Publications by authors named "Ju Le Tan"

41 Publications

Cardiovascular magnetic resonance-assessed fast global longitudinal strain parameters add diagnostic and prognostic insights in right ventricular volume and pressure loading disease conditions.

J Cardiovasc Magn Reson 2021 04 1;23(1):38. Epub 2021 Apr 1.

National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, 169609, Singapore, Singapore.

Background: Parameters of myocardial deformation may provide improved insights into right ventricular (RV) dysfunction. We quantified RV longitudinal myocardial function using a fast, semi-automated method and investigated its diagnostic and prognostic values in patients with repaired tetralogy of Fallot (rTOF) and pulmonary arterial hypertension (PAH), who respectively exemplify patients with RV volume and pressure overload conditions.

Methods: The study enrolled 150 patients (rTOF, n = 75; PAH, n = 75) and 75 healthy controls. RV parameters of interest were fast global longitudinal strain (GLS) and strain rates during systole (GLSR), early diastole (GLSR) and late diastole (GLSR), obtained by tracking the distance from the medial and lateral tricuspid valve insertions to the RV epicardial apex on cine cardiovascular magnetic resonance (CMR).

Results: The RV fast GLS exhibited good agreement with strain values obtained by conventional feature tracking approach (bias - 4.9%, error limits (± 2·standard deviation) ± 4.3%) with fast GLS achieving greater reproducibility and requiring reduced analysis time. Mean RV fast GLS was reduced in PAH and rTOF groups compared to healthy controls (PAH < rTOF < healthy controls: 15.1 ± 4.9 < 19.3 ± 2.4 < 24.4 ± 3.0%, all P < 0.001 in pairwise comparisons). In rTOF patients, RV fast GLS was significantly associated with metabolic equivalents, peak oxygen consumption (PVO) and percentage of predicted PVO achieved during cardiopulmonary exercise testing. Lower RV fast GLS was associated with subnormal exercise capacity in rTOF (area under the curve (AUC) = 0.822, sensitivity = 72%, specificity = 91%, cut-off = 19.3%). In PAH patients, reduced RV fast GLS was associated with RV decompensated hemodynamics (AUC = 0.717, sensitivity = 75%, specificity = 58%, cut-off = 14.6%) and higher risk of clinical worsening (AUC = 0.808, sensitivity = 79%, specificity = 70 %, cut-off = 16.0%).

Conclusions: Quantitative RV fast strain and strain rate parameters assessed from CMR identify abnormalities of RV function in rTOF and PAH and are predictive of exercise capacity, RV decompensation and clinical risks in these patients. Trial registry Clinicaltrials.gov: NCT03217240.
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http://dx.doi.org/10.1186/s12968-021-00724-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015087PMC
April 2021

Patient-Specific Computational Analysis of Hemodynamics and Wall Mechanics and Their Interactions in Pulmonary Arterial Hypertension.

Front Bioeng Biotechnol 2020 28;8:611149. Epub 2021 Jan 28.

Department of Mechanical Engineering, Michigan State University, East Lansing, MI, United States.

Vascular wall stiffness and hemodynamic parameters are potential biomechanical markers for detecting pulmonary arterial hypertension (PAH). Previous computational analyses, however, have not considered the interaction between blood flow and wall deformation. Here, we applied an established computational framework that utilizes patient-specific measurements of hemodynamics and wall deformation to analyze the coupled fluid-vessel wall interaction in the proximal pulmonary arteries (PA) of six PAH patients and five control subjects. Specifically, we quantified the linearized stiffness (), relative area change (RAC), diastolic diameter (), regurgitant flow, and time-averaged wall shear stress (TAWSS) of the proximal PA, as well as the total arterial resistance ( ) and compliance ( ) at the distal pulmonary vasculature. Results found that the average proximal PA was stiffer [median: 297 kPa, interquartile range (IQR): 202 kPa vs. median: 75 kPa, IQR: 5 kPa; = 0.007] with a larger diameter (median: 32 mm, IQR: 5.25 mm vs. median: 25 mm, IQR: 2 mm; = 0.015) and a reduced RAC (median: 0.22, IQR: 0.10 vs. median: 0.42, IQR: 0.04; = 0.004) in PAH compared to our control group. Also, higher total resistance ( ; median: 6.89 mmHg × min/l, IQR: 2.16 mmHg × min/l vs. median: 3.99 mmHg × min/l, IQR: 1.15 mmHg × min/l; = 0.002) and lower total compliance ( ; median: 0.13 ml/mmHg, IQR: 0.15 ml/mmHg vs. median: 0.85 ml/mmHg, IQR: 0.51 ml/mmHg; = 0.041) were observed in the PAH group. Furthermore, lower TAWSS values were seen at the main PA arteries (MPAs) of PAH patients (median: 0.81 Pa, IQR: 0.47 Pa vs. median: 1.56 Pa, IQR: 0.89 Pa; = 0.026) compared to controls. Correlation analysis within the PAH group found that was directly correlated to the PA regurgitant flow ( = 0.84, = 0.018) and inversely related to TAWSS ( = -0.72, = 0.051). Results suggest that the estimated elastic modulus may be closely related to PAH hemodynamic changes in pulmonary arteries.
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http://dx.doi.org/10.3389/fbioe.2020.611149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901991PMC
January 2021

Clinical Updates on the Diagnosis and Management of Chronic Thromboembolic Pulmonary Hypertension.

Ann Acad Med Singap 2020 May;49(5):320-330

Department of Cardiology, National Heart Centre Singapore, Singapore.

Introduction: Chronic thromboembolic pulmonary hypertension (CTEPH) is a known sequela after acute pulmonary embolism (PE). It is a debilitating disease, and potentially fatal if left untreated. This review provides a clinically relevant overview of the disease and discusses the usefulness and limitations of the various investigational and treatment options.

Methods: A PubMed search on articles relevant to PE, pulmonary hypertension, CTEPH, pulmonary endarterectomy, and balloon pulmonary angioplasty were performed. A total of 68 articles were found to be relevant and were reviewed.

Results: CTEPH occurs as a result of non-resolution of thrombotic material, with subsequent fibrosis and scarring of the pulmonary arteries. Risk factors have been identified, but the underlying mechanisms have yet to be fully elucidated. The cardinal symptom of CTEPH is dyspnoea on exertion, but the diagnosis is often challenging due to lack of awareness. The ventilation/perfusion scan is recommended for screening for CTEPH, with other modalities (eg. dual energy computed tomography pulmonary angiography) also being utilised in expert centres. Conventional pulmonary angiography with right heart catheterisation is important in the final diagnosis of CTEPH.

Conclusion: Operability assessment by a multidisciplinary team is crucial for the management of CTEPH, as pulmonary endarterectomy (PEA) remains the guideline recommended treatment and has the best chance of cure. For inoperable patients or those with residual disease post-PEA, medical therapy or balloon pulmonary angioplasty are potential treatment options.
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May 2020

Three-dimensional biventricular strains in pulmonary arterial hypertension patients using hyperelastic warping.

Comput Methods Programs Biomed 2020 Jun 17;189:105345. Epub 2020 Jan 17.

National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore; Duke-NUS Medical School, Singapore. Electronic address:

Background And Objective: Evaluation of biventricular function is an essential component of clinical management in pulmonary arterial hypertension (PAH). This study aims to examine the utility of biventricular strains derived from a model-to-image registration technique in PAH patients in comparison to age- and gender-matched normal controls.

Methods: A three-dimensional (3D) model was reconstructed from cine short- and long-axis cardiac magnetic resonance (CMR) images and subsequently partitioned into right ventricle (RV), left ventricle (LV) and septum. The hyperelastic warping method was used to register the meshed biventricular finite element model throughout the cardiac cycle and obtain the corresponding biventricular circumferential, longitudinal and radial strains.

Results: Intra- and inter-observer reproducibility of biventricular strains was excellent with all intra-class correlation coefficients > 0.84. 3D biventricular longitudinal, circumferential and radial strains for RV, LV and septum were significantly decreased in PAH patients compared with controls. Receiver operating characteristic (ROC) analysis showed that the 3D biventricular strains were better early markers (Area under the ROC curve = 0.96 for RV longitudinal strain) of ventricular dysfunction than conventional parameters such as two-dimensional strains and ejection fraction.

Conclusions: Our highly reproducible methodology holds potential for extending CMR imaging to characterize 3D biventricular strains, eventually leading to deeper understanding of biventricular mechanics in PAH.
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http://dx.doi.org/10.1016/j.cmpb.2020.105345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198336PMC
June 2020

Elevated Right Atrial Pressure Associated with Alteration of Left Ventricular Contractility and Ventricular-Arterial Coupling in Pulmonary Artery Hypertension.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:820-823

Pulmonary artery hypertension (PAH) is a progressive disorder which leads to heart failure and death. Development of dilated right ventricle (RV), progressive RV dysfunction and increased right atrial (RA) pressure make the RV transition from a compensated to a decompensated phase and eventually leads to heart failure. However, the relationship between elevated RA pressure and left ventricular contractility and ventricular arterial coupling (VAC) has not been well studied. 36 patients were recruited and underwent both right heart catheterization (RHC) and cardiac magnetic resonance (CMR). Left ventricular (LV) pressure-volume loops were reconstructed from RHC and CMR. LV contractility was assessed by end-systolic elastance (E) using single-beat method and arterial elastance (E) was estimated as the ratio of end-systolic pressure and stroke volume (SV). The VAC was calculated as the ratio of E and E (i.e. E/E). The results demonstrated a nonlinear relationship between RA pressure and E, RA pressure and VAC. E increased when RA pressure increased to 7 mmHg and then decreased when RA pressure exceeded 7 mmHg. E were 2.79 ± 1.61 mmHg/ml, 4.27 ±1 33 mmHg/ml, 2.69 ± 0.89 mmHg/ml and 2.36± 1.10 mmHg/ml at ascending quartiles of RA pressure, respectively (quartile 1: RAP≤5 mmHg; quartile 2: 5<; RAP≤7 mmHg; quartile 3: 7<; RAP 10 mmHg and quartile 4: RAP>10 mmHg). Similarly, VAC were 1.36 ± 0.61, 1.93±0.86, 1.16 ± 0.55 and 0.95± 0.27 the four quartiles (both ANOVA P <; 0.05). We found that there was a nonlinear relationship between RA pressure and LV contractility, and between RA pressure and ventricular-arterial coupling. A cut-off value of 7 mmHg of RAP may indicate a decompensated LV hemodynamics.
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http://dx.doi.org/10.1109/EMBC.2019.8856814DOI Listing
July 2019

Mortality and hospitalization outcomes of interstitial lung disease and pulmonary hypertension in the Singapore systemic sclerosis cohort.

Semin Arthritis Rheum 2020 06 13;50(3):473-479. Epub 2019 Nov 13.

Department of Rheumatology and Immunology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore. Electronic address:

Objectives: We compared mortality and hospitalization rates in four groups of patients with systemic sclerosis (SSc) [isolated pulmonary arterial hypertension (PAH) or interstitial lung disease (ILD), concomitant ILD-pulmonary hypertension (PH), and no/mild pulmonary involvement].

Methods: In the Systemic Sclerosis Cohort Singapore (SCORE), ILD was diagnosed by HRCT and significant ILD was defined by forced vital capacity <70% predicted. Patients were classified as PAH if echocardiographic systolic pulmonary artery pressure (sPAP) ≥50 mmHg or right heart catheterization (RHC) mean PAP ≥25 mmHg. Multivariable regression analyses were performed to determine factors associated with mortality and hospital admissions per year. Cox proportional hazard model was used to analyze survival.

Results: Of 490 SSc patients, 50 patients had PAH, 92 patients had ILD and 43 patients had ILD-PH. Of 93 patients with PAH or ILD-PH, 56 were based on echocardiography and 37 on RHC. Patients with ILD-PH (HR 3.77, 95% CI: 2.05-6.93) had the highest risk of death, followed by PAH (HR 3.03, 95% CI: 1.60-5.76) and ILD (HR 1.84, 95% CI: 1.04-3.28). After adjustment for confounders, PAH (HR 2.39, 95% CI: 1.13-5.07) remained independently associated with mortality, but not ILD-PH or ILD. Other factors associated with mortality were male gender, age at SSc diagnosis, malabsorption and digital ulcer/ gangrene. Increased hospitalization rate was associated with renal crisis, right heart failure and PAH medications, but not SSc groups.

Conclusion: PAH is an independent risk factor of mortality in SSc. Increased hospitalization rate was not associated with SSc groups. Other factors associated with increased mortality and hospital admissions were identified.
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http://dx.doi.org/10.1016/j.semarthrit.2019.11.005DOI Listing
June 2020

Computational quantification of patient-specific changes in ventricular dynamics associated with pulmonary hypertension.

Am J Physiol Heart Circ Physiol 2019 12 1;317(6):H1363-H1375. Epub 2019 Nov 1.

Simula Research Laboratory, Oslo, Norway.

Pulmonary arterial hypertension (PAH) causes an increase in the mechanical loading imposed on the right ventricle (RV) that results in progressive changes to its mechanics and function. Here, we quantify the mechanical changes associated with PAH by assimilating clinical data consisting of reconstructed three-dimensional geometry, pressure, and volume waveforms, as well as regional strains measured in patients with PAH ( = 12) and controls ( = 6) within a computational modeling framework of the ventricles. Modeling parameters reflecting regional passive stiffness and load-independent contractility as indexed by the tissue active tension were optimized so that simulation results matched the measurements. The optimized parameters were compared with clinical metrics to find usable indicators associated with the underlying mechanical changes. Peak contractility of the RV free wall (RVFW) γ was found to be strongly correlated and had an inverse relationship with the RV and left ventricle (LV) end-diastolic volume ratio (i.e., RVEDV/LVEDV) (RVEDV/LVEDV)+ 0.44,  = 0.77). Correlation with RV ejection fraction ( = 0.50) and end-diastolic volume index ( = 0.40) were comparatively weaker. Patients with with RVEDV/LVEDV > 1.5 had 25% lower γ ( < 0.05) than that of the control. On average, RVFW passive stiffness progressively increased with the degree of remodeling as indexed by RVEDV/LVEDV. These results suggest a mechanical basis of using RVEDV/LVEDV as a clinical index for delineating disease severity and estimating RVFW contractility in patients with PAH. This article presents patient-specific data assimilation of a patient cohort and physical description of clinical observations.
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http://dx.doi.org/10.1152/ajpheart.00094.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132315PMC
December 2019

Impaired Cardiovascular Magnetic Resonance-Derived Rapid Semiautomated Right Atrial Longitudinal Strain Is Associated With Decompensated Hemodynamics in Pulmonary Arterial Hypertension.

Circ Cardiovasc Imaging 2019 05;12(5):e008582

National Heart Research Institute Singapore, National Heart Centre Singapore (S.L., X.D.Z., W.R., A.S.K., R.-S.T., J.L.T., L.Z.).

Background The transition of right ventricle (RV) from a compensated to decompensated state contributes to survival in pulmonary arterial hypertension (PAH). This study investigates the significance of right atrial (RA) dysfunction on disease progression in PAH. Methods Eighty patients with PAH, including 58 with hemodynamically compensated RV function (PAH-C) and 22 with decompensated RV function (PAH-D), were compared with 80 age-matched and sex-matched normal controls. RA longitudinal strain and strain rate (SR) parameters corresponding to reservoir (total strain ε and strain rate SR), conduit (passive strain ε and strain rate SR), and booster pump (active strain ε and strain rate SR) phases were derived by a rapid semiautomated method on cine cardiovascular magnetic resonance. Results In PAH compared with controls, significantly reduced RA strains and SRs were observed. Among patients with PAH, PAH-D had significantly impaired RA strains and SRs compared with PAH-C. RA total strain and passive strain were the best parameters for differentiating PAH-D from PAH-C. Lower RA strain correlated with increased RA pressure ( r=-0.57; P<0.0001), RV volume ( r=-0.37; P=0.002) and biomarker ( r=-0.53; P<0.0001), impaired RV function ( r=0.46-0.72; P<0.0001), and lower exercise capacity ( r=0.41; P<0.0001). Reduced RA strains were significantly associated with higher risk of clinical worsening in PAH. RA passive strain was the best predictor of a composite adverse event end point (Harrell's C statistic,0.75; hazard ratio,0.84; P=0.019) compared with other conventional RA and RV functional measurements. Conclusions RA phasic functions are impaired in PAH. Among patients with PAH, impaired RA strains reflect RV decompensation and higher risks and predict adverse clinical outcomes. Clinical Trial Registration https://www.clinicaltrials.gov . Unique identifier: NCT02790918.
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http://dx.doi.org/10.1161/CIRCIMAGING.118.008582DOI Listing
May 2019

Computational Platform Based on Deep Learning for Segmenting Ventricular Endocardium in Long-axis Cardiac MR Imaging.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:4500-4503

This paper presents an automated computational platform based on deep learning (DL) approach for left ventricular (LV) and right ventricular (RV) endocardium segmentation in long-axis cine cardiovascular magnetic resonance (CMR). The proposed method uses modified deep U-Net convolutional networks. We trained our model using 4800 images from 40 human subjects (20 healthy volunteers, 20 patients with various cardiac diseases) and validated the technique in 6000 images from 50 subjects (10 healthy volunteers, 40 patients). An average Dice metric of 0.929 ± 0.036 along with an average Jaccard index of 0.869 ± 0.059 were achieved for all the studied subjects. In addition, a high level of correlation and agreement with the ground truth contours for LV ejection fraction (R=0.975), LV fractional area change (R=0.959 to 0.971), and RV fractional area change (R=0.927) were observed. The proposed DL-based segmentation process took less than 3 seconds per subject (or < 30 milliseconds per image over 120 images for each subject). Therefore, our proposed framework offers a promising means to achieve fully automated and rapid segmentation for both LV and RV endocardium in long-axis cine CMR images using an appropriately trained deep convolutional neural network.
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http://dx.doi.org/10.1109/EMBC.2018.8513140DOI Listing
July 2018

Comparison of Image Acquisition Techniques in Four-Dimensional Flow Cardiovascular MR on 3 Tesla in Volunteers and Tetralogy of Fallot Patients.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:1115-1118

Four-dimensional phase-contrast (PC) velocity-encoded flow magnetic resonance imaging (4D flow MRI) is a potentially valuable tool for studying cardiovascular hemodynamics for disease monitoring and/or treatment planning. In this study we compared the performance of two 4D flow MRI pulse sequences - echo-planar imaging (EPI) and segmented gradient-echo (turbo-field-echo or TFE on vendor's platform) - on a clinical 3T system in 6 human subjects including 3 patients with Tetralogy of Fallot (TOF). For aortic flow rate, the coefficients of variation (COV) between 2D and 4D EPI were 7.0% and 7.7% for controls and patients respectively. The corresponding COV between 2D and 4D TFE were 19.0% and 18.3% for controls and patients respectively. The COV between 4D TFE and 4D EPI were larger than 18.7% in kinetic energy analysis. 4D EPI demonstrated acceptable accuracy of intra-cardiac flow quantification, which was also shown in the ex-vivo phantom measurements.
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http://dx.doi.org/10.1109/EMBC.2018.8512412DOI Listing
July 2018

Increased incidence of infective endocarditis in patients with ventricular septal defect.

Congenit Heart Dis 2018 Nov 27;13(6):1005-1011. Epub 2018 Sep 27.

National Heart Centre, Singapore.

Background: Ventricular septal defect (VSD) is one of the most common congenital heart anomalies in childhood and there is an increasing prevalence of VSDs in the adult population. The long-term risk of infective endocarditis (IE) is of concern. The aim of this study was to clarify and compare the incidence of IE in adults with repaired and unrepaired VSDs.

Methods: Patients with VSDs were identified using the Adult Congenital Heart Disease registry at the National Heart Centre Singapore. Patients were divided into Group 1 (repaired VSD) and Group 2 (unrepaired VSDs). The electronic medical records were searched for hospitalization due to IE during a 10-year period (October 2, 2007-October 1, 2017).

Results: Four hundred seventy-nine patients (53% male) were identified, with a mean age of 35.0 ± 13.7 years. There were 164 patients (34.2%) in Group 1 and 315 patients (65.8%) in Group 2. In total, there were eight episodes of IE from six patients (3 male, mean age of 42.2 ± 20.7 years). Two patients had recurrent IE. The overall incidence of IE was 1.67/1000 y, and this is 11-15-fold higher compared to general adult population. The incidence of IE in Group 2 was 1.90/1000 y. There were no IE cases in Group 1.

Conclusion: Patients with VSDs, especially if unrepaired, carry a substantially increased risk of IE compared to the general population.
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http://dx.doi.org/10.1111/chd.12667DOI Listing
November 2018

Is subdural hemorrhage after pulmonary endarterectomy underrecognized?

J Thorac Cardiovasc Surg 2018 11 3;156(5):2039-2042. Epub 2018 Jul 3.

Department of Cardiology, National Heart Centre Singapore, Singapore.

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http://dx.doi.org/10.1016/j.jtcvs.2018.06.029DOI Listing
November 2018

Comparative analysis of right heart chamber remodeling after surgical and device secundum atrial septal defect closure in adults.

J Interv Cardiol 2018 Oct 4;31(5):672-678. Epub 2018 Jun 4.

Department of Cardiology, National Heart Centre Singapore, Singapore.

Background: To determine differences in right heart remodeling for patients with ASD who underwent surgical compared to device closure.

Methods: Retrospective analysis of echo data of 121 adult patients with ASD from 2005 to 2015 performed prior to closure and within 6-8 weeks, 6 months, and 1 year post closure.

Results: 121 patients with median age of 39 were studied. Patients who underwent device closure were older (46 vs 37 years, P < 0.05) with smaller mean ASD size (1.9 cm vs 2.3 cm, P < 0.05). We observed a similar and significant reduction in right heart parameters and PASP for both surgical and device closure groups on serial echos up to 1 year. Device closure was associated with preservation of TAPSE compared to surgical closure (reduction of 0.2 cm vs 0.6 cm, P < 0.001). Younger adults with ASD intervention (<40 years) had lower baseline PASP (33 mmHg vs 40 mmHg, P < 0.05) compared to older adults (>40 years). This difference persisted up to 1 year with no difference in rate of right heart remodeling. The effects of device closure with better preservation of TAPSE and S' compared to surgery were consistent within both groups of younger and older adults.

Conclusion: Device and surgical closure of ASD both result in similar improvements in right heart parameters. However, device closure is associated with better preservation of TAPSE at 1 year post intervention. Intervention for older adults with ASD, when compared to younger ones, did not result in a difference in rate of right heart remodeling.
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http://dx.doi.org/10.1111/joic.12528DOI Listing
October 2018

Efficient estimation of personalized biventricular mechanical function employing gradient-based optimization.

Int J Numer Method Biomed Eng 2018 07 22;34(7):e2982. Epub 2018 Apr 22.

Simula Research Laboratory, 1325, Lysaker, Norway.

Individually personalized computational models of heart mechanics can be used to estimate important physiological and clinically-relevant quantities that are difficult, if not impossible, to directly measure in the beating heart. Here, we present a novel and efficient framework for creating patient-specific biventricular models using a gradient-based data assimilation method for evaluating regional myocardial contractility and estimating myofiber stress. These simulations can be performed on a regular laptop in less than 2 h and produce excellent fit between measured and simulated volume and strain data through the entire cardiac cycle. By applying the framework using data obtained from 3 healthy human biventricles, we extracted clinically important quantities as well as explored the role of fiber angles on heart function. Our results show that steep fiber angles at the endocardium and epicardium are required to produce simulated motion compatible with measured strain and volume data. We also find that the contraction and subsequent systolic stresses in the right ventricle are significantly lower than that in the left ventricle. Variability of the estimated quantities with respect to both patient data and modeling choices are also found to be low. Because of its high efficiency, this framework may be applicable to modeling of patient specific cardiac mechanics for diagnostic purposes.
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http://dx.doi.org/10.1002/cnm.2982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043386PMC
July 2018

Image-based computational assessment of vascular wall mechanics and hemodynamics in pulmonary arterial hypertension patients.

J Biomech 2018 02 27;68:84-92. Epub 2017 Dec 27.

Department of Mechanical Engineering, Michigan State University, 2555 Engineering Building, East Lansing, MI 48824, USA. Electronic address:

Pulmonary arterial hypertension (PAH) is a disease characterized by an elevated pulmonary arterial (PA) pressure. While several computational hemodynamic models of the pulmonary vasculature have been developed to understand PAH, they are lacking in some aspects, such as the vessel wall deformation and its lack of calibration against measurements in humans. Here, we describe a computational modeling framework that addresses these limitations. Specifically, computational models describing the coupling of hemodynamics and vessel wall mechanics in the pulmonary vasculature of a PAH patient and a normal subject were developed. Model parameters, consisting of linearized stiffness E of the large vessels and Windkessel parameters for each outflow branch, were calibrated against in vivo measurements of pressure, flow and vessel wall deformation obtained, respectively, from right-heart catheterization, phase-contrast and cine magnetic resonance images. Calibrated stiffness E of the proximal PA was 2.0 and 0.5 MPa for the PAH and normal models, respectively. Calibrated total compliance C and resistance R of the distal vessels were, respectively, 0.32 ml/mmHg and 11.3 mmHg∗min/l for the PAH model, and 2.93 ml/mmHg and 2.6 mmHg∗min/l for the normal model. These results were consistent with previous findings that the pulmonary vasculature is stiffer with more constricted distal vessels in PAH patients. Individual effects on PA pressure due to remodeling of the distal and proximal compartments of the pulmonary vasculature were also investigated in a sensitivity analysis. The analysis suggests that the remodeling of distal vasculature contributes more to the increase in PA pressure than the remodeling of proximal vasculature.
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http://dx.doi.org/10.1016/j.jbiomech.2017.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783768PMC
February 2018

Percutaneous Decommissioning of Left Ventricular Assist Device.

Heart Lung Circ 2018 Jul 19;27(7):853-855. Epub 2017 Aug 19.

Department of Cardiothoracic Surgery, National Heart Centre Singapore, Singapore.

Background: The left ventricular assist device (LVAD) has revolutionised our treatment of advanced stage heart failure, giving debilitated patients a new lease on life. A small proportion of these LVAD patients can be bridged-to-recovery. The identification of these patients and decision to wean, however, can be challenging.

Methods: The need to fully explant the device upon recovery has evolved to a minimalist approach aiming to avoid injury to the 'recovered' heart. A review of the evolution of explant strategies was performed to guide our decision to wean the LVAD in our early experience.

Results: Between 2009 and 2014, two patients in our series of 69 LVAD implants (2.9%) were successfully weaned off their LVADs. The second patient had a minimal access implantation of his HeartWare Ventricular Assist Device (HVAD, Medtronic Inc, Framingham, MA, USA). His clinical variables and minimalist weaning strategy are described.

Conclusions: A case of LVAD decommissioning by thrombosis of the outflow graft, using percutaneous Amplatzer Vascular Plug II (St. Jude Medical, St. Paul, MN, USA) without surgery is reported.
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http://dx.doi.org/10.1016/j.hlc.2017.07.011DOI Listing
July 2018

Multiple pregnancy in a primigravida with uncorrected Pentalogy of Fallot.

BMJ Case Rep 2017 Jan 18;2017. Epub 2017 Jan 18.

Department of Obstetrics and Gynaecology, Singapore General Hospital, Singapore, Singapore.

Pentalogy of Fallot is a cyanotic congenital heart disease that has guarded prognosis without surgical intervention in infancy. Women with uncorrected defects rarely survive into childbearing age and pregnancy in this group is associated with a high rate of perinatal loss. Physiological cardiovascular changes in pregnancy can lead to maternal haemodynamic instability with subsequent adverse cardiac sequelae with or without fetal decompensation. Optimum management and pregnancy outcomes in mother with uncorrected Pentalogy of Fallot and twin pregnancy have not been described in the literature. We describe a successful case of monochorionic diamniotic twin pregnancy in an affected woman who has not undergone surgical repair. Her pregnancy progressed without any adverse cardiopulmonary complications. Her caesarean delivery and postpartum recovery were favourable, with successful birth of two healthy babies at 35.7 weeks. This case emphasises the importance of a multidisciplinary team, especially of obstetricians with expertise in high-risk pregnancies, adult congenital heart disease cardiologists and anaesthesiologist.
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http://dx.doi.org/10.1136/bcr-2016-216809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256472PMC
January 2017

Patient-Specific Computational Analysis of Ventricular Mechanics in Pulmonary Arterial Hypertension.

J Biomech Eng 2016 11;138(11)

Department of Mechanical Engineering, Michigan State University, East Lansing, MI 48824-1226 e-mail:

Patient-specific biventricular computational models associated with a normal subject and a pulmonary arterial hypertension (PAH) patient were developed to investigate the disease effects on ventricular mechanics. These models were developed using geometry reconstructed from magnetic resonance (MR) images, and constitutive descriptors of passive and active mechanics in cardiac tissues. Model parameter values associated with ventricular mechanical properties and myofiber architecture were obtained by fitting the models with measured pressure-volume loops and circumferential strain calculated from MR images using a hyperelastic warping method. Results show that the peak right ventricle (RV) pressure was substantially higher in the PAH patient (65 mmHg versus 20 mmHg), who also has a significantly reduced ejection fraction (EF) in both ventricles (left ventricle (LV): 39% versus 66% and RV: 18% versus 64%). Peak systolic circumferential strain was comparatively lower in both the left ventricle (LV) and RV free wall (RVFW) of the PAH patient (LV: -6.8% versus -13.2% and RVFW: -2.1% versus -9.4%). Passive stiffness, contractility, and myofiber stress in the PAH patient were all found to be substantially increased in both ventricles, whereas septum wall in the PAH patient possessed a smaller curvature than that in the LV free wall. Simulations using the PAH model revealed an approximately linear relationship between the septum curvature and the transseptal pressure gradient at both early-diastole and end-systole. These findings suggest that PAH can induce LV remodeling, and septum curvature measurements may be useful in quantifying transseptal pressure gradient in PAH patients.
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http://dx.doi.org/10.1115/1.4034559DOI Listing
November 2016

Three-Dimensional Tricuspid Annular Motion Analysis from Cardiac Magnetic Resonance Feature-Tracking.

Ann Biomed Eng 2016 12 19;44(12):3522-3538. Epub 2016 Jul 19.

National Heart Centre Singapore, 5 Hospital Drive, Singapore, 169609, Singapore.

Right ventricular (RV) dysfunction is known to be highly correlated with mortality and morbidity; nevertheless, imaging-based assessment of RV anatomy and physiology lags far behind that of the left ventricle. In this study, we advance RV imaging using cardiac magnetic resonance (CMR) to accomplish the following aims: (i) track the motion of six tricuspid annular (TA) sites using a semi-automatic tracking system; (ii) extract clinically important TA measurements-systolic velocity (Sm), early diastolic velocity (Em), late diastolic velocity (Am), and TA plane systolic excursion (TAPSE)-for each TA site and compare these CMR-derived measurements in healthy subjects vs. patients with heart failure, repaired tetralogy of Fallot, pulmonary hypertension, and hypertrophic cardiomyopathy; (iii) investigate how the TA motion related measurements compare with information provided by invasive right heart catheterization (RHC); (iv) evaluate the rate of change in surface area swept out by the reconstructed tricuspid annulus over time and (v) assess the reproducibility of this CMR-based technique. Results indicate that TA motion parameter data obtained in three dimensions using the proposed CMR-based systematic methodology achieve superior diagnostic performance (Sm: AUC = 0.957; TAPSE: AUC = 0.981) compared to two-dimensional CMR imaging. Both Sm and TAPSE from CMR correlated positively with dP/dt /IP from RHC (Sm: r = 0.621, p < 0.01; TAPSE: r = 0.648, p < 0.01). Our highly reproducible and robust methodology holds potential for extending CMR imaging to characterization of TA morphology and dynamic behaviour, eventually leading to deeper understanding of RV function and improved diagnostic capability.
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http://dx.doi.org/10.1007/s10439-016-1695-2DOI Listing
December 2016

Aortic Dilatation at Different Levels of the Ascending Aorta in Patients with Bicuspid Aortic Valve.

Ann Acad Med Singap 2016 Jun;45(6):251-5

Cardiology Department, National Heart Centre Singapore, Singapore.

Introduction: Bicuspid aortic valve (BAV) is the most common form of adult congenital heart disease. When compared to patients with a normal trileaflet aortic valve, dilatation of the aortic root and the ascending aorta (Asc Ao) are the common findings in patients with BAV, with consequent higher risk of developing aortic aneurysm, aortic dissection and rupture. We aim to determine the site of the Asc Ao where maximum dilatation occurs in Asian adult patients with BAV.

Materials And Methods: All subjects underwent full echocardiography examination. The diameter of the Asc Ao was measured at 3 cm, 4 cm, 5 cm, 6 cm and 7 cm from the level of aortic annulus to the Asc Ao in 2D from the parasternal long-axis view.

Results: A total of 80 patients (male/female: 45/35; mean age: 45.3 ± 16.2 years) with congenital BAV and 30 normal control group (male/female: 16/14; mean age: 45.9 ± 15.1 years) were enrolled. The indexed diameters of the Asc Ao were significantly larger than the control group. In patients with BAV, maximum dilatation of Asc Ao occurred around 6 cm distal to the aortic annulus.

Conclusion: In patients with BAV, dilatation of Asc Ao is maximal at the mid Asc Ao region around 6 cm distal to the aorta annulus.
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June 2016

Surgical correction of persistent truncus arteriosus on a 33-year-old male with unilateral pulmonary hypertension from migration of pulmonary artery band.

J Cardiothorac Surg 2016 Mar 29;11:39. Epub 2016 Mar 29.

Department of Cardiothoracic Surgery, National Heart Centre Singapore, Level 12, 5 Hospital Drive, Singapore, 169609, Singapore.

Background: Persistent truncus arteriosus is a rare congenital condition with which survival into adulthood is dismal without surgery. This is the oldest patient reported to our knowledge demonstrating the feasibility of assessing operability in persistent truncus arteriosus with unilateral pulmonary stenosis, and performing full corrective surgery in adulthood.

Case Presentation: We report a Chinese male with successful correction of Type I persistent truncus arteriosus at 33 years of age. He had unilateral pulmonary hypertension from migration of pulmonary artery band from the main to the right pulmonary artery, severe truncal valve regurgitation from previous infective endocarditis, and progressive congestive heart failure. Improvement of lung perfusion was demonstrated 21 months post operation.

Conclusion: This case demonstrated that in patients with persistent truncus arteriosus and two pulmonary arteries, pulmonary vascular disease or underdevelopment of one lung does not preclude a full corrective surgery so long as the other vascular bed is normal. It is important to emphasize the importance of assessing patient's operability in totality.
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http://dx.doi.org/10.1186/s13019-016-0435-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812612PMC
March 2016

Cardiac MRI based numerical modeling of left ventricular fluid dynamics with mitral valve incorporated.

J Biomech 2016 05 10;49(7):1199-1205. Epub 2016 Mar 10.

National Heart Centre Singapore, 5 Hospital Drive, 169609, Singapore; Duke-NUS Graduate Medical School Singapore, Singapore. Electronic address:

Recent numerical studies were focused on the modeling of flow in patient-specific left ventricle (LV); however, the mitral valve (MV) was usually excluded. In this study, both patient-specific LV and MV were modeled to achieve a more realistic intraventricular flow. Cardiac MRI images were acquired from a pulmonary arterial hypertension (PAH) patient and a healthy volunteer, and manual segmentation was conducted to reconstruct three-dimensional (3D) LV and MV geometries at each frame. Based on these 3D geometries, vortex formation time (VFT) was derived, and the values were 4.0 and 6.5 for the normal subject and the PAH patient, respectively. Based on studies in the literature, VTF in the healthy subject fell within the normal range, while that in the PAH patient exceeded the threshold for normality. The vortex structures in the LV clearly showed that the vortex ring was initiated from the tips of the MV instead of the mitral annulus. The excessive VFT during the rapid filling phase in the PAH patient resulted in a trailing flow structure behind the primary vortex ring, which was not observed in the normal subject. It can be deduced from this study that incorporating the MV into a patient-specific model is necessary to produce more reasonable VFT and intraventricular flow.
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http://dx.doi.org/10.1016/j.jbiomech.2016.03.008DOI Listing
May 2016

Molecular pathogenesis of Marfan syndrome.

Int J Cardiol 2015 31;187:585-91. Epub 2015 Mar 31.

National Heart Research Institute Singapore, Singapore; Cardiovascular & Metabolic Disorders Program, DUKE-NUS Graduate Medical School, Singapore. Electronic address:

Marfan syndrome (MFS) is a genetic disorder that affects multiple organs. Mortality imposed by aortic aneurysm and dissections represent the most serious clinical manifestation of MFS. Progressive pathological aortic root enlargement as the result of degeneration of microfibril architecture and consequential loss of extracellular matrix integrity due to fibrillin-1 (FBN1) mutations are commonly diagnosed clinical manifestations of MFS. However, overlapping clinical manifestations with other aneurysmal disorders present a significant challenge in early and accurate diagnosis of MFS. While FBN1 mutations, abnormal transforming growth factor-β signaling and dysregulated matrix metalloproteinases have been implicated in MFS, clinically accepted risk-stratifying biomarkers have yet to be reliably identified. In this review, we summarize current consensus and recent insights in the understanding of MFS pathogenesis. Finally, we introduce the application of induced pluripotent stem cells (iPSCs) as cellular models for MFS and its potential as a novel platform into providing better appreciation of mechanisms underlying MFS diverse manifestations in the cardiovascular system.
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http://dx.doi.org/10.1016/j.ijcard.2015.03.423DOI Listing
May 2016

Graph-cuts based reconstructing patient specific right ventricle: first human study.

Annu Int Conf IEEE Eng Med Biol Soc 2014 ;2014:6770-3

Right ventricular (RV) function is increasingly recognized to play an important role in the clinical status and long-term outcome in patients with congenital heart disease as well as ischemic cardiomyopathy with left ventricular dysfunction. However, quantification of RV characteristics and function are still challenging due to its complex morphology and its thin wall with coarse trabeculations. To assess RV functions quantitatively, establishing the patient-specific model from medical images is a prerequisite task. This study aims to develop a novel method for RV model reconstruction. Magnetic resonance images were acquired and preprocessed. Contours of right ventricle, right atrium and pulmonary artery were manually delineated at all slices and all time frames. The contour coordinates as well as the medical image specifications such as image pixel resolution and slick thickness were exported. The contours were transformed to the correct positions. Reorientation and matching were executed in between neighboring contours; extrapolation and interpolation were conducted upon all contours. After preprocessing, the more dense point set was reconstructed through a variational tool. A Delaunay-based tetrahedral mesh was generated on the region of interest. The weighted minimal surface model was used to describe RV surface. The graphcuts technique, i.e., max-flow/min-cut algorithm, was applied to minimize the energy defined by the model. The reconstructed surface was extracted from the mesh according to the mincut. Smoothing and remeshing were performed. The CPU time to reconstruct the model for one frame was approximately 2 minutes. In 10 consecutive subjects referred for cardiac MRI (80% female), right ventricular volumes were measured using our method against the commercial available CMRtools package. The results demonstrated that there was a significant correlation in end-diastolic and end-systolic volumes between our method and commercial software (r= 0.89 for end-diastolic volume and r=0.79 for end-systolic volume, both P<;0.0001). The time to obtain right ventricular volumes was shorter using our method than commercial one. In conclusion, a new method for right ventricle reconstruction has been developed. We envisage that this automatic modeling tool could be used by radiographer and cardiologists to assess the RV function in diverse heart diseases.
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http://dx.doi.org/10.1109/EMBC.2014.6945182DOI Listing
October 2015

Assessment of left ventricular preload by cardiac magnetic resonance imaging predicts exercise capacity in adult operated tetralogy of Fallot: a retrospective study.

BMC Cardiovasc Disord 2014 Sep 23;14:122. Epub 2014 Sep 23.

Department of Cardiology, National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore.

Background: The optimal timing of pulmonary homograft valve replacement (PVR) is uncertain. Cardiopulmonary exercise testing (CPET) and cardiac magnetic resonance (CMR) are often used to guide the clinical decision for PVR in operated tetralogy of Fallot (TOF) patients with significant pulmonary regurgitation (PR). We aim to study the relationship between exercise capacity and CMR in these patients.

Methods: The study is a single-centre retrospective analysis of 36 operated TOF patients [median 21.4 (interquartile range 16.4, 26.4) years post-repair; 30 NYHA I, 6 NYHA II; median age 25.2 (interquartile range 19.5-31.7) years, 29 males] with significant PR on CMR who underwent CPET within 15 [median 2.0 (interquartile range 0.8-7.2)] months from CMR. CPET parameters were compared with 30 age- and sex-matched healthy controls [median age 27.8 (interquartile range 21.0-32.8) years; 24 males].

Results: Peak systolic blood pressure (177 versus 192 mmHg, p = 0.007), Mets (7.3 versus 9.9, p < 0.001), peak oxygen consumption (VO2max) (29.2 versus 34.5 ml/kg/min, p < 0.001) and peak oxygen pulse (11.0 versus 13.7 ml/beat, p = 0.003) were significantly lower in TOF group versus control. Univariate analyses showed negative correlation between PR fraction and anaerobic threshold. There was a positive correlation between indexed left (LV) and right (RV) ventricular end-diastolic volumes, as well as indexed LV and effective RV stroke volumes, on CMR and VO2max and Mets achieved on CPET. These remained significant after adjustment for age and sex.

Conclusions: TOF subjects have near normal exercise capacity but significantly lower Mets, VO2max and peak oygen pulse achieved compared to controls. Increased PR fraction in TOF subjects was associated with lower anaerobic threshold. Higher indexed effective RV stroke volume, a measure of LV preload, was associated with higher VO2max and Mets achieved, and may potentially be used as a predictor of exercise capacity.
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http://dx.doi.org/10.1186/1471-2261-14-122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177590PMC
September 2014

Pattern of aortic dilatation in different bicuspid aortic valve phenotypes and its association with aortic valvular dysfunction and elasticity.

Heart Lung Circ 2014 Jan 11;23(1):32-8. Epub 2013 Jul 11.

Cardiology Department, National Heart Centre Singapore, Singapore. Electronic address:

Objectives: We aim to study the pattern of aortic dilatation in different BAV phenotypes and to find any correlations between aortic dilatation, aortic elasticity and AS and/or AR in our local population.

Methods: All BAV patients and controls were retrospectively studied. Aortic distensibility and stiffness index of the ascending aorta were calculated.

Results: A total of 191 patients with BAV and 180 controls were enrolled. Aortic dilatation involving a single site was more common with dilatation involving only the ascending aorta (R-N phenotype) and aortic root (N-L phenotype). AR was most common in patients with N-L and R-L phenotypes and AS in R-N phenotype. Aortic elasticity had no correlation with the different BAV phenotypes.

Conclusions: There are different patterns of aortic dilatation in different BAV phenotypes, which may further contribute to the development of aortic stenosis or regurgitation. Aortic elasticity is independent of the BAV phenotypes and is impaired in BAV patients regardless of AS or AR severity.
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http://dx.doi.org/10.1016/j.hlc.2013.05.644DOI Listing
January 2014

An unusual cause of severe pulmonary hypertension in a young woman.

Ann Acad Med Singap 2013 Feb;42(2):91-2

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February 2013

Fragmented QRS complexes predict right ventricular dysfunction and outflow tract aneurysms in patients with repaired tetralogy of Fallot.

Int J Cardiol 2013 Aug 21;167(4):1366-72. Epub 2012 Apr 21.

National Heart Centre Singapore, Singapore.

Background: Fragmented QRS complexes (fQRS) correlate with myocardial scar, and may predict arrhythmias in patients with repaired tetralogy of Fallot (TOF). We investigated the relationship between fQRS in operated TOF patients with right ventricular (RV) dysfunction and RV outflow tract (RVOT) aneurysm.

Methods: We studied 56 operated TOF patients with moderate/severe pulmonary regurgitation, referred for cardiac magnetic resonance imaging (MRI) over a 4.5 year period. The presence of fQRS (additional notches in the R/S wave in ≥ 2 contiguous leads on the ECG) was correlated with MRI findings.

Results: fQRS was observed in 44 (78.6%) patients. Patients with fQRS had significantly larger RV end diastolic volume index (RVEDVi; 162 ml vs 141 ml, p=0.028) and RV end systolic volume index (RVESVi; 88 ml vs 70 ml, p=0.031). Increasing number of leads with fragmentation was independently associated with increasingly lower RV ejection fraction (adjusted co-efficient -0.97, 95%CI -1.83 to -0.12, p=0.026), greater pulmonary regurgitation fraction (1.65, 0.28 to 3.01, p=0.019), larger RVEDVi (6.78, 2.00 to 11.56, p=0.006) and RVESVi (5.41, 1.66 to 9.15, p=0.005). Anterior fragmentation correlated most significantly with RV dysfunction (p<0.05). fQRS had no significant association with LV dysfunction. Presence of any fQRS (OR 17.5, 95%CI 2.1-147.8, p=0.009) and inferior fQRS (OR 9.0, 95%CI 2.7-30.1, p<0.001) were found to be significant predictors for RVOT aneurysm.

Conclusions: The presence of fQRS on the ECG is significantly associated with RV dysfunction and RVOT aneurysms in repaired TOF patients. Increasing burden of fragmentation, especially in the anterior leads, is associated with increasing RV dysfunction.
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http://dx.doi.org/10.1016/j.ijcard.2012.04.004DOI Listing
August 2013

Right ventricular regional wall curvedness and area strain in patients with repaired tetralogy of Fallot.

Am J Physiol Heart Circ Physiol 2012 Mar 30;302(6):H1306-16. Epub 2011 Dec 30.

Cardiac Mechanics Engineering and Physiology Unit, National Heart Centre Singapore, Singapore.

A quantitative understanding of right ventricular (RV) remodeling in repaired tetralogy of Fallot (rTOF) is crucial for patient management. The objective of this study is to quantify the regional curvatures and area strain based on three-dimensional (3-D) reconstructions of the RV using cardiac magnetic resonance imaging (MRI). Fourteen (14) rTOF patients and nine (9) normal subjects underwent cardiac MRI scan. 3-D RV endocardial surface models were reconstructed from manually delineated contours and correspondence between end-diastole (ED) and end systole (ES) was determined. Regional curvedness (C) and surface area at ED and ES were calculated as well as the area strain. The RV shape and deformation in rTOF patients differed from normal subjects in several respects. Firstly, the curvedness at ED (mean for 13 segments, 0.030 ± 0.0076 vs. 0.029 ± 0.0065 mm(-1); P < 0.05) and ES (mean for 13 segments, 0.040 ± 0.012 vs. 0.034 ± 0.0072 mm(-1); P < 0.001) was decreased by chronic pulmonary regurgitation. Secondly, the surface area increased significantly at ED (mean for 13 segments, 982 ± 192 vs. 1,397 ± 387 mm(2); P < 0.001) and ES (mean for 13 segments, 576 ± 130 vs. 1,012 ± 302 mm(2); P < 0.001). In particular, rTOF patients had significantly larger surface area than that in normal subjects in the free wall but not for the septal wall. Thirdly, area strain was significantly decreased (mean for 13 segments, 56 ± 6 vs. 34 ± 7%; P < 0.0001) in rTOF patients. Fourthly, there were increases in surface area at ED (5,726 ± 969 vs. 6,605 ± 1,122 mm(2); P < 0.05) and ES (4,280 ± 758 vs. 5,569 ± 1,112 mm(2); P < 0.01) and decrease in area strain (29 ± 8 vs. 18 ± 8%; P < 0.001) for RV outflow tract. These findings suggest significant geometric and strain differences between rTOF and normal subjects that may help guide therapeutic treatment.
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http://dx.doi.org/10.1152/ajpheart.00679.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3311479PMC
March 2012