Left Ventricular Stiffness in Adolescents and Young Adults with Repaired Tetralogy of Fallot

www.nature.com/scientificreports OPEN Received: 19 December 2016 Accepted: 30 March 2017 Published: xx xx xxxx Left Ventricular Stiffness in Adolescents and Young Adults with Repaired Tetralogy of Fallot Clement Kwong-man Yu, Wilfred Hing-sang Wong, Vivian Wing-yi Li & Yiu-fai Cheung Left ventricular (LV) remodeling after tetralogy of Fallot (TOF) repair may influence LV stiffness. We hypothesized that LV stiffness is altered after TOF repair and related to myocardial calibrated integrated backscatter (cIB) and LV diastolic myocardial deformation. Seventy-seven TOF patients and 80 controls were studied. LV stiffness was assessed by diastolic wall strain (DWS) as defined by (LVPWsystole-LVPWdiastole)/LVPWsystole, where LVPW is LV posterior wall thickness, and stiffness index as defined by (E/e/LV end-diastolic dimension), where E and e are respectively early diastolic transmitral inflow and mitral annular velocities. Septal and LVPW cIB and LV diastolic strain rates were determined. Patients had significantly lower DWS (p < 0.001), higher stiffness index (p < 0.001), and greater cIB (p < 0.001). LV DWS correlated negatively with LV stiffness index (r = −0.31, p < 0.001), septal cIB (r = −0.21, p = 0.01), E/e ratio (r = −0.30, p < 0.001) and RV end-diastolic area (r = −0.31, p < 0.001), and positively with LV early (r = 0.33, p < 0.001) and late (r = 0.20, p = 0.01) diastolic strain rates and RV fractional area change (FAC) (r = 0.24, p = 0.003). Multivariate analysis revealed E/e (β = −0.26, p = 0.008), RV end-diastolic area (β = −0.20, p = 0.02), and RV FAC (β = 0.18, p = 0.01) as significant correlates of DWS. Left ventricular stiffening occurs after TOF repair and is related to impaired LV diastolic myocardial deformation, myocardial cIB, and RV volume overload. Right ventricular (RV) dilation and dysfunction secondary to chronic severe pulmonary regurgitation are well documented in patients late after repair of tetralogy of Fallot (TOF)1–3. On the other hand, increasing evidence suggests that left ventricular (LV) dysfunction may also have prognostic significance in these patients4. Left ventricular systolic dysfunction has been attributed to several factors including preoperative hypoxaemia5, LV fibrosis6, 7, LV dyssynchrony8 and adverse right-left ventricular interaction9. On the other hand, the phenotype and understanding of pathogenetic mechanism of LV diastolic dysfunction in repaired TOF is less clear. Diastolic ventricular dysfunction may be related to relaxation abnormality and/or stiffening of the myocardium. Previous studies in repaired TOF patients have primarily assessed indirectly LV early diastolic relaxation and estimated late diastolic filling using Doppler imaging10, 11. Importantly, however, recent data suggest that potential alteration of myocardial substrates occurs in repaired TOF, which may predispose to stiffening of LV myocardium. In these patients, increased levels of circulating biomarkers of collagen synthesis have been reported12, 13. Cardiac magnetic resonance (CMR) imaging with late gadolinium enhancement6 and T1 mapping7 techniques has further revealed evidence of LV fibrosis. The potential consequence on LV stiffness of LV remodeling related to myocardial fibrosis and geometric eccentricity secondary to RV volume overload has, however, not been explored in patients after TOF repair. Recently, there has been increasing use of echocardiography for non-invasive assessment of myocardial stiffness. The parameter of diastolic wall strain (DWS)14, which quantifies the thinning of myocardium during diastole, has been found to be useful in assessing diastolic myocardial stiffness and prognostication in heart failure patients with preserved ejection fraction15. Another potentially useful LV stiffness index that relates Doppler-estimated LV filling pressure to LV end-diastolic dimension has been used to interrogate myocardial stiffness in athletes16. In this study we aimed to utilize these indices to test the hypothesis that LV stiffness is altered in adolescents and young adults with repaired TOF and to determine its relationship to myocardial calibrated integrated backscatter (cIB) as a marker of fibrosis17 and LV diastolic myocardial deformation. Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. Correspondence and requests for materials should be addressed to Y.-f.C. (email: ) Scientific Reports | 7: 1252 | DOI:10.1038/s41598-017-01448-2 1 www.nature.com/scientificreports/ Methods Subjects. This was a retrospective study of our echocardiographic database of congenital heart disease that included 77 consecutively studied TOF patients post total surgical repair. The following patient data were retrieved from case notes: cardiac and associated lesions, type of operation performed, date and age of operation, and the need for additional procedures. A total of 80 age-matched healthy controls were retrieved from the healthy control database for the purpose of comparisons. These included healthy staff volunteers, their friends, and subjects with chest pain or palpitation for which no organic causes had been identified. The body weight and height of all subjects were measured at the time of echocardiographic acquisitions and the body surface area was calculated accordingly. The total number of around 80 subjects in each group gave a statistical power of 80% with 5% level of significance with two-sided testing to detect a minimum DWS difference of 0.03 with a variation of 0.08 based on the previously reported standard deviation15. This study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster, Hong Kong, and all of the methods as described were performed in accordance with the approved guidelines and regulations. Informed consent had been obtained from all of the participants at the time of acquisition of echocardiographic images. Conventional echocardiographic assessment. Echocardiographic acquisitions were made using Vivid 7 ultrasound machine (General Electric, Vingmed, Horten, Norway). Offline analyses of the recordings were performed using EchoPAC software (General Electric, Vingmed, Horten, Norway). Measurements of all echocardiographic parameters were made in three cardiac cycles and the average was taken for statistical analyses. From the four-chamber view, RV end-diastolic and end-systolic areas were measured and RV fractional area change was calculated accordingly. Transmitral pulsed-wave Doppler examination was performed to obtain peak early diastolic inflow velocity (E), late diastolic inflow velocity (A), E/A ratio, and E deceleration time. Tissue Doppler echocardiography was performed with sample volume positioned at the basal LV free wall-mitral annular junction to obtain the peak early diastolic myocardial tissue velocity (e), late diastolic myocardial tissue velocity (a), e/a ratio, and (...truncated)