Departments of 1Child Health and 2Haematology, Sultan Qaboos University Hospital, Muscat, Oman *Corresponding Author e-mail: alsineidiksk@hotmail.com أدلة على وجود اختالل مبكر يف وظيفة القلب االنبساطية باستخدام ختطيط القلب عند األطفال املصابني مبرض تكون العظم الناقص خلفان �سامل ال�سنيدي، عرفان اهلل، ها�سم جواد، مرت�سى اخلابوري، �سيف اليعربي abstract: Objectives: Structural and functional cardiovascular abnormalities have been reported in adults with osteogenesis imperfecta (OI); however, there is a lack of paediatric literature on this topic. This study aimed to investigate cardiovascular abnormalities in children with OI in comparison to a control group. Methods: This case-control study was conducted at the Sultan Qaboos University Hospital in Muscat, Oman, between May 2013 and August 2014. Data from eight patients with OI and 24 healthy controls were compared using conventional and tissue Doppler echocardiography (TDE). Results: The OI group had significantly lower peak early mitral valve flow velocity (P = 0.027), peak a-wave reversal in the pulmonary vein (P = 0.030) and peak early diastolic velocity of the mitral valve and upper septum (P = 0.001 each). The peak late diastolic velocities of the mitral valve (P = 0.002) and the upper septum (P = 0.037) were significantly higher in the OI group; however, the peak early/late diastolic velocity ratios of the mitral valve (P = 0.002) and upper septum (P = 0.001) were significantly lower. Left ventricular dimensions and aortic and pulmonary artery diameters were larger in the OI group when indexed for body surface area. Both groups had normal systolic cardiac function. Conclusion: Children with OI had normal systolic cardiac function. However, changes in myocardial tissue Doppler velocities were suggestive of early diastolic cardiac dysfunction. They also had increased left ventricular dimensions and greater vessel diameters. These findings indicate the need for early and detailed structural and functional echocardiographic assessment and follow-up of young patients with OI. Keywords: Children; Osteogenesis Imperfecta; Cardiovascular Abnormalities; Doppler Echocardiography. امللخ�ص: الهدف: اأظهرت الدرا�سات العلمية وجود اختاللت تكوينية ووظيفية يف القلب والأوعية الدموية يف البالغني الذين يعانون من مر�ض تكون العظم الناق�ض )OI( اإل اأن هناك نق�ض يف الدرا�سات املتعلقة بهذا املر�ض عند الأطفال. الطريقة: هدفت هذه الدرا�سة اإىل التحقق من مدى وجود اختاللت يف القلب والأوعية الدموية لدى الأطفال امل�سابني بهذا املر�ض باملقارنة مع جمموعة املراقبة. الطريقة: اأجريت هذه الدرا�سة يف م�ست�سفى جامعة ال�سلطان قابو�ض يف م�سقط، عمان، بني مايو 2013 واأغ�سط�ض 2014 حيث متت مقارنة بيانات اأ�سعة �سدى القلب التكوينية والوظيفية بني 8 مر�سى م�سابني مبر�ض تكون العظم الناق�ض و 24 حالة من جمموعة املراقبة ال�سليمة. النتائج: بينت الدرا�سة اأن مر�سى تكون العظم الناق�ض لديهم قيا�سات اأقل بكثري من جمموعة املقارنة لذروة �رسعة التدفق املبكر لل�سمام التاجي )P = 0.027( وذروة موجة الرتاجع يف الوريد الرئوي )P = 0.030( وذروة ال�رسعة النب�ساطية املبكرة لل�سمام التاجي واحلاجز العلوي )P = 0.001 لكل منهما(. وكانت ذروة ال�رسعة النب�ساطية املتاأخرة لل�سمام التاجي )P = 0.002( واحلاجز العلوي )P = 0.037( اأعلى بكثري يف جمموعة مر�سى تكون العظم )P = 0.001( واحلاجز العلوي )P = 0.002( الناق�ض؛ ومع ذلك، فاإن ن�سبة الذروة يف ال�رسعة النب�ساطية املبكرة/املتاأخرة لل�سمام التاجي كانت اأقل من جمموعة املقارنة بكثري. اأي�سا كانت اأبعاد البطني الأي�رس واأقطار ال�رسيان الأبهر و الرئوي اأكرب يف جمموعة مر�سى تكون العظم الناق�ض عندما مت فهر�ستها مل�ساحة �سطح اجل�سم. وبينت الدرا�سة كذلك اأن وظيفة القلب النقبا�سية لكال الفريقني ذات معدل طبيعي. اخلال�صة: بينت الدرا�سة اأن وظيفة القلب النقبا�سية لدى الأطفال امل�سابني مبر�ض تكون العظم الناق�ض ذات معدل طبيعي اإل اأنه توجد تغريات ب�سيطة توحي بوجود خلل اأّويل يف وظائف القلب النب�ساطية. كما اأنها بينت عن وجود زيادة اأبعاد البطني الأي�رس وكذلك كرب حجم الأوعية الدموية الرئي�سية. هذه النتائج ت�سري اإىل احلاجة اإىل التقييم املبكر واملتابعة امل�ستمرة للمر�سى ال�سغار امل�سابني مبر�ض تكون العظم الناق�ض بتخطيط �سدى القلب الوظيفي. مفتاح الكلمات: الأطفال؛ مر�ض تكون العظم الناق�ض؛ ت�سوهات القلب والأوعية الدموية؛ دوبلر �سدى القلب. Echocardiographic Evidence of Early Diastolic Dysfunction in Asymptomatic Children with Osteogenesis Imperfecta *Khalfan S. Al-Senaidi,1 Irfan Ullah,1 Hashim Javad,1 Murtadha Al-Khabori,2 Saif Al-Yaarubi1 Advances in Knowledge - This study highlights for the first time early changes in the myocardial tissue Doppler velocities of a group of children with osteogenesis imperfecta (OI). These changes suggest the early development of diastolic cardiac dysfunction and preservation of systolic cardiac function in young patients with this genetic disorder. Application to Patient Care - Cardiovascular assessment of children with OI provides important additional information to support management of this disease. clinical & basic research Sultan Qaboos University Med J, November 2015, Vol. 15, Iss. 4, pp. e456–462, Epub. 23 Nov 15 Submitted 3 Jan 15 Revisions Req. 9 Apr & 5 May 15; Revisions Recd. 22 Apr & 19 May 15 Accepted 28 May 15 doi: 10.18295/squmj.2015.15.04.003 Khalfan S. Al-Senaidi, Irfan Ullah, Hashim Javad, Murtadha Al-Khabori and Saif Al-Yaarubi Clinical and Basic Research | e457 Previously, physicians focused primarily on skeletal malformation and structural and systolic cardiac function; however, with the availability of non-invasive echocardiographic tests, this focus can be extended to diastolic function. - Early and newer therapeutic modalities could help treat or modify the progression of OI. This could prevent further deterioration of cardiac function. Early intervention is essential considering the tendency for this group of patients to be limited in their activities and in sports when they reach adulthood. Osteogenesis imperfecta (oi) is a group of autosomal disorders of the connective tissues and is commonly caused by mutations in genes encoding the α-1 and α-2 chains of type 1 collagen or proteins involved in the post- translational modification of type 1 collagen.1 OI is characterised by various skeletal and extraskeletal manifestations.2 The disease has considerable clinical and biochemical heterogeneity between and within different patients. Common clinical manifestations of this disease are well-known and include blue sclera, brittle bones, conductive hearing defects and dental abnormalities.2 Tissue Doppler echocardiography (TDE) offers a non-invasive quantitative method of assessing longi- tudinal systolic and diastolic ventricular performance by measuring velocities directly from the myocar- dium.3–5 While a few studies have described cardio- vascular involvement among adults with OI, there is very little data available for paediatric patients.6,7 To the best of the authors’ knowledge, this is the first study assessing cardiovascular abnormalities, particularly systolic and diastolic function, in paediatric patients with OI using both conventional and TDE techniques. Methods This case-control study was conducted at the Sultan Qaboos University Hospital (SQUH) in Muscat, Oman, between May 2013 and August 2014. All patients diagnosed with OI and followed-up at SQUH during the study period were enrolled in the study. The diagnosis of OI was based on the classification developed by Sillence et al.8 Age- and gender-matched healthy children were included in the study as the control group. The selected controls were either healthy volunteers or had been referred to the clinic because of heart murmurs which were later found to be innocent. A detailed medical history was recorded for each subject, including any existing comorbidities. Anthropometric and physical examinations were performed and heart rates were measured for all participants. Routine complete blood count tests, 12-lead electrocardiography, two-dimensional Doppler echocardiography and pulse TDE were performed on all of the subjects during routine visits to the hospital. Blood pressure was measured in the right arm with an age-appropriate cuff size. Systolic and diastolic cardiac function was assessed using conventional and TDE techniques. Two- dimensional echocardiography was performed using an ultrasound echocardiography machine (Vivid E9, GE Vingmed Ultrasound AS, Horten, Norway) while the subjects were at rest. Motion (M)-mode, two- dimensional Doppler echocardiography and pulse TDE data were collected by a qualified echocardiographer. The subjects were fully awake during the procedure according to the recommendations of the American Society of Echocardiography.9 The left ventricular end systolic (LVISd) and diastolic (LVIDd) dimensions, as well as the septal (IVSd) and left ventricular posterior wall thickness in diastole (LVPWd) were assessed using M-mode from the parasternal long axis view. Subsequently, the shortening fraction (SF) and ejection fraction (EF) were determined.9 Using the left parasternal long axis view, the aortic annulus (AoAn), sinus of Valsalva (SinVals), sinotubular junction (Sintubj) and ascending aorta (AscAo) diameters were measured. From the parasternal high short axis view, diameter measurements of the pulmonary valve annulus (PVAn), main pulmonary artery (MPA) and left (LPA) and right (RPA) pulmonary arteries were taken. The early (Em) and late (Am) peak velocities of the mitral valve inflow, deceleration time of the Em wave (DTm) and Am wave duration were measured from the four chamber view with placement of the pulse Doppler sample volume at the tips of the valve leaflets. Isovolumic relaxation time (IVRT) was measured by placing the continuous Doppler sample volume in the left ventricular outflow tract in the three chamber view. Assessment of the right upper pulmonary vein pulse Doppler pattern was taken from a four chamber view to measure the systolic (Spv), diastolic (Dpv) and a-wave reversal peak velocity (Apv) and duration (Apvd). The Spv/Dpv ratio and the mitral valve inflow late velocity duration and a-wave duration ratio of the pulmonary veins (Amd/Apvd) were obtained. TDE was performed by placing the sample volume at the corner of the mitral annulus, the upper part of the interventricular septum and the corner of the tricuspid valve in the four chamber view. In each region, the systolic (S’) wave, early diastolic (E’) and late diastolic (A’) velocities were recorded and the Echocardiographic Evidence of Early Diastolic Dysfunction in Asymptomatic Children with Osteogenesis Imperfecta e458 | SQU Medical Journal, November 2015, Volume 15, Issue 4 Em/peak early diastolic velocity of the mitral valve (E’m) ratio was obtained. Global systolic myocardial function was evaluated by EF and SF using M-mode in addition to the peak systolic velocities (S’) of the TDE. In the early stages of diastolic dysfunction, impaired relaxation and passive filling of the left ventricle predominates, resulting in a low Em and E’m, high Am and peak late diastolic velocity of the mitral valve (A’m) and low Em/Am and E’m/A’m ratios.10 Another reliable indicator of diastolic dysfunction is a high Em/E’m ratio, which is an estimate of the filling pressure of the left ventricle.11 Assessment of pulmonary hypertension was performed by measuring the maximum velocity of the tricuspid valve regurgitation jet, if present, as well as the pulmonary valve regurgitation peak velocity. The Z score was calculated for AoAn, SinVals, Sintubj, PVAn, MPA, RPA, LPA and left ventricular dimensions.12 All measurements reported in this study represent the average value of at least three cardiac cycles per subject. Statistical analysis of the data was performed using the Statistical Package for the Social Sciences (SPSS), Version 20.0 (IBM Corp., Chicago, Illinois, USA). All results were expressed as means ± standard deviation. The independent Student’s t-test and Mann-Whitney U test were used when appropriate. A multivariate linear regression was used to find the impact of baseline differences between the two groups, including the diagnosis of OI. Differences were considered statistically significant at P <0.050. This study was approved by the Medical Research & Ethics Committee of the College of Medicine & Health Sciences at Sultan Qaboos University (MREC #672). Informed written consent was obtained from the parents or caregivers of all subjects before inclusion in the study. Results A total of eight OI patients with a mean age of 7.3 ± 4.3 years were diagnosed and followed-up at SQUH during the study period. The male-to-female ratio was 3:5. Seven of these patients had OI type Ш while one had OI type IV. A total of 24 controls with a mean age of 6.9 ± 2.5 years were also included. The male-to-female ratio was 11:13. Both groups were proportionately similar in age and gender; however, there were significant differences in their height, weight and body surface area (BSA) [Table 1]. All of the OI patients had fractures and had been receiving pamidronate infusions every three months as part of their disease management plans. There was no evidence of systemic disease and none of the patients were taking other medications. The OI subjects were asymptomatic from a cardiac point of view and none had mitral or aortic valve regurgitation. None of the OI subjects had systemic hypertension and they were all in sinus rhythm. There was no electrocardiographic evidence of Wolff-Parkinson-White syndrome among any of the patients. Standard two-dimensional echocardiography mea- surements and Z scores for both groups are reported in Table 2. Left ventricle and left atrium dimensions, aortic and pulmonary artery diameters and left ventricular systolic function data were not statistically significant between the two groups. However, when the left ventricular dimensions, aortic and pulmonary artery diameters were corrected for BSA, there was a statistically significant difference between the two groups. None of the subjects who had mild tricuspid valve regurgitation showed evidence of pulmonary hypertension (18.6 ± 1.4 mmHg [n = 7] versus 17.4 ± 2.7 mmHg [n = 22]; P = 0.278) and the other subjects did not have echocardiographic evidence of elevated right ventricular pressure from assessment of the septal curvature and pulmonary valve regurgitation jet. Corrected IVRT for heart rate was comparable between the OI and control group (88.1 ± 17.4 ms versus 79.5 ± 11.9 ms; P = 0.125). Calculations of the Z score revealed that there was a statistically significant difference between the OI and the control group regarding aortic and pulmonary artery diameters. Regarding the left ventricular dimensions, the OI group had a larger Z score for the IVSd and LVPWd, but no significant difference was observed for the LVISd and LVIDd Z scores. None of the control subjects had a Z score of >2. Other conventional and TDE assessment data are summarised in Table 3. There was a statistically significant decrease in the Em velocity for the OI group compared to the controls (84.8 ± 23.4 cm/s versus 103.4 ± 18.4 cm/s; P = 0.027). However, the Am and DTm measurements and Em/Am ratio were similar. A significant difference was observed in the TDE measurements of the lateral mitral valve and upper septum but with a comparable Em/E’m ratio and peak systolic velocity at all the measured sites. TDE measurements at the lateral tricuspid valve were similar between the two groups. Right upper pulmonary vein Doppler velocities and duration showed no statistically significant difference between the two groups with respect to Spv and Dpv peak velocities. However, a significant difference was observed for the Spv/Dpv ratio, peak a-wave reversal and duration. In contrast, there was a comparable Amd/ Apvd ratio for the OI and control subjects (1.6 ± 0.5 versus 1.3 ± 0.4; P = 0.136). Multiple linear regression analysis showed that BSA was a significant predictor for LVIDd, LVISd, Khalfan S. Al-Senaidi, Irfan Ullah, Hashim Javad, Murtadha Al-Khabori and Saif Al-Yaarubi Clinical and Basic Research | e459 Table 1: Characteristics of children with osteogenesis imperfecta in comparison to an age- and gender- matched control group (N = 32) Characteristic Mean ± SD P value OI group (n = 8) Control group (n = 24) Male-to-female ratio 3:5 11:13 0.692 Age in years 7.3 ± 4.3 6.9 ± 2.5 0.743 Height in cm 87.3 ± 24.9 124.0 ± 14.3 0.001 Weight in kg 15.0 ± 9.9 22.7 ± 7.4 0.025 BSA in m2 0.60 ± 0.28 0.89 ± 0.19 0.001 Systolic BP in mmHg 100.6 ± 5.0 103.4 ± 6.8 0.324 Diastolic BP in mmHg 57.1 ± 4.0 60.5 ± 5.0 0.136 Heart rate in beats per minute 105.5 ± 22.0 85.9 ± 17.0 0.054 QTc in ms 422.4 ± 11.0 418.4 ± 22.0 0.623 Haemoglobin in g/dL 11.9 ± 1.3 11.7 ± 0.6 0.634 Median haematocrit % (IQR) 0.4 (0.34‒0.40) 0.4 (0.35‒0.38) 0.717 Age started on pamidronate in months 38.9 ± 29.1 - - Duration of pamidronate therapy in months 54.5 ± 60.8 - - SD = standard deviation; OI = osteogenesis imperfecta; BSA = body surface area; BP = blood pressure; QTc = QT interval corrected for heart rate; IQR = interquartile range. Table 2: Echocardiographic measurements and Z scores of children with osteogenesis imperfecta in comparison to an age- and gender-matched control group (N = 32) Measurement/Z score Mean ± SD P value OI group (n = 8) Control group (n = 24) Median LVIDd in mm (IQR) 31.0 (25.5–38.0) 38.0 (33.0–41.0) 0.051 LVIDd/BSA ratio 61.4 ± 13.6 44.1 ± 7.1 0.009 LVIDd Z score 0.7 ± 1.1 0.1 ± 0.8 0.080 LVISd in mm 20.0 ± 5.3 24.3 ± 3.6 0.065 LVISd/BSA ratio 37.4 ± 8.5 27.9 ± 3.9 0.015 LVISd Z score 0.4 ± 1.1 0.2 ± 0.7 0.441 IVSd in mm 6.5 ± 1.3 5.7 ± 1.0 0.151 IVSd/BSA ratio 12.7 ± 4.3 6.7 ± 1.8 0.005 IVSd Z score 1.4 ± 0.8 -0.1 ± 0.9 0.001 Median LVPWd in mm (IQR) 5.0 (5.0–6.5) 5.0 (4.0–5.0) 0.160 LVPWd/BSA ratio 10.7 ± 2.8 5.7 ± 1.6 0.001 LVPWd Z score 1.6 ± 0.3 -0.3 ± 0.8 0.001 EF in % 71.0 ± 4.2 66.4 ± 5.8 0.050 SF in % 39.1 ± 3.1 36.3 ± 4.6 0.068 AoAn in mm 14.8 ± 2.5 15.1 ± 1.8 0.680 AoAn/BSA ratio 28.5 ± 7.8 17.3 ± 2.0 0.005 AoAn Z score 2.9 ± 1.2 0.3 ± 0.5 0.001 SinVals in mm 18.6 ± 2.5 18.9 ± 2.7 0.793 SinVals/BSA ratio 36.6 ± 11.1 21.7 ± 2.6 0.007 SinVals Z score 1.8 ± 1.6 -0.5 ± 8.0 0.001 Sintubj in mm 16.9 ± 2.0 16.6 ± 2.3 0.786 Sintubj/BSA ratio 33.2 ± 10.5 19.1 ± 2.6 0.007 Sintubj Z score 2.4 ± 1.3 0.2 ± 0.7 0.001 AscAo in mm 17.3 ± 3.6 16.9 ± 2.2 0.758 AscAo/BSA ratio 33.5 ± 11.6 19.4 ± 2.4 0.011 AscAo Z score 2.1 ± 2.3 -0.3 ± 1.0 0.001 PVAn in mm 15.4 ± 2.9 16.0 ± 2.8 0.570 PVAn/BSA ratio 29.4 ± 7.2 18.4 ± 2.8 0.003 PVAn Z score 1.6 ± 2.3 -0.7 ± 0.8 0.001 MPA in mm 16.4 ± 1.8 15.3 ± 2.1 0.189 MPA/BSA ratio 32.1 ± 9.6 17.7 ± 3.3 0.003 MPA Z score 1.2 ± 1.1 -1.1 ± 0.8 0.001 LPA in mm 11.5 ± 1.9 11.5 ± 1.1 0.941 LPA/BSA ratio 22.3 ± 6.0 13.5 ± 3.2 0.004 LPA Z score 2.7 ± 0.9 0.9 ± 0.8 0.001 RPA in mm 11.9 ± 3.1 11.3 ± 1.2 0.473 RPA/BSA 22.3 ± 5.0 13.2 ± 2.6 0.001 RPA Z score 2.0 ± 0.7 0.0 ± 0.8 0.001 TVmax in mmHg 18.6 ± 1.4 (7)* 17.4 ± 2.7 (22)* 0.278 LA/AO ratio 1.4 ± 0.2 1.5 ± 0.2 0.315 IVRT in ms 67.5 ± 14.1 67.2 ± 11.2 0.946 Corrected IVRT† in ms 88.1 ± 17.4 79.5 ± 11.9 0.125 SD = standard deviation; OI = osteogenesis imperfecta; LVIDd = left ventricular end diastolic dimension; IQR = interquartile range; BSA = body surface area; LVISd = left ventricular end systolic dimension; IVSd = interventricular septal dimension in diastole; LVPWd = left ventricular posterior wall dimension in diastole; EF = ejection fraction; SF = shortening fraction; AoAn = aortic valve annulus; SinVals = sinus of Valsalva; Sintubj = sinotubular junction; AscAo = ascending aorta; PVAn = pulmonary valve annulus; MPA = main pulmonary artery; LPA = left pulmonary artery; RPA = right pulmonary artery; TVmax = tricuspid valve regurgitation maximum peak velocity; LA/AO = left atrium aortic dimension ratio by M-mode; IVRT = isovolumic relaxation time. *Number of subjects with mild tricusoid valve regurgitation and for whom TVmax could be measured. †Corrected for heart rate. Echocardiographic Evidence of Early Diastolic Dysfunction in Asymptomatic Children with Osteogenesis Imperfecta e460 | SQU Medical Journal, November 2015, Volume 15, Issue 4 IVSd, LVPWd, AoAn, AscAo and SinVals diameters (P = 0.01, 0.01, 0.04, 0.03, 0.01, 0.01 and 0.03, respectively). In comparison, OI was a significant predictor for IVSd, LVPWd, AoAn, SinVals and Sintubj (P = 0.03, 0.01, 0.04, 0.029 and 0.01, respectively). Systolic blood pressure was not a significant predictor for any of the tested independent variables [Table 4]. Discussion In comparison to control subjects, there was significantly decreased peak early diastolic velocity and its ratio with the peak late diastolic velocity of the lateral mitral valve and upper septum among the studied group of OI patients. In addition, peak late diastolic velocity was significantly increased at the same sites among OI patients. Furthermore, the OI group had lower Em and lower peak a-wave reversal velocity and duration at the pulmonary vein. These findings indicate mild early changes in myocardial diastolic function; however, these changes are not considered as severe as those indicated by the Em/E’m and Amd/Apvd ratios, which were similar in the two groups. Migliaccio et al. compared adult OI patients with controls (n = 40 each) and observed a decrease in the Em velocity and Em/Am ratio with a significant increase in the IVRT and DTm.13 In the current study, pulmonary vein wave velocity data in OI patients compared to the control subjects showed a significant decrease in the a-wave reversal velocity and duration and an increase in the peak systolic and diastolic ratio. The likely explanation of such changes in OI patients is the greater stiffness of the myocardial tissue and decreased elasticity, leading to echocardiographic changes and altered myocardial relaxation.11 While OI is primarily a bone disease, it presents with important extraskeletal abnormalities. Involve- ment of the heart is due to an alteration in type 1 collagen fibres.14 Myocardial collagen is primarily made up of collagen type 1, which contributes significantly to the myocardial and aortic wall strength and stiffness.15 Mutations in OI can directly alter the properties of collagen, either by decreasing synthesis or by altering functional and structural properties.16–18 Such alterations in the collagen fibres could lead to the abnormalities seen in the myocardial and aortic wall echocardiographic parameters; this has been demonstrated in histological analyses of animal models.19–21 Radunovic et al. reported increased LVIDd, indexed aortic diameters for BSA and mitral and aortic regurgitation in OI adult patients compared to controls.22 The current study showed that left ventricular dimensions and wall thicknesses were similar between the two groups. However, the OI group had higher dimensions when corrected for BSA. Table 3: Tissue Doppler echocardiographic measurements of children with osteogenesis imperfecta in comparison to an age- and gender-matched control group (N = 32) Measurement Mean ± SD P value OI group (n = 8) Control group (n = 24) Mitral valve Em in cm/s 84.8 ± 23.4 103.4 ± 18.4 0.027 Am in cm/s 52.4 ± 20.9 50.9 ± 11.6 0.810 Em/Am ratio 1.8 ± 0.6 2.1 ± 0.4 0.156 Amd in ms 102.1 ± 21.7 110.9 ± 24.7 0.380 DTm in ms 130.6 ± 23.3 137.3 ± 22.9 0.485 Corrected DTm† in ms 169.4 ± 20.7 162.7 ± 26.3 0.519 S’m in cm/s 8.4 ± 1.9 8.8 ± 1.6 0.551 E’m in cm/s 14.4 ± 2.5 18.9 ± 2.8 0.001 A’m in cm/s 8.6 ± 2.2 6.7 ± 0.9 0.002 E’m/A’m ratio 1.8 ± 0.6 2.9 ± 0.4 0.002 Em/E’m ratio 6.1 ± 2.2 5.6 ± 1.3 0.484 Septum Median S’s in cm/s (IQR) 7.0 (7.0‒8.5) 8.0 (7.25‒8.0) 0.204 E’s in cm/s 10.6 ± 1.7 14.9 ± 2.2 0.001 Median A’s in cm/s (IQR) 6.5 (6.0‒7.0) 6.0 (5.25‒8.0) 0.037 E’s/A’s ratio 1.6 ± 0.3 2.6 ± 0.54 0.001 Tricuspid valve Median S’t in cm/s (IQR) 12.0 (7.5‒14.7) 12.0 (12.0‒13.0) 0.611 E’t in cm/s 14.5 ± 2.7 15.8 ± 1.8 0.141 A’t in cm/s 10.6 ± 2.9 10.1 ± 1.8 0.543 E’t/A’t ratio 1.4 ± 0.38 1.6 ± 0.45 0.217 Pulmonary vein Spv in cm/s 52.9 ± 4.6 49.3 ± 8.9 0.288 Dpv in cm/s 51.6 ± 14.0 60.9 ± 11.9 0.080 Apv in cm/s 17.4 ± 3.4 21.1 ± 5.2 0.030 Apvd in ms 68.3 ± 18.4 88.7 ± 17.0 0.018 Spv/Dpv ratio 1.1 ± 0.3 0.8 ± 0.2 0.002 Amd/Apvd ratio 1.6 ± 0.5 1.3 ± 0.4 0.136 SD = standard deviation; OI = osteogenesis imperfecta; Em = peak early mitral valve flow velocity; Am = peak late mitral valve flow velocity; Amd = Am duration; DTm = deceleration time of the Em wave; S’m = peak systolic velocity of the mitral valve; E’m = peak early diastolic velocity of the mitral valve; A’m = peak late diastolic velocity of the mitral valve; S’s = peak systolic velocity of the septum; IQR = interquartile range; E’s = peak early diastolic velocity of the septum; A’s = peak late diastolic velocity of the septum; S’t = peak systolic velocity of the tricuspid valve; E’t = peak early diastolic velocity of the tricuspid valve; A’t = peak late diastolic velocity of the tricuspid valve; Spv = peak systolic velocity of the pulmonary vein; Dpv = peak diastolic velocity of the pulmonary vein; Apv = peak a-wave reversal in the pulmonary vein; Apvd = peak a-wave reversal duration in the pulmonary vein. †Corrected for heart rate. Khalfan S. Al-Senaidi, Irfan Ullah, Hashim Javad, Murtadha Al-Khabori and Saif Al-Yaarubi Clinical and Basic Research | e461 This has been similarly reported in both adult and paediatric OI patients.7,13 The incidence of mitral valve prolapse in OI is about 3–8%;6,7 however, none of the patients in the current study had mitral valve prolapse or aortic valve regurgitation. The studied subjects had normal systolic cardiac function and IVRT. There was no significant difference between the OI and control groups regarding the four aortic and pulmonary artery diameters. However, these diameters were significantly larger in the OI group compared to the control subjects when indexed for BSA. Moreover, regression analysis revealed that the diagnosis of OI was a significant predictor for larger left ventricular wall diameters in diastole and a larger diameter of the AoAn, SinVals and Sintubj. Karamifar et al. described aortic valve regurgitation in two out of 24 OI patients (8.3%).23 Radunovic et al. reported increased right ventricular outflow tract measurements and main pulmonary artery diameters in adult OI patients when indexed for BSA, indicating involvement of both the right and left sides of the heart.22 When the significant increase in the four pulmonary artery diameters were indexed to BSA and their Z scores were calculated, the findings of the current study were in line with the findings of Radunovic et al.22 The patients in the current study did not have any systemic illnesses, including hypertension or anaemia to confound the above changes. Moreover, none of the subjects had evidence of pulmonary hypertension. This study highlights the need for detailed assessments of cardiac function in OI patients who are limited in their physical activities. Early therapeutic modalities could help to treat or modify the progression of the disease to prevent the deterioration of cardiac function. In order to draw a definitive conclusion, large- scale, multicentre research is recommended to assess cardiovascular involvement in children with OI. As there are insufficient data available describing cardio- vascular involvement in children with OI, patients in the current study will be followed-up and OI patients with altered diastolic parameters or great vessel dilation will be monitored. Patients with progressive aortic dilation may be prescribed beta blockers and angiotensin receptor blockers as both of these approaches have been suggested to prevent the progression of aortic root dilation in Marfan syndrome.24 This study was limited by its small sample size. Additionally, the patients were not symptomatic from a cardiac point of view and no normal values exist for the echocardiographic parameters in this particular group of patients. For this reason, age-matched controls were used for comparative purposes. It was not possible to perform further cardiac function assessments using two-dimensional speckle tracking as only limited echocardiographic views could be obtained due to Table 4: Simple regression analysis of left ventricular and four aortic dimensions of children with osteogenesis imperfecta in comparison to an age- and gender-matched control group (N = 32) Dimension B regression coefficient (95% CI) R2 OI* Age Gender SBP DBP BSA LVIDd -0.51 (-2.92, 3.94) 0.69 (0.07, 1.31)† -2.70 (-5.06, -0.34)† 0.09 (-0.10, 0.27) 0.19 (-0.05, 0.43) 11.34 (3.05, 19.62)† 0.83 LVISd 0.61 (-3.91, 2.69) 0.09 (-0.51, 0.68) 0.11 (-2.16, 2.38) 0.03 (-0.16, 0.21) 0.09 ( -0.14, 0.32) 13.47 (5.50, 21.44)† 0.71 IVSd -1.49 (-2.80, -0.18)† -0.19 (-0.43, 0.05) 1.03 (0.13, 1.94)† 0.04 (-0.03, 0.11) -0.05 (-0.14, 0.05) 3.31 (0.13, 6.48)† 0.33 LVPWd -1.26 (-2.11, -0.41)† 0.03 (-0.12, 0.19) -0.44 (-1.03, 0.14) 0.01 (-0.04, 0.05) -0.07 (-0.13, -0.01)† 2.35 (0.25, 4.37)† 0.57 AoAn -1.20 (-2.32, -0.08)† 0.20 (-0.01, 0.40) -0.08 (-0.85, 0.70) 0.02 (-0.04, 0.09) 0.04 (-0.04, 0.12) 5.56 (2.84, 8.28)† 0.86 SinVals -1.68 (-4.36, 1.00)† 0.15 (-0.34, 0.63) 0.71 (-1.13, 2.56) -0.01 (-0.16, 0.14) 0.03 (-0.16, 0.22) 7.12 (0.63, 13.59)† 0.72 Sintubj -2.00 (-3.55, -0.45)† 0.10 (-0.18, 0.38) 1.50 (0.46, 2.59)† 0.09 (-0.01, 0.18) -0.01 ( -0.11, 0.11) 6.14 (2.4, 9.88) 0.77 AscAo -2.04 (-4.15, -0.08) 0.11 (-0.28, 0.49) 1.14 (-0.31, 2.59) 0.07 (-0.05, 0.18) 0.03 (-0.12, 0.18) 7.14 (2.04, 12.25)† 0.67 CI = confidence interval; OI = osteogenesis imperfecta; SBP = systolic blood pressure; DBP = diastolic blood pressure; BSA = body surface area; LVIDd = left ventricular end diastolic dimensions; LVISd = left ventricular end systolic dimensions; IVSd = interventricular septal thickness at diastole; LVPWd = left ventricular posterior wall thickness in diastole; AoAn = aortic annulus; SinVals = sinus of Valsalva; Sintubj = sinotubular junction; AscAo = ascending aorta. *In comparison to the control group. †P <0.05. Echocardiographic Evidence of Early Diastolic Dysfunction in Asymptomatic Children with Osteogenesis Imperfecta e462 | SQU Medical Journal, November 2015, Volume 15, Issue 4 chest deformities. Additionally, the echocardiographers performing the scans were not blinded to the study subjects, which may have introduced observer bias. As the majority of the OI subjects were diagnosed with type Ш OI, it was not possible to analyse the group of OI patients by disease subtype. Conclusion The paediatric OI subjects in the current study had normal systolic cardiac function and early changes in myocardial tissue Doppler velocities. This is suggestive of early diastolic cardiac dysfunction. Since these changes may worsen with time, careful cardiological evaluation and follow-up of these patients is warranted. Larger observational TDE studies assessing diastolic function in children with OI are recommended. c o n f l i c t o f i n t e r e s t The authors declare no conflicts of interest. 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