Blanca Rodriguez

University of Oxford | OX · Department of Computer Science

Background: Ventricular fibrillation (VF) is the deadliest arrhythmia, often caused by myocardial ischaemia. VF patients require urgent intervention planned quickly and non-invasively. However, the accuracy with which electrocardiographic (ECG) markers reflect the underlying arrhythmic substrate is unknown. Methods: We analysed how ECG metrics ref...

Virtual evaluation of medical therapy through human‐based modelling and simulation can accelerate and augment clinical investigations. Treatment of the most common cardiac arrhythmia, atrial fibrillation (AF), requires novel approaches. This study prospectively evaluates and mechanistically explains three novel pharmacological therapies for AF thro...

A healthy heart shows intrinsic electrical heterogeneities that play a significant role in cardiac activation and repolarization. However, cardiac diseases may perturb the baseline electrical properties of the healthy cardiac tissue, leading to increased arrhythmic risk and compromised cardiac functions. Moreover, biological variability among patie...

Sudden death after myocardial infarction (MI) is associated with electrophysiological heterogeneities and ionic remodelling, which are reflected as variable phenotypes. Low ejection fraction (EF) is used in risk stratification, but its mechanistic links with the post-MI pro-arrhythmic heterogeneities are unknown. We aim to provide a mechanistic exp...

Background Cell therapy is being explored to restore the damaged and intrinsically irreparable human heart. Whilst preclinical studies showed improvements in cardiac function after injury, they also highlighted a critical pro-arrhythmic window when delivered cells produce ectopy-induced ventricular tachycardia. Recent experiments investigating the...

Background Inhibiting the atrial-selective SK and K2P channels represents a promising strategy for cardioverting atrial fibrillation (AF), but its efficacy has not been evaluated in a large human cohort. Objectives This study employed in-silico trials in 1000 virtual patients (i.e., clinical trials conducted in a population of virtual human subjec...

Cardiac digital twins (CDTs) are personalized virtual representations used to understand complex cardiac mechanisms. A critical component of CDT development is solving the ECG inverse problem, which enables the reconstruction of cardiac sources and the estimation of patient-specific electrophysiology (EP) parameters from surface ECG data. Despite c...

Background Type 2 diabetes mellitus (T2DM) is a major risk factor for heart failure with preserved ejection fraction and cardiac arrhythmias. Precursors of these complications, such as diabetic cardiomyopathy, remain incompletely understood and underdiagnosed. Detection of early signs of cardiac deterioration in T2DM patients is critical for preven...

Cardiac digital twins represent the required functional mechanisms of patient hearts to evaluate therapies and inform clinical decision-making virtually. A scalable generation of cardiac digital twins can enable virtual clinical trials on virtual cohorts to fast-track therapy development. Here, we present an open-source digital twinning framework f...

Cardiac digital twins (CDTs) offer personalized \textit{in-silico} cardiac representations for the inference of multi-scale properties tied to cardiac mechanisms. The creation of CDTs requires precise information about the electrode position on the torso, especially for the personalized electrocardiogram (ECG) calibration. However, current studies...

Background and Aims The effective refractory period (ERP) is one of the main electrophysiological properties governing arrhythmia, yet ERP personalisation is rarely performed when creating patient-specific computer models of the atria to inform clinical decision-making. This study evaluates the impact of integrating clinical ERP measurements into p...

Background and Aim: Type 2 diabetes mellitus (T2DM) is a major risk factor for heart failure, ischemic heart disease, and cardia c arrhythmias. Our goal is to examine the association of T2DM with ECG and cardiac imaging biomarkers, providing a window into the adverse effects of T2DM on cardiac health. Methods: Using data from the UK Biobank, we inv...

Cardiac digital twins are personalized virtual representations used to understand complex heart mechanisms. Solving the ECG inverse problem is crucial for accurate virtual heart modelling, enabling the derivation of internal electrical activity information from recorded surface potentials. Despite challenges from cardiac complexity, noisy ECG data,...

Background and Aims Patients with persistent atrial fibrillation (AF) experience 50% recurrence despite pulmonary vein isolation (PVI), and no consensus is established for second treatments. The aim of our i-STRATIFICATION study is to provide evidence for stratifying patients with AF recurrence after PVI to optimal pharmacological and ablation ther...

Background and Aims: The effective refractory period is one of the main electrophysiological properties governing arrhythmia maintenance, yet effective refractory period personalisation is rarely performed when creating patient-specific computer models of the atria to inform clinical decision-making. The aim of this study is to evaluate the impact...

During atrial fibrillation (AF), electrical remodeling occurs, involving ion channels like NaV1.5, KV1.5, and TASK-1. A promising AF treatment encompasses inhibiting these channels. In this study, acetamide compounds were designed based on the local anesthetic pharmacophore as potential NaV1.5, KV1.5, and TASK-1 inhibitors. Compound 6f emerged as t...

Background Virtual evaluation of medical therapy through human-based modelling and simulation can accelerate and augment clinical investigations. Treatment of the most common cardiac arrhythmia, atrial fibrillation (AF), requires novel approaches. Objectives To prospectively evaluate and mechanistically explain novel pharmacological therapies for...

Background and Aims Patients with persistent atrial fibrillation (AF) experience 50% recurrence despite pulmonary vein isolation (PVI), and no consensus is established for second treatments. The aim of our i-STRATIFICATION study is to provide evidence for stratifying patients with AF recurrence after PVI to optimal pharmacological and ablation ther...

Sudden death after myocardial infarction (MI) is associated with electrophysiological heterogeneities and ionic remodelling, which are reflected as variable phenotypes. Low ejection fraction (EF) is used in risk stratification, but its mechanistic links with the post-MI pro-arrhythmic heterogeneities are unknown. We aim to provide a mechanistic exp...

Sudden death after myocardial infarction (MI) is associated with electrophysiological heterogeneities and ionic remodelling, which are reflected as variable phenotypes. Low ejection fraction (EF) is used in risk stratification, but its mechanistic links with the post-MI pro-arrhythmic heterogeneities are unknown. We aim to provide a mechanistic exp...

Cardiac digital twins (CDTs) have the potential to offer individualized evaluation of cardiac function in a non-invasive manner, making them a promising approach for personalized diagnosis and treatment planning of myocardial infarction (MI). The inference of accurate myocardial tissue properties is crucial in creating a reliable CDT of MI. In this...

Cardiac in silico clinical trials can virtually assess the safety and efficacy of therapies using human-based modelling and simulation. These technologies can provide mechanistic explanations for clinically observed pathological behaviour. Designing virtual cohorts for in silico trials requires exploiting clinical data to capture the physiological...

Cardiac digital twins are computational tools capturing key functional and anatomical characteristics of patient hearts for investigating disease phenotypes and predicting responses to therapy. When paired with large-scale computational resources and large clinical datasets, digital twin technology can enable virtual clinical trials on virtual coho...

Human-based modelling and simulation offer an ideal testbed for novel medical therapies to guide experimental and clinical studies. Myocardial infarction (MI) is a common cause of heart failure and mortality, for which novel therapies are urgently needed. Although cell therapy offers promise, electrophysiological heterogeneity raises pro-arrhythmic...

Cardiac Purkinje networks are a fundamental part of the conduction system and are known to initiate a variety of cardiac arrhythmias. However, patient-specific modeling of Purkinje networks remains a challenge due to their high morphological complexity. This work presents a novel method based on optimization principles for the generation of Purkinj...

The best pharmacological treatment for each atrial fibrillation (AF) patient is unclear. We aim to exploit AF simulations in 800 virtual atria to identify key patient characteristics that guide the optimal selection of anti‐arrhythmic drugs. The virtual cohort considered variability in electrophysiology and low voltage areas (LVA) and was developed...

Myocardial infarction (MI) demands precise and swift diagnosis. Cardiac digital twins (CDTs) have the potential to offer individualized evaluation of cardiac function in a non-invasive manner, making them a promising approach for personalized diagnosis and treatment planning of MI. The inference of accurate myocardial tissue properties is crucial i...

Cardiac in silico clinical trials can virtually assess the safety and efficacy of therapies using human-based modelling and simulation. These technologies can provide mechanistic explanations for clinically observed pathological behaviour. Designing virtual cohorts for in silico trials requires exploiting clinical data to capture the physiological...

The vision of digital twins for precision cardiology is to combine expert knowledge and data of patients’ cardiac pathophysiology with advanced computational methods, in order to generate accurate, personalised treatment strategies. When studying cardiac electrophysiology, the twinning pipeline commonly requires a large amount of simulations, e.g....

The interplay between structural and electrical changes in the heart after myocardial infarction (MI) plays a key role in the initiation and maintenance of arrhythmia. The anatomical and electrophysiological properties of scar, border zone, and normal myocardium modify the electrocardiographic morphology, which is routinely analysed in clinical set...

The interplay between structural and electrical changes in the heart after myocardial infarction (MI) plays a key role in the initiation and maintenance of arrhythmia. The anatomical and electrophysiological properties of scar, border zone, and normal myocardium modify the electrocardiographic morphology, which is routinely analysed in clinical set...

Cardiac Purkinje networks are a fundamental part of the conduction system and are known to initiate a variety of cardiac arrhythmias. However, patient-specific modeling of Purkinje networks remains a challenge due to their high morphological complexity. This work presents a novel method based on optimization principles for the generation of Purkinj...

Levetiracetam (LEV), a well-established anti-seizure medication (ASM), was launched before the original ICH S7B nonclinical guidance assessing QT prolongation potential and the introduction of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm. No information was available on its effects on cardiac channels. The goal of this work was to...

Patient-specific cardiac computational models are essential for the efficient realization of precision medicine and in-silico clinical trials using digital twins. Cardiac digital twins can provide non-invasive characterizations of cardiac functions for individual patients, and therefore are promising for the patient-specific diagnosis and therapy s...

Cardiomyopathies have unresolved genotype–phenotype relationships and lack disease-specific treatments. Here we provide a framework to identify genotype-specific pathomechanisms and therapeutic targets to accelerate the development of precision medicine. We use human cardiac electromechanical in-silico modelling and simulation which we validate wit...

Mathematical models of cardiac cellular electrophysiology have matured and evolved over the last 50 years. They have played an important role in shaping our understanding of physiology through iterations with experiments. A large scientific community in computational cardiovascular science has contributed to developing cardiac models of different c...

The preclinical identification of drug-induced cardiotoxicity and its translation into human risk are still major challenges in pharmaceutical drug discovery. The ICH S7B Guideline and Q&A on Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential promotes human in silico drug trials as a novel tool for proar...

Background Personalisation of pharmacological treatment for atrial fibrillation (AF) is challenging. Pharmacological ionic current blockers such as digoxin or flecainide are commonly used, with caution given possible cardiotoxicity and proarrhythmia. Moreover, patients are stratified based on their associated heart disease rather than individual el...

Atrial fibrillation (AF) inducibility, sustainability and response to pharmacological treatment of individual patients are expected to be determined by their ionic current properties, especially in structurally-healthy atria. Mechanisms underlying AF and optimal cardioversion are however still unclear. In this study, in-silico drug trials were cond...

Patient-specific cardiac computational models are essential for the efficient realization of precision medicine and in-silico clinical trials using digital twins. Cardiac digital twins can provide non-invasive characterizations of cardiac functions for individual patients, and therefore are promising for the patient-specific diagnosis and therapy s...

Cardiomyopathies have unresolved genotype-phenotype relationships and lack disease-specific treatments. Here we identify genotype-specific pathomechanisms and therapeutic targets combining experimental hiPSC-CM modelling and human-based cardiac electromechanical in-silico modelling and simulation bridging from specific mutations to clinical biomark...

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): BHF Background Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) enable accessible human data-based cardiology studies. However, a caveat in hiPSC-CM-based studies is their immature electrophysiological and contractile phenotype. One of the mo...

Aims Sudden death after myocardial infarction (MI) is associated with electrophysiological heterogeneities and ionic remodelling, which are reflected as variable phenotypes. Low ejection fraction (EF) is used in risk stratification, but its mechanistic links with the post-MI electrophysiological heterogeneities are unknown. We aim to unravel how ph...

Background and Purpose Preclinical identification and understanding of drug-induced cardiotoxicity is still a major challenge. The ICH S7B Q&A promote human in silico drug trials for proarrhythmia risk assessment. However, additional evidence is needed to support further regulatory impact and for their integration in the current preclinical assessm...

Background: The Nav 1.8 sodium channel has a key role in generating repetitive action potentials in nociceptive human dorsal root ganglion neurons. Nav 1.8 is differentiated from other voltage-gated sodium channels by its unusually slow inactivation kinetics and depolarised voltage-dependence of activation. These features are particularly pronounce...

Cardiac magnetic resonance (CMR) imaging is a valuable modality in the diagnosis and characterization of cardiovascular diseases, since it can identify abnormalities in structure and function of the myocardium non-invasively and without the need for ionizing radiation. However, in clinical practice, it is commonly acquired as a collection of separa...

Hypertrophic cardiomyopathy (HCM) affects as many as ~1 in 500 individuals, and is often typified by hyperdynamic contraction and poor cellular relaxation. HCM can be caused by mutations in a variety of key contractile proteins of the sarcomere. A large proportion of these variants are found in MYBPC3, MYH7, TNNT2, and TNNI3. These genes encode pro...

The helix orientated fibres in the ventricular wall modulate the cardiac electromechanical functions. Experimental data of the helix angle through the ventricular wall have been reported from histological and image-based methods, exhibiting large variability. It is, however, still unclear how this variability influences electrocardiographic charact...

The realisation of precision cardiology requires novel techniques for the non-invasive characterisation of individual patients’ cardiac function to inform therapeutic and diagnostic decision-making. Both electrocardiography and imaging are used for the clinical diagnosis of cardiac disease. The integration of multi-modal datasets through advanced c...

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement 764738. British Heart Foundation Intermediate Basic Science Fellowship (FS/17/22/32644). Background The pathogenic TNNI3R21C/+ varia...

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NC3Rs Infrastructure for Impart Award (NC/P001076/1) Wellcome Trust Senior Research Fellowship in Basic Biomedical Sciences (214290/Z/18/Z) Background Human-based computer modelling and simulations have been widely used in cardiac elec...

Rationale: Calcium transient analysis is central to understanding inherited and acquired cardiac physiology and disease. While the development of novel calcium reporters enables assays of CRISPR/Cas-9 genome edited pluripotent stem cell derived cardiomyocytes (iPSC-CMs) and primary adult cardiomyocytes, existing calcium-detection technologies are o...

We applied a set of in silico and in vitro assays, compliant with the CiPA (Comprehensive In Vitro Proarrhythmia Assay) paradigm, to assess the risk of chloroquine or hydroxychloroquine‐mediated QT prolongation and Torsades de Pointes (TdP), alone and combined with erythromycin and azithromycin, drugs repurposed during the first wave of COVID‐19. E...

Cardiotoxicity, defined as toxicity that affects the heart, is one of the most common adverse drug effects. Numerous drugs have been shown to have the potential to induce lethal arrhythmias by affecting cardiac electrophysiology, which is the focus of current preclinical testing. However, a substantial number of drugs can also affect cardiac functi...

Objectives: Improvements in human stem cell-derived cardiomyocyte (hSC-CM) technology have promoted their use for drug testing and disease investigations. Several in silico hSC-CM models have been proposed to augment interpretation of experimental findings through simulations. This work aims to assess the response of three hSC-CM in silico models (...

Develop, calibrate and evaluate with clinical data a human electromechanical modelling and simulation framework for multiscale, mechanistic investigations in healthy and post-myocardial infarction (MI) conditions, from ionic to clinical biomarkers. Human healthy and post-MI electromechanical simulations were conducted with a novel biventricular m...