Study protocol: MyoFit46—the cardiac sub-study of the MRC National Survey of Health and Development

Background The life course accumulation of overt and subclinical myocardial dysfunction contributes to older age mortality, frailty, disability and loss of independence. The Medical Research Council National Survey of Health and Development (NSHD) is the world’s longest running continued surveillance birth cohort providing a unique opportunity to understand life course determinants of myocardial dysfunction as part of MyoFit46–the cardiac sub-study of the NSHD. Methods We aim to recruit 550 NSHD participants of approximately 75 years+ to undertake high-density surface electrocardiographic imaging (ECGI) and stress perfusion cardiovascular magnetic resonance (CMR). Through comprehensive myocardial tissue characterization and 4-dimensional flow we hope to better understand the burden of clinical and subclinical cardiovascular disease. Supercomputers will be used to combine the multi-scale ECGI and CMR datasets per participant. Rarely available, prospectively collected whole-of-life data on exposures, traditional risk factors and multimorbidity will be studied to identify risk trajectories, critical change periods, mediators and cumulative impacts on the myocardium. Discussion By combining well curated, prospectively acquired longitudinal data of the NSHD with novel CMR–ECGI data and sharing these results and associated pipelines with the CMR community, MyoFit46 seeks to transform our understanding of how early, mid and later-life risk factor trajectories interact to determine the state of cardiovascular health in older age. Trial registration: Prospectively registered on ClinicalTrials.gov with trial ID: 19/LO/1774 Multimorbidity Life-Course Approach to Myocardial Health- A Cardiac Sub-Study of the MCRC National Survey of Health and Development (NSHD).Sources of funding used for staff salaries, CMR scan costs, consumables and relevant travel costs required for data collection, analysis and interpretation: British Heart Foundation special project grant (to G.C. SP/20/2/34841). This study has undergone peer-review by the funding body. Medical Research Council (Core Unit Level Funding:—MC UU 00019/1).Peer Reviewed"Article signat per 30 autors/es: Matthew Webber, Debbie Falconer, Mashael AlFarih, George Joy, Fiona Chan, Clare Davie, Lee Hamill Howes, Andrew Wong, Alicja Rapala, Anish Bhuva, Rhodri H. Davies, Christopher Morton, Jazmin Aguado-Sierra, Mariano Vazquez, Xuyuan Tao, Gunther Krausz, Slobodan Tanackovic, Christoph Guger, Hui Xue, Peter Kellman, Iain Pierce, Jonathan Schott, Rebecca Hardy, Nishi Chaturvedi, Yoram Rudy, James C. Moon, Pier D. Lambiase, Michele Orini, Alun D. Hughes & Gabriella Captur"Postprint (published version

Ventricular anatomical complexity and sex differences impact predictions from electrophysiological computational models

The aim of this work was to analyze the influence of sex hormones and anatomical details (trabeculations and false tendons) on the electrophysiology of healthy human hearts. Additionally, sex- and anatomy-dependent effects of ventricular tachycardia (VT) inducibility are presented. To this end, four anatomically normal, human, biventricular geometries (two male, two female), with identifiable trabeculations, were obtained from high-resolution, ex-vivo MRI and represented by detailed and smoothed geometrical models (with and without the trabeculations). Additionally one model was augmented by a scar. The electrophysiology finite element model (FEM) simulations were carried out, using O’Hara-Rudy human myocyte model with sex phenotypes of Yang and Clancy. A systematic comparison between detailed vs smooth anatomies, male vs female normal hearts was carried out. The heart with a myocardial infarction was subjected to a programmed stimulus protocol to identify the effects of sex and anatomical detail on ventricular tachycardia inducibility. All female hearts presented QT-interval prolongation however the prolongation interval in comparison to the male phenotypes was anatomy-dependent and was not correlated to the size of the heart. Detailed geometries showed QRS fractionation and increased T-wave magnitude in comparison to the corresponding smoothed geometries. A variety of sustained VTs were obtained in the detailed and smoothed male geometries at different pacing locations, which provide evidence of the geometry-dependent differences regarding the prediction of the locations of reentry channels. In the female phenotype, sustained VTs were induced in both detailed and smooth geometries with RV apex pacing, however no consistent reentry channels were identified. Anatomical and physiological cardiac features play an important role defining risk in cardiac disease. These are often excluded from cardiac electrophysiology simulations. The assumption that the cardiac endocardium is smooth may produce inaccurate predictions towards the location of reentry channels in in-silico tachycardia inducibility studiesJA-S, FS, GH and MV are supported by the European Union’s Horizon 2020 research and innovation programme under grant agreements No 675451 (Compbiomed project phase 1) and No 823712 (CompBioMed project, phase 2) and project No 777204 (SilicoFCM project). Part of the simulation computing hours were provided by the CompBioMed project phase 1. JA-S was awarded computation time from Red Espanola de Supercomputacion (RES). (Activity IDs: FI-2018-2-0049 and BCV-2019-2-0014) JA-S is funded by a Ramon y Cajal fellowship (RYC-2017-22532), Ministerio de Ciencia e Innovacion, Spain; and by Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2017-2020 from the Ministerio de Ciencia e Innovacion y Universidades (PID2019-104356RBC41/AEI/10.13039/501100011033): meHeart ME PID2019-104356RB-C44. CB is funded by the Torres Quevedo Program (PTQ2018-010290), Ministerio de Ciencia e Innovacion, Spain. MV, GH and CB are funded by the Spanish Neotec project EXP - 00123159/SNEO-20191113 Generador de corazones virtuales. LKGM was funded by Fundacion Carolina-BBVA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study.Peer Reviewed"Article signat per 11 autors/es: Pablo Gonzalez-Martin,Federica Sacco,Constantine Butakoff,Ruben Doste,Carlos Bederian,Lilian K. Gutierrez Espinosa de los Monteros,Guillaume Houzeaux,Paul A. Iaizzo,Tinen L. Iles,Mariano Vazquez,Jazmin Aguado-Sierra"Postprint (published version

Three-dimensional cardiac fibre disorganization as a novel parameter for ventricular arrhythmia stratification after myocardial infarction

Aims: Myocardial infarction (MI) alters cardiac fibre organization with unknown consequences on ventricular arrhythmia. We used diffusion tensor imaging (DTI) of three-dimensional (3D) cardiac fibres and scar reconstructions to identify the main parameters associated with ventricular arrhythmia inducibility and ventricular tachycardia (VT) features after MI. Methods and results: Twelve pigs with established MI and three controls underwent invasive electrophysiological characterization of ventricular arrhythmia inducibility and VT features. Animal-specific 3D scar and myocardial fibre distribution were obtained from ex vivo high-resolution contrast-enhanced T1 mapping and DTI sequences. Diffusion tensor imaging-derived parameters significantly different between healthy and scarring myocardium, scar volumes, and left ventricular ejection fraction (LVEF) were included for arrhythmia risk stratification and correlation analyses with VT features. Ventricular fibrillation (VF) was the only inducible arrhythmia in 4 out of 12 infarcted pigs and all controls. Ventricular tachycardia was also inducible in the remaining eight pigs during programmed ventricular stimulation. A DTI-based 3D fibre disorganization index (FDI) showed higher disorganization within dense scar regions of VF-only inducible pigs compared with VT inducible animals (FDI: 0.36; 0.36-0.37 vs. 0.32; 0.26-0.33, respectively, P = 0.0485). Ventricular fibrillation induction required lower programmed stimulation aggressiveness in VF-only inducible pigs than VT inducible and control animals. Neither LVEF nor scar volumes differentiated between VF and VT inducible animals. Re-entrant VT circuits were localized within areas of highly disorganized fibres. Moreover, the FDI within heterogeneous scar regions was associated with the median VT cycle length per animal (R2 = 0.5320). Conclusion: The amount of scar-related cardiac fibre disorganization in DTI sequences is a promising approach for ventricular arrhythmia stratification after MI.The CNIC (Madrid, Spain) is supported by the Ministry of Science, Innovation and Universities and the Pro CNIC Foundation. The CNIC and the BSC (Barcelona, Spain) are Severo Ochoa Centers of Excellence (SEV-2015-0505 and SEV-2011-0067, respectively). This study was supported by grants from Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (RD12/0042/0036, CB16/11/00458), Spanish Ministry of Science, Innovation and Universities (SAF2016-80324-R, PI16/02110, and DTS17/00136), and by the European Commission [ERA-CVD Joint Call (JTC2016/APCIN-ISCIII-2016), grant#AC16/00021]. The study was also partially supported by the Fundacion Interhospitalaria para la Investigacion Cardiovascular (FIC, Madrid, Spain), the Spanish Society of Cardiology (Dr. Pedro Zarco award) and the Heart Rhythm section of the Spanish Society of Cardiology (DFR). J.J. is supported by R01 Grant HL122352 from the National Heart Lung and Blood Institute, USA National Institutes of Health. J.A.S. is funded by the CompBioMed project, H2020-EU.1.4.1.3 European Union's Horizon 2020 research and innovation programme, grant#675451. D.G.L. has received financial support through the 'la Caixa' Fellowship Grant for Doctoral Studies, 'la Caixa' Banking Foundation, Barcelona, Spain.S

Time-efficient three-dimensional transmural scar assessment provides relevant substrate characterization for ventricular tachycardia features and long-term recurrences in ischemic cardiomyopathy

Delayed gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) imaging requires novel and time-efficient approaches to characterize the myocardial substrate associated with ventricular arrhythmia in patients with ischemic cardiomyopathy. Using a translational approach in pigs and patients with established myocardial infarction, we tested and validated a novel 3D methodology to assess ventricular scar using custom transmural criteria and a semiautomatic approach to obtain transmural scar maps in ventricular models reconstructed from both 3D-acquired and 3D-upsampled-2D-acquired LGE-CMR images. The results showed that 3D-upsampled models from 2D LGE-CMR images provided a time-efficient alternative to 3D-acquired sequences to assess the myocardial substrate associated with ischemic cardiomyopathy. Scar assessment from 2D-LGE-CMR sequences using 3D-upsampled models was superior to conventional 2D assessment to identify scar sizes associated with the cycle length of spontaneous ventricular tachycardia episodes and long-term ventricular tachycardia recurrences after catheter ablation. This novel methodology may represent an efficient approach in clinical practice after manual or automatic segmentation of myocardial borders in a small number of conventional 2D LGE-CMR slices and automatic scar detection.The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación and the ProCNIC Foundation (Madrid, Spain). The CNIC and the Barcelona Supercomputing Center (BSC, Barcelona, Spain) are Severo Ochoa Centers of Excellence (SEV-2015-0505 and SEV-2011-0067, respectively). This study was also supported by grants from the Fondo Europeo de Desarrollo Regional (CB16/11/00458), the Ministerio de Ciencia e Innovación (PID2019-109329RB-I00) and the Heart Rhythm Association of the Spanish Society of Cardiology (ARC). The study was also part of a Master Research Agreement between CNIC and Philips Healthcare. The study was partially supported by the Fundación Interhospitalaria para la Investigación Cardiovascular (FIC, Madrid, Spain) and the Fundación Eugenio Rodríguez Pascual (Madrid, Spain). J.A.-S. is funded by the CompBioMed2 project grant agreement 823712, H2020-EU.1.4.1.3 European Union’s Horizon 2020 research and innovation program, the SILICOFCM project, grant agreement 777204, H2020-EU.3.1.5 and by a Ramón y Cajal fellowship (RYC-2017-22532), MINECO, Spain. L.K.G was funded by the Fundación Carolina-BBVA. Grant TEC2017-82408-R is also acknowledged.Peer Reviewed"Article signat per 25 autors/es: Susana Merino-Caviedes, Lilian K. Gutierrez, José Manuel Alfonso-Almazán, Santiago Sanz-Estébanez, Lucilio Cordero-Grande, Jorge G. Quintanilla, Javier Sánchez-González, Manuel Marina-Breysse, Carlos Galán-Arriola, Daniel Enríquez-Vázquez, Carlos Torres, Gonzalo Pizarro, Borja Ibáñez, Rafael Peinado, Jose Luis Merino, Julián Pérez-Villacastín, José Jalife, Mariña López-Yunta, Mariano Vázquez, Jazmín Aguado-Sierra, Juan José González-Ferrer, Nicasio Pérez-Castellano, Marcos Martín-Fernández, Carlos Alberola-López & David Filgueiras-Rama"Postprint (published version

Concomitant respiratory failure can impair myocardial oxygenation in patients with acute cardiogenic shock supported by VA-ECMO

Venous-arterial extracorporeal membrane oxygenation (VA-ECMO) treatment for acute cardiogenic shock in patients who also have acute lung injury predisposes development of a serious complication called “north-south syndrome” (NSS) which causes cerebral hypoxia. NSS is poorly characterized and hemodynamic studies have focused on cerebral perfusion ignoring the heart. We hypothesized in NSS the heart would be more likely to receive hypoxemic blood than the brain due to the proximity of the coronary arteries to the aortic annulus. To test this, we conducted a computational fluid dynamics simulation of blood flow in a human supported by VA-ECMO. Simulations quantified the fraction of blood at each aortic branching vessel originating from residual native cardiac output versus VA-ECMO. As residual cardiac function was increased, simulations demonstrated myocardial hypoxia would develop prior to cerebral hypoxia. These results illustrate the conditions where NSS will develop and the relative cardiac function that will lead to organ-specific hypoxia.This work was supported in part by the University of Minnesota’s Medical School Academic Investment Education Program grant and the Institute for Engineering in Medicine. We also acknowledge the Partnership for Advanced Computing in Europe (PRACE) for awarding us access to Joliot-Curie Rome supercomputer at Bruyères-le-Châtel, under the project Cardiovascular-COVID. Additionally, we would like to acknowledge the Torres Quevedo Program, the Ramón y Cajal Program, and the European Institute of Innovation and Technology for support.Peer ReviewedPostprint (published version

Implications of bipolar voltage mapping and magnetic resonance imaging resolution in biventricular scar characterization after myocardial infarction

Aims: We aimed to study the differences in biventricular scar characterization using bipolar voltage mapping compared with state-of-the-art in vivo delayed gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) imaging and ex vivo T1 mapping. Methods and results: Ten pigs with established myocardial infarction (MI) underwent in vivo scar characterization using LGE-CMR imaging and high-density voltage mapping of both ventricles using a 3.5-mm tip catheter. Ex vivo post-contrast T1 mapping provided a high-resolution reference. Voltage maps were registered onto the left and right ventricular (LV and RV) endocardium, and epicardium of CMR-based geometries to compare voltage-derived scars with surface-projected 3D scars. Voltage-derived scar tissue of the LV endocardium and the epicardium resembled surface projections of 3D in vivo and ex vivo CMR-derived scars using 1-mm of surface projection distance. The thinner wall of the RV was especially sensitive to lower resolution in vivo LGE-CMR images, in which differences between normalized low bipolar voltage areas and CMR-derived scar areas did not decrease below a median of 8.84% [interquartile range (IQR) (3.58, 12.70%)]. Overall, voltage-derived scars and surface scar projections from in vivo LGE-CMR sequences showed larger normalized scar areas than high-resolution ex vivo images [12.87% (4.59, 27.15%), 18.51% (11.25, 24.61%), and 9.30% (3.84, 19.59%), respectively], despite having used optimized surface projection distances. Importantly, 43.02% (36.54, 48.72%) of voltage-derived scar areas from the LV endocardium were classified as non-enhanced healthy myocardium using ex vivo CMR imaging. Conclusion: In vivo LGE-CMR sequences and high-density voltage mapping using a conventional linear catheter fail to provide accurate characterization of post-MI scar, limiting the specificity of voltage-based strategies and imaging-guided procedures.The CNIC (Madrid, Spain) is supported by the Ministry of Economy, Industry and Competitiveness (MEIC) and the Pro CNIC Foundation; The CNIC and the BSC (Barcelona, Spain) are Severo Ochoa Centers of Excellence (SEV-2015-0505 and SEV-2011-0067, respectively); Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (RD12/0042/0036, CB16/11/00458), Spanish Ministry of Economy and Competitiveness (MINECO) (SAF2016-80324-R, PI16/02110, and DTS17/00136), and by the European Commission [ERA-CVD Joint Call (JTC2016/APCIN-ISCIII-2016), Grant no. AC16/00021]; Fundacion Interhospitalaria para la Investigacion Cardiovascular (FIC, Madrid, Spain) and the heart rhyhtm section of the Spanish Society of Cardiology (DFR), in part; R01 Grant HL122352 from the National Heart Lung and Blood Institute, USA, National Institutes of Health to J.J.; CompBioMed project, H2020-EU.1.4.1.3 European Union's Horizon 2020 research and innovation program, (Grant no. 675451 to J.A.-S.); D.G.L. has received financial support through the 'la Caixa' Fellowship Grant for Doctoral Studies, 'la Caixa' Banking Foundation, Barcelona, Spain.S

Characterizing single-mode fibres and single-mode fibre lenses

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