Machine learning evaluation of LV outflow obstruction in hypertrophic cardiomyopathy using three-chamber cardiovascular magnetic resonance.

Left ventricular outflow tract obstruction (LVOTO) is common in hypertrophic cardiomyopathy (HCM), but relationships between anatomical metrics and obstruction are poorly understood. We aimed to develop machine learning methods to evaluate LVOTO in HCM patients and quantify relationships between anatomical metrics and obstruction. This retrospective analysis of 1905 participants of the HCM Registry quantified 11 anatomical metrics derived from 14 landmarks automatically detected on the three-chamber long axis cine CMR images. Linear and logistic regression was used to quantify strengths of relationships with the presence of LVOTO (defined by resting Doppler pressure drop of > 30 mmHg), using the area under the receiver operating characteristic (AUC). Intraclass correlation coefficients between the network predictions and three independent observers showed similar agreement to that between observers. The distance from anterior mitral valve leaflet tip to basal septum (AML-BS) was most highly correlated with Doppler pressure drop (R2 = 0.19, p < 10-5). Multivariate stepwise regression found the best predictive model included AML-BS, AML length to aortic valve diameter ratio, AML length to LV width ratio, and midventricular septal thickness metrics (AUC 0.84). Excluding AML-BS, metrics grouped according to septal hypertrophy, LV geometry, and AML anatomy each had similar associations with LVOTO (AUC 0.71, 0.71, 0.68 respectively, p = ns), significantly less than their combination (AUC 0.77, p < 0.05 for each). Anatomical metrics derived from a standard three-chamber CMR cine acquisition can be used to highlight risk of LVOTO, and suggest further investigation if necessary. A combination of geometric factors is required to provide the best risk prediction.

The Future of Cardiac Magnetic Resonance Clinical Trials.

Over the past 2 decades, cardiac magnetic resonance (CMR) has become an essential component of cardiovascular clinical care and contributed to imaging-guided diagnosis and management of coronary artery disease, cardiomyopathy, congenital heart disease, cardio-oncology, valvular, and vascular disease, amongst others. The widespread availability, safety, and capability of CMR to provide corresponding anatomical, physiological, and functional data in 1 imaging session can improve the design and conduct of clinical trials through both a reduction of sample size and provision of important mechanistic data that may augment clinical trial findings. Moreover, prospective imaging-guided strategies using CMR can enhance safety, efficacy, and cost-effectiveness of cardiovascular pathways in clinical practice around the world. As the future of large-scale clinical trial design evolves to integrate personalized medicine, cost-effectiveness, and mechanistic insights of novel therapies, the integration of CMR will continue to play a critical role. In this document, the attributes, limitations, and challenges of CMR's integration into the future design and conduct of clinical trials will also be covered, and recommendations for trialists will be explored. Several prominent examples of clinical trials that test the efficacy of CMR-imaging guided pathways will also be discussed.

Right ventricular shape and function: cardiovascular magnetic resonance reference morphology and biventricular risk factor morphometrics in UK Biobank.

BACKGROUND: The associations between cardiovascular disease (CVD) risk factors and the biventricular geometry of the right ventricle (RV) and left ventricle (LV) have been difficult to assess, due to subtle and complex shape changes. We sought to quantify reference RV morphology as well as biventricular variations associated with common cardiovascular risk factors. METHODS: A biventricular shape atlas was automatically constructed using contours and landmarks from 4329 UK Biobank cardiovascular magnetic resonance (CMR) studies. A subdivision surface geometric mesh was customized to the contours using a diffeomorphic registration algorithm, with automatic correction of slice shifts due to differences in breath-hold position. A reference sub-cohort was identified consisting of 630 participants with no CVD risk factors. Morphometric scores were computed using linear regression to quantify shape variations associated with four risk factors (high cholesterol, high blood pressure, obesity and smoking) and three disease factors (diabetes, previous myocardial infarction and angina). RESULTS: The atlas construction led to an accurate representation of 3D shapes at end-diastole and end-systole, with acceptable fitting errors between surfaces and contours (average error less than 1.5 mm). Atlas shape features had stronger associations than traditional mass and volume measures for all factors (p < 0.005 for each). High blood pressure was associated with outward displacement of the LV free walls, but inward displacement of the RV free wall and thickening of the septum. Smoking was associated with a rounder RV with inward displacement of the RV free wall and increased relative wall thickness. CONCLUSION: Morphometric relationships between biventricular shape and cardiovascular risk factors in a large cohort show complex interactions between RV and LV morphology. These can be quantified by z-scores, which can be used to study the morphological correlates of disease.

Independent Left Ventricular Morphometric Atlases Show Consistent Relationships with Cardiovascular Risk Factors: A UK Biobank Study.

Left ventricular (LV) mass and volume are important indicators of clinical and pre-clinical disease processes. However, much of the shape information present in modern imaging examinations is currently ignored. Morphometric atlases enable precise quantification of shape and function, but there has been no objective comparison of different atlases in the same cohort. We compared two independent LV atlases using MRI scans of 4547 UK Biobank participants: (i) a volume atlas derived by automatic non-rigid registration of image volumes to a common template, and (ii) a surface atlas derived from manually drawn epicardial and endocardial surface contours. The strength of associations between atlas principal components and cardiovascular risk factors (smoking, diabetes, high blood pressure, high cholesterol and angina) were quantified with logistic regression models and five-fold cross validation, using area under the ROC curve (AUC) and Akaike Information Criterion (AIC) metrics. Both atlases exhibited similar principal components, showed similar relationships with risk factors, and had stronger associations (higher AUC and lower AIC) than a reference model based on LV mass and volume, for all risk factors (DeLong p < 0.05). Morphometric variations associated with each risk factor could be quantified and visualized and were similar between atlases. UK Biobank LV shape atlases are robust to construction method and show stronger relationships with cardiovascular risk factors than mass and volume.

Fully-automated left ventricular mass and volume MRI analysis in the UK Biobank population cohort: evaluation of initial results.

UK Biobank, a large cohort study, plans to acquire 100,000 cardiac MRI studies by 2020. Although fully-automated left ventricular (LV) analysis was performed in the original acquisition, this was not designed for unsupervised incorporation into epidemiological studies. We sought to evaluate automated LV mass and volume (Siemens syngo InlineVF versions D13A and E11C), against manual analysis in a substantial sub-cohort of UK Biobank participants. Eight readers from two centers, trained to give consistent results, manually analyzed 4874 UK Biobank cases for LV end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF) and LV mass (LVM). Agreement between manual and InlineVF automated analyses were evaluated using Bland-Altman analysis and the intra-class correlation coefficient (ICC). Tenfold cross-validation was used to establish a linear regression calibration between manual and InlineVF results. InlineVF D13A returned results in 4423 cases, whereas InlineVF E11C returned results in 4775 cases and also reported LVM. Rapid visual assessment of the E11C results found 178 cases (3.7%) with grossly misplaced contours or landmarks. In the remaining 4597 cases, LV function showed good agreement: ESV -6.4 ± 9.0 ml, 0.853 (mean ± SD of the differences, ICC) EDV -3.0 ± 11.6 ml, 0.937; SV 3.4 ± 9.8 ml, 0.855; and EF 3.5 ± 5.1%, 0.586. Although LV mass was consistently overestimated (29.9 ± 17.0 g, 0.534) due to larger epicardial contours on all slices, linear regression could be used to correct the bias and improve accuracy. Automated InlineVF results can be used for case-control studies in UK Biobank, provided visual quality control and linear bias correction are performed. Improvements between InlineVF D13A and InlineVF E11C show the field is rapidly advancing, with further improvements expected in the near future.

Comparison of effects of losartan and metoprolol on left ventricular and aortic function at rest and during exercise in chronic aortic regurgitation.

Aortic regurgitation (AR) increases the hemodynamic load on both the left ventricle (LV) and the aorta. Vasodilators and beta-blockers both reduce systemic blood pressure, but their relative effects on the LV and aortic function and aortic regurgitant fraction in chronic AR are uncertain. We aimed to compare short-term effects of losartan and metoprolol on LV and aortic function in asymptomatic patients with chronic moderate to severe AR, both at rest and during exercise, using cardiac magnetic resonance (CMR) imaging. 17 chronic AR patients were randomized to 4-6 weeks losartan followed by metoprolol, or vice versa, in a cross-over design. Aortic regurgitant fraction, aortic distensibility, pulse wave velocity and LV function were assessed at rest and after moderate exercise stress (29 ± 7 W, heart rate increase 25 ± 6 bpm) using CMR. Chronic AR patients on metoprolol had a significantly lower mean heart rate, cardiac power index and rate-pressure product, than on losartan (all p < 0.01). However, aortic regurgitant fraction was greater on metoprolol compared to losartan (by 7 ± 11%, p = 0.02). Metoprolol was also associated with a greater reduction in aortic distensibility during exercise than losartan (- 2.4 ± 1.5 × 10-3 vs - 1.7 ± 2.1 × 10-3 mmHg-1 respectively, p = 0.04). End-diastolic volume index was higher on metoprolol than losartan at exercise (difference 6.6 ± 7.8 ml/m2, p < 0.01), as was end-systolic volume index (difference 4.0 ± 5.2 ml/m2, p < 0.01). Losartan and metoprolol have significantly different short-term effects on aortic regurgitation and LV and aortic function in chronic AR. Further research is required to determine the long-term clinical significance of these changes.

Three-Dimensional Volumetric Assessment of Diastolic Function by Cardiac Magnetic Resonance Imaging: The Multi-Ethnic Study of Atherosclerosis (MESA) / Avaliação Volumétrica Tridimensional da Função Diastólica Por Ressonância Magnética Cardíaca: Multi-Ethnic Study Of Atherosclerosis (MESA)

Abstract Background: Cardiac Magnetic Resonance is in need of a simple and robust method for diastolic function assessment that can be done with routine protocol sequences. Objective: To develop and validate a three-dimensional (3D) model-based volumetric assessment of diastolic function using cardiac magnetic resonance (CMR) imaging and compare the results obtained with the model with those obtained by echocardiography. Methods: The study participants provided written informed consent and were included if having undergone both echocardiography and cine steady-state free precession (SSFP) CMR on the same day. Guide points at the septal and lateral mitral annulus were used to define the early longitudinal relaxation rate (E'), while a time-volume curve from the 3D model was used to assess diastolic filling parameters. We determined the correlation between 3D CMR and echocardiography and the accuracy of CMR in classifying the diastolic function grade. Results: The study included 102 subjects. The E/A ratio by CMR was positively associated with the E/A ratio by echocardiography (r = 0.71, p < 0.0001). The early diastolic relaxation velocity by tissue Doppler and longitudinal relaxation rate for the lateral mitral annulus displacement were positively associated (p = 0.007), as were the ratio between Doppler E/e' and CMR E/E' (p = 0.01). CMR-determined normalized peak E (NE) and deceleration time (DT) were able to predict diastolic dysfunction (areas under the curve [AUCs] = 0.70 and 0.72, respectively). In addition, the lateral E/E' ratio showed good utility in identifying diastolic dysfunction (AUC = 0.80). Overall, echocardiography and CMR interobserver and intraobserver agreements were excellent (intraclass correlation coefficient range 0.72 - 0.97). Conclusion: 3D modeling of standard cine CMR images was able to identify study subjects with reduced diastolic function and showed good reproducibility, suggesting a potential for a routine diastolic function assessment by CMR.

Resumo Fundamento: A ressonância magnética cardíaca necessita de um método simples e robusto para a avaliação da função diastólica que pode ser feito com sequências protocolares de rotina. Objetivo: Desenvolver e validar a avaliação volumétrica da função diastólica através de um modelo tridimensional (3D) com utilização de imagens de ressonância magnética cardíaca (RMC) e comparar os resultados obtidos com este modelo com os obtidos por ecocardiografia. Métodos: Os participantes do estudo assinaram um termo de consentimento e foram incluídos se tivessem sido submetidos no mesmo dia tanto à ecocardiografia quanto à cine RMC com precessão livre no estado estacionário (steady-state free precession, SSFP). Pontos-guia foram utilizados no anel mitral septal e lateral para definir a velocidade de estiramento no início da diástole (E'), enquanto curvas de volume-tempo do modelo 3D foram utilizadas para avaliar os parâmetros de enchimento diastólico. Foram determinadas a correlação entre a RMC 3D e a ecocardiografia, além da acurácia da RMC em classificar o grau de função diastólica. Resultados: Ao todo, 102 sujeitos foram incluídos no estudo. A razão E/A pela RMC esteve positivamente associada com a razão E/A obtida pela ecocardiografia (r = 0,71, p < 0,0001). Estiveram positivamente associadas a velocidade de relaxamento diastólico inicial ao Doppler tecidual e a velocidade de relaxamento longitudinal de deslocamento do anel mitral lateral (p = 0,007), bem como a razão entre E/e' por Doppler e E/E' pela RMC (p = 0,01). A velocidade normalizada de pico de enchimento (EM) determinada pela RMC e o tempo de desaceleração (TD) foram capazes de predizer a disfunção diastólica (áreas sob a curva [AUCs] = 0,70 e 0,72, respectivamente). Além disso, a razão E/E' lateral mostrou boa utilidade para a identificação da disfunção diastólica (AUC = 0,80). No geral, a ecocardiografia e a RMC apresentaram excelente concordância interobservador e intraobservador (coeficiente de correlação intraclasse 0,72 - 0,97). Conclusão: Uma modelagem 3D de imagens padrões de cine RMC foi capaz de identificar os indivíduos do estudo com função diastólica reduzida e mostrou uma boa reprodutibilidade, sugerindo ter potencial na avaliação rotineira da função diastólica por RMC.

Quantification of LV function and mass by cardiovascular magnetic resonance: multi-center variability and consensus contours.

BACKGROUND: High reproducibility of LV mass and volume measurement from cine cardiovascular magnetic resonance (CMR) has been shown within single centers. However, the extent to which contours may vary from center to center, due to different training protocols, is unknown. We aimed to quantify sources of variation between many centers, and provide a multi-center consensus ground truth dataset for benchmarking automated processing tools and facilitating training for new readers in CMR analysis. METHODS: Seven independent expert readers, representing seven experienced CMR core laboratories, analyzed fifteen cine CMR data sets in accordance with their standard operating protocols and SCMR guidelines. Consensus contours were generated for each image according to a statistical optimization scheme that maximized contour placement agreement between readers. RESULTS: Reader-consensus agreement was better than inter-reader agreement (end-diastolic volume 14.7 ml vs 15.2-28.4 ml; end-systolic volume 13.2 ml vs 14.0-21.5 ml; LV mass 17.5 g vs 20.2-34.5 g; ejection fraction 4.2 % vs 4.6-7.5 %). Compared with consensus contours, readers were very consistent (small variability across cases within each reader), but bias varied between readers due to differences in contouring protocols at each center. Although larger contour differences were found at the apex and base, the main effect on volume was due to small but consistent differences in the position of the contours in all regions of the LV. CONCLUSIONS: A multi-center consensus dataset was established for the purposes of benchmarking and training. Achieving consensus on contour drawing protocol between centers before analysis, or bias correction after analysis, is required when collating multi-center results.

T-tubule disease: Relationship between t-tubule organization and regional contractile performance in human dilated cardiomyopathy.

Evidence from animal models suggest that t-tubule changes may play an important role in the contractile deficit associated with heart failure. However samples are usually taken at random with no regard as to regional variability present in failing hearts which leads to uncertainty in the relationship between contractile performance and possible t-tubule derangement. Regional contraction in human hearts was measured by tagged cine MRI and model fitting. At transplant, failing hearts were biopsy sampled in identified regions and immunocytochemistry was used to label t-tubules and sarcomeric z-lines. Computer image analysis was used to assess 5 different unbiased measures of t-tubule structure/organization. In regions of failing hearts that showed good contractile performance, t-tubule organization was similar to that seen in normal hearts, with worsening structure correlating with the loss of regional contractile performance. Statistical analysis showed that t-tubule direction was most highly correlated with local contractile performance, followed by the amplitude of the sarcomeric peak in the Fourier transform of the t-tubule image. Other area based measures were less well correlated. We conclude that regional contractile performance in failing human hearts is strongly correlated with the local t-tubule organization. Cluster tree analysis with a functional definition of failing contraction strength allowed a pathological definition of 't-tubule disease'. The regional variability in contractile performance and cellular structure is a confounding issue for analysis of samples taken from failing human hearts, although this may be overcome with regional analysis by using tagged cMRI and biopsy mapping.

Left ventricular shape variation in asymptomatic populations: the Multi-Ethnic Study of Atherosclerosis.

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.

Multi-parameter in vivo cardiac magnetic resonance imaging demonstrates normal perfusion reserve despite severely attenuated beta-adrenergic functional response in neuronal nitric oxide synthase knockout mice.

AIMS: The role of neuronal nitric oxide synthase (nNOS) in regulating contractile function remains controversial, and in regulating myocardial perfusion is uninvestigated. We used magnetic resonance imaging (MRI) to phenotype nNOS(-/-) and wild-type (WT) mice regarding left ventricular (LV) structure, baseline function, beta-adrenergic responsiveness, and perfusion reserve. METHODS AND RESULTS: Cine MRI showed higher LV mass to end-diastolic volume ratio (2.3 +/- 0.2 mg/microL nNOS(-/-) vs. 1.7 +/- 0.1 mg/microL WT; P=0.032) and LV ejection fraction (64.9 +/- 2.1% nNOS(-/-) vs. 55.8 +/- 1.1% WT; P = 0.003) in nNOS(-/-). Myocardial tagging demonstrated similar baseline systolic circumferential strain (Ecc) in nNOS(-/-) and WT. With dobutamine, the normal change in Ecc was nearly absent in nNOS(-/-) (-0.5 +/- 0.3% nNOS(-/-) vs. -2.2 +/- 0.3% WT; P = 0.001), and the systolic strain rate (dEcc/dt) response to dobutamine seen in WT was reduced in nNOS(-/-) (-29 +/- 13%/s nNOS(-/-) vs. -106+/-16%/s WT; P = 0.001). Diastolic strain rate increased significantly with dobutamine only in WT. Arterial spin labelling showed that baseline perfusion and perfusion reserve with either dobutamine or an adenosine receptor agonist are normal in nNOS(-/-). CONCLUSION: MRI provides non-invasive in vivo evidence that nNOS does not play a role in basal contractile function or myocardial perfusion, but is required for increasing cardiac inotropy and lusitropy upon beta-adrenergic stimulation.