic lupus erythe-

matosus. Arthritis Rheum 1997;40:1725.

[15] American Diabetes Association. Diagnosis and classification of

diabetes mellitus. Diabetes Care 2008;31:S55–60.

[16] Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH,

et al. Derivation of the SLEDAI: a disease activity index for

lupus patients. The Committee on Prognosis Studies in SLE.

Arthritis Rheum 1992;35:630–40.

[17] Werner N, Junk S, Laufs U, Link A, Walenta K, Bohm M, et al.

Intravenous Transfusion of endothelial progenitor cells reduces

neointima formation after vascular injury. Circ Res

2003;93:e17–24.

[18] Kong D, Melo LG, Gnecchi M, Zhang L, Mostoslavsky G, Liew

CC, et al. Cytokine-induced mobilization of circulating endothe-

lial progenitor cells enhances repair of injured arteries. Circulation

2004;110(14):2039–46.

[19] Burt RK, Testori A, Oyama Y, Rodriguez HE, Yaung K, Villa M,

et al. Autologous peripheral blood CD133+ cell implantation for

limb salvage in patients with critical limb ischemia. Bone Marrow

Transplant 2010;45:111–6.

[20] Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg

RV, et al. Repair of infarcted myocardium by autologous

intracoronary mononuclear bone marrow cell transplantation in

humans. Circulation 2002;106:1913–8.

[21] Schachinger V, Assmus B, Britten MB, Honold J, Lehmann R,

Teupe C, et al. Transplantation of progenitor cells and regener-

ation enhancement in acute myocardial Infarction. Final one-year

results of the TOPCARE-AMI Trial. J Am Coll Cardiol

2004;44:1690–9.

[22] Denny MF, Thacker S, Mehta H, Somers EC, Dodick T, Barrat

FJ, et al. Interferon-a promotes abnormal vasculogenesis in

lupus: a potential pathway for premature atherosclerosis. Blood

2007;110:2907–15.

[23] Lee PY, Li Y, Richards HB, Chan FS, Zhuang H, Narain S, et al.

Type I interferon as a novel risk factor for endothelial progenitor

cell depletion and endothelial dysfunction in systemic lupus

erythematosus. Arthritis Rheum 2007;56:3759–69.

[24] Moonen JR, De Leeuw K, Van Seijen XJ, Kallenberg CG, van

Luyn MJ, Bijl M, et al. Reduced number and impaired function

of circulating progenitor cells in patients with systemic lupus

erythematosus. Arthritis Res Ther 2007;9:R84.

[25] Westerweel PE, Luijten RK, Hoefer IE, Koomans HA, Derksen

RH, Verhaar MC. Haematopoietic and endothelial progenitor

cells are deficient in quiescent systemic lupus erythematosus. Ann

Rheum Dis 2007;66:865–70.

[26] Herbrig K, Haensel S, Oelschlaegel U, Pistrosch F, Foerster S,

Passauer J. Endothelial dysfunction in patients with rheumatoid

arthritis is associated with a reduced number and impaired

function of endothelial progenitor cells. Ann Rheum Dis

2006;65:157–63.

[27] Choi JH, Kim KL, Huh W, Kim B, Byun J, Suh W, et al.

Decreased number and impaired angiogenic function of endothe-

lial progenitor cells in patients with chronic renal failure.

Arterioscler Thromb Vasc Biol 2004;24:1246–52.

Left ventricular function in systemic lupus erythematosus patients S41

[28] Zhang Y, Herbert BS, Rajashekhar G, Ingram DA, Yoder MC,

Clauss M, et al. Premature senescence of highly proliferative

endothelial progenitor cells is induced by tumor necrosis factor-

alpha via the p38 mitogen activated protein kinase pathway.

FASEB J 2009;23:1358–65.

[29] Chin CW, Chin CY, Ng MX, Le TT, Huang FQ, Fong KY, et al.

Endothelial function is associated with myocardial diastolic

function in women with systemic lupus erythematosus.

Rheumatol Int 2014;34:1281–5.

[30] Klinkhoff AV, Thompson CR, Reid GD, Tomlinson CW. M-

mode and two-dimensional echocardiographic abnormalities in

systemic lupus erythematosus. JAMA 1985;253:3273–7.

[31] Doherty NE, Feldman G, Maurer G, Siegel RJ.

Echocardiographic findings in systemic lupus erythematosus.

Am J Cardiol 1988;61:1144.

[32] Cervera R, Font J, Pare C, Azqueta M, Perez-Villa F, Lopez-Soto

A, et al. Cardiac disease in systemic lupus erythematosus:

prospective study of 70 patients. Ann Rheum Dis 1992;51:156–9.

[33] Crozier IG, Li E, Milne MJ, Nicholls MG. Cardiac involvement

in systemic lupus erythematosus detected by echocardiography.

Am J Cardiol 1990;65:1145–8.

[34] Cacciapuoti F, Galzerano D, Capogrosso P, Arciello A, Liberti

D, Cacciapuoti F, et al. Impairment of left ventricular function in

systemic lupus erythematosus evaluated by measuring myocardial

performance index with tissue Doppler echocardiography.

Echocardiography 2005;22:315–9.

[35] Lee SW, Park MC, Park YB, Lee SK. E/E0 ratio is more sensitive

than E/A ratio for detection of left ventricular diastolic dysfunc-

tion in systemic lupus erythematosus. Lupus 2008;17:195–201.

[36] Buss SJ, Wolf D, Korosoglou G, Max R, Weiss CS, Fischer C,

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.

[37] Huang BT, Yao HM, Huang H. Left ventricular remodeling and

dysfunction in systemic lupus erythematosus: a three dimensional

speckle tracking study. Echocardiography 2014;31:1085–94.

[38] Kalke S, Balakrishanan C, Mangat G, Mittal G, Kumar N, Joshi

VR. Echocardiography in systemic lupus erythematosus. Lupus

1998;7:540–4.

[39] Wislowska M, Deren D, Kochmanski M, Sypua S, Rozbicka J.

Systolic and diastolic heart function in SLE patients. Rheumatol

Int 2009;29:1469–76.

[40] Zimmerman J, Fainaru M, Eisenberg S. The effects of prednisone

therapy on plasma lipoproteins and apolipoproteins: a prospective

study. Metabolism 1984;33:521–6.

[41] Ettinger WH, Klinefelter HF, Kwiterovitch PO. Effect of short-

term, low-dose corticosteroids on plasma lipoprotein lipids.

Atherosclerosis 1987;63:167–72.

[42] Bruce IN, Burns RJ, Gladman DD, Urowitz MB. Single photon

emission computed tomography dual isotope myocardial perfu-

sion imaging in women with systemic lupus erythematosus. I.

Prevalence and distribution of abnormalities. J Rheumatol

2000;27:2372–7.

[43] Schillaci O, Lagana B, Danieli R, Gentile R, Tubani L, Baratta L,

et al. Technetium-99m sestamibi single-photon emission tomog-

raphy detects subclinical myocardial perfusion abnormalities in

patients with systemic lupus erythematosus. Eur J Nucl Med

1999;26:713–7.

[44] Doria A, Shoenfeld Y, Wu R, Gambari PF, Puato M, Ghirardello

A, et al. Risk factors for subclinical atherosclerosis in a prospec-

tive cohort of patients with systemic lupus erythematosus. Ann

Rheum Dis 2003;62:1071–7.

[45] Manzi S, Selzer F, Sutton-Tyrrel K, Fitzgerald SG, Rairie JE,

Tracy RP, et al. Prevalence and risk factors of carotid plaque in

women with systemic lupus erythematosus. Arthritis Rheum

1999;42:51–60.

[46] Allam NT, Darweesh HEA, Hamadnallah N, Ashour ZA.

Evaluation of left ventricular myocardial function in Egyptian

patients with systemic lupus erythematosus: tissue Doppler study

and its relation to disease activity. Egypt Rheumatol

2013;35(4):217–23.

[47] Scholte AJ, Nucifora G, Delgado V, Djaberi R, Boogers MJ,

Schuijf JD, et al. Subclinical left ventricular dysfunction and

coronary atherosclerosis in asymptomatic patients with type 2

diabetes. Eur J Echocardiogr 2011;12:148–55.

[48] Valgimigli M, Rigolin GM, Fucili A, Porta MD,

Soukhomovskaia O, Malagutti P, et al. CD34+ and endothelial

progenitor cells in patients with various degrees of congestive

heart failure. Circulation 2004;110:1209–12.

[49] Leone AM, Rutella S, Bonanno G, Abbate A, Rebuzzi AG,

Giovannini S, et al. Mobilization of bone marrow-derived stem

cells after myocardial infarction and left ventricular function. Eur

Heart J 2005;26:1196–204.