Increased availability and access to medical image data has enabled more quantitative approaches to clinical diagnosis, prognosis, and treatment planning for congenital heart disease. Here we present an overview of long-term clinical management of tetralogy of Fallot (TOF) and its intersection with novel computational and data science approaches to discovering biomarkers of functional and prognostic importance. Efforts in translational medicine that seek to address the clinical challenges associated with cardiovascular diseases using personalized and precision-based approaches are then discussed. The considerations and challenges of translational cardiovascular medicine are reviewed, and examples of digital platforms with collaborative, cloud-based, and scalable design are provided.

Background

Although left ventricular cardiac geometric indices such as size and sphericity characterize adverse remodeling and have prognostic value in symptomatic patients, little is known of shape distributions in subclinical populations. We sought to quantify shape variation across a large number of asymptomatic volunteers, and examine differences among sub-cohorts.

Methods

An atlas was constructed comprising 1,991 cardiovascular magnetic resonance (CMR) cases contributed from the Multi-Ethnic Study of Atherosclerosis baseline examination. A mathematical model describing regional wall motion and shape was used to establish a coordinate map registered to the cardiac anatomy. The model was automatically customized to left ventricular contours and anatomical landmarks, corrected for breath-hold mis-registration between image slices. Mathematical techniques were used to characterize global shape distributions, after removal of translations, rotations, and scale due to height. Differences were quantified among ethnicity, sex, smoking, hypertension and diabetes sub-cohorts.

Results

The atlas construction process yielded accurate representations of global shape (errors between manual and automatic surface points in 244 validation cases were less than the image pixel size). After correction for height, the dominant shape component was associated with heart size, explaining 32% of the total shape variance at end-diastole and 29% at end-systole. After size, the second dominant shape component was sphericity at end-diastole (13%), and concentricity at end-systole (10%). The resulting shape components distinguished differences due to ethnicity and risk factors with greater statistical power than traditional mass and volume indices.

Conclusions

We have quantified the dominant components of global shape variation in the adult asymptomatic population. The data and results are available at cardiacatlas.org. Shape distributions were principally explained by size, sphericity and concentricity, which are known correlates of adverse outcomes. Atlas-based global shape analysis provides a powerful method for quantifying left ventricular shape differences in asymptomatic populations.

Trial registration

ClinicalTrials.gov NCT00005487.

Remodeling in adults with repaired tetralogy of Fallot (rToF) may occur due to chronic pulmonary regurgitation, but may also be related to altered flow patterns, including vortices. We aimed to correlate and quantify relationships between vorticity and ventricular shape derived from atlas-based analysis of biventricular shape. Adult rToF (n = 12) patients underwent 4D flow and cine MRI imaging. Vorticity in the RV was computed after noise reduction using a neural network. A biventricular shape atlas built from 95 rToF patients was used to derive principal component modes, which were associated with vorticity and pulmonary regurgitant volume (PRV) using univariate and multivariate linear regression. Univariate analysis showed that indexed PRV correlated with 3 modes (r = -0.55,-0.50, and 0.6, all p < 0.05) associated with RV dilatation and an increase in basal bulging, apical bulging and tricuspid annulus tilting with more severe regurgitation, as well as a smaller LV and paradoxical movement of the septum. RV outflow and inflow vorticity were also correlated with these modes. However, total vorticity over the whole RV was correlated with two different modes (r = -0.62,-0.69, both p < 0.05). Higher vorticity was associated with both RV and LV shape changes including longer ventricular length, a larger bulge beside the tricuspid valve, and distinct tricuspid tilting. RV flow vorticity was associated with changes in biventricular geometry, distinct from associations with PRV. Flow vorticity may provide additional mechanistic information in rToF remodeling. Both LV and RV shapes are important in rToF RV flow patterns.

Abstract Background Cardiovascular imaging studies generate a wealth of data which is typically used only for individual study endpoints. By pooling data from multiple sources, quantitative comparisons can be made of regional wall motion abnormalities between different cohorts, enabling reuse of valuable data. Atlas-based analysis provides precise quantification of shape and motion differences between disease groups and normal subjects. However, subtle shape differences may arise due to differences in imaging protocol between studies. Methods A mathematical model describing regional wall motion and shape was used to establish a coordinate system registered to the cardiac anatomy. The atlas was applied to data contributed to the Cardiac Atlas Project from two independent studies which used different imaging protocols: steady state free precession (SSFP) and gradient recalled echo (GRE) cardiovascular magnetic resonance (CMR). Shape bias due to imaging protocol was corrected using an atlas-based transformation which was generated from a set of 46 volunteers who were imaged with both protocols. Results Shape bias between GRE and SSFP was regionally variable, and was effectively removed using the atlas-based transformation. Global mass and volume bias was also corrected by this method. Regional shape differences between cohorts were more statistically significant after removing regional artifacts due to imaging protocol bias. Conclusions Bias arising from imaging protocol can be both global and regional in nature, and is effectively corrected using an atlas-based transformation, enabling direct comparison of regional wall motion abnormalities between cohorts acquired in separate studies.

Current indications for pulmonary valve replacement (PVR) in repaired tetralogy of Fallot (rTOF) rely on cardiovascular magnetic resonance (CMR) image-based indices but are inconsistently applied, lead to mixed outcomes, and remain debated. This study aimed to test the hypothesis that specific markers of biventricular shape may discriminate differences between rTOF patients who did and did not require subsequent PVR better than standard imaging indices. In this cross-sectional retrospective study, biventricular shape models were customized to CMR images from 84 rTOF patients. A statistical atlas of end-diastolic shape was constructed using principal component analysis. Multivariate regression was used to quantify shape mode and imaging index associations with subsequent intervention status (PVR, n = 48 vs. No-PVR, n = 36), while accounting for confounders. Clustering analysis was used to test the ability of the most significant shape modes and imaging indices to discriminate PVR status as evaluated by a Matthews correlation coefficient (MCC). Geometric strain analysis was also conducted to assess shape mode associations with systolic function. PVR status correlated significantly with shape modes associated with right ventricular (RV) apical dilation and left ventricular (LV) dilation (p < 0.01), RV basal bulging and LV conicity (p < 0.05), and pulmonary valve dilation (p < 0.01). PVR status also correlated significantly with RV ejection fraction (p < 0.05) and correlated marginally with LV end-systolic volume index (p < 0.07). Shape modes discriminated subsequent PVR better than standard imaging indices (MCC = 0.49 and MCC = 0.28, respectively) and were significantly associated with RV and LV radial systolic strain. Biventricular shape modes discriminated differences between patients who did and did not require subsequent PVR better than standard imaging indices in current use. These regional features of cardiac morphology may provide insight into adaptive vs. maladaptive types of structural remodeling and point toward an improved quantitative, patient-specific assessment tool for clinical use.

BACKGROUND: Relationships between right ventricular (RV) and left ventricular (LV) shape and function may be useful in determining optimal timing for pulmonary valve replacement in patients with repaired tetralogy of Fallot (rTOF). However, these are multivariate and difficult to quantify. We aimed to quantify variations in biventricular shape associated with pulmonary regurgitant volume (PRV) in rTOF using a biventricular atlas. METHODS: In this cross-sectional retrospective study, a biventricular shape model was customized to cardiovascular magnetic resonance (CMR) images from 88 rTOF patients (median age 16, inter-quartile range 11.8-24.3 years). Morphometric scores quantifying biventricular shape at end-diastole and end-systole were computed using principal component analysis. Multivariate linear regression was used to quantify biventricular shape associations with PRV, corrected for age, sex, height, and weight. Regional associations were confirmed by univariate correlations with distances and angles computed from the models, as well as global systolic strains computed from changes in arc length from end-diastole to end-systole. RESULTS: PRV was significantly associated with 5 biventricular morphometric scores, independent of covariates, and accounted for 12.3% of total shape variation (p < 0.05). Increasing PRV was associated with RV dilation and basal bulging, in conjunction with decreased LV septal-lateral dimension (LV flattening) and systolic septal motion towards the RV (all p < 0.05). Increased global RV radial, longitudinal, circumferential and LV radial systolic strains were significantly associated with increased PRV (all p < 0.05). CONCLUSION: A biventricular atlas of rTOF patients quantified multivariate relationships between left-right ventricular morphometry and wall motion with pulmonary regurgitation. Regional RV dilation, LV reduction, LV septal-lateral flattening and increased RV strain were all associated with increased pulmonary regurgitant volume. Morphometric scores provide simple metrics linking mechanisms for structural and functional alteration with important clinical indices.

Background

Although adverse left ventricular shape changes (remodeling) after myocardial infarction (MI) are predictive of morbidity and mortality, current clinical assessment is limited to simple mass and volume measures, or dimension ratios such as length to width ratio. We hypothesized that information maximizing component analysis (IMCA), a supervised feature extraction method, can provide more efficient and sensitive indices of overall remodeling.

Methods

IMCA was compared to linear discriminant analysis (LDA), both supervised methods, to extract the most discriminatory global shape changes associated with remodeling after MI. Finite element shape models from 300 patients with myocardial infarction from the DETERMINE study (age 31-86, mean age 63, 20 % women) were compared with 1991 asymptomatic cases from the MESA study (age 44-84, mean age 62, 52 % women) available from the Cardiac Atlas Project. IMCA and LDA were each used to identify a single mode of global remodeling best discriminating the two groups. Logistic regression was employed to determine the association between the remodeling index and MI. Goodness-of-fit results were compared against a baseline logistic model comprising standard clinical indices.

Results

A single IMCA mode simultaneously describing end-diastolic and end-systolic shapes achieved best results (lowest Deviance, Akaike information criterion and Bayesian information criterion, and the largest area under the receiver-operating-characteristic curve). This mode provided a continuous scale where remodeling can be quantified and visualized, showing that MI patients tend to present larger size and more spherical shape, more bulging of the apex, and thinner wall thickness.

Conclusions

IMCA enables better characterization of global remodeling than LDA, and can be used to quantify progression of disease and the effect of treatment. These data and results are available from the Cardiac Atlas Project ( http://www.cardiacatlas.org ).

BACKGROUND: Maladaptive remodelling mechanisms occur in patients with repaired tetralogy of Fallot (rToF) resulting in a cycle of metabolic and structural changes. Biventricular shape analysis may indicate mechanisms associated with adverse events independent of pulmonary regurgitant volume index (PRVI). We aimed to determine novel remodelling patterns associated with adverse events in patients with rToF using shape and function analysis. METHODS: Biventricular shape and function were studied in 192 patients with rToF (median time from TOF repair to baseline evaluation 13.5 years). Linear discriminant analysis (LDA) and principal component analysis (PCA) were used to identify shape differences between patients with and without adverse events. Adverse events included death, arrhythmias, and cardiac arrest with median follow-up of 10 years. RESULTS: LDA and PCA showed that shape characteristics pertaining to adverse events included a more circular left ventricle (LV) (decreased eccentricity), dilated (increased sphericity) LV base, increased right ventricular (RV) apical sphericity, and decreased RV basal sphericity. Multivariate LDA showed that the optimal discriminative model included only RV apical ejection fraction and one PCA mode associated with a more circular and dilated LV base (AUC = 0.77). PRVI did not add value, and shape changes associated with increased PRVI were not predictive of adverse outcomes. CONCLUSION: Pathological remodelling patterns in patients with rToF are significantly associated with adverse events, independent of PRVI. Mechanisms related to incident events include LV basal dilation with a reduced RV apical ejection fraction.