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Deep Learning-based Modelling of Complex Hypertensive Multi-Organ Damage with Uncertainty Quantification from Simple Clinical Measures
Hypertension is a leading risk factor for a number of diseases and can cause severe damage to the vital organs such as the brain and heart. However, the level of hypertension itself does not necessarily reflect the full extent of underlying end-organ changes, which may hinder the development of effective treatment strategies. While recent research has demonstrated that these end-organ changes can be measured with deep phenotyping, its clinical translation may not be feasible. In this study, we propose a state-of-art deep learning approach that can quantify multi-organ (e.g., heart, brain, vasculature) phenotypical changes due to persistent hypertension from simple and popular clinical measures such as electrocardiogram (ECG), routinely acquired clinical data (age, BMI, diastolic and systolic blood pressures), and cardiac short axis (SAX) images from the UK Biobank, one of the largest open-access biomedical databases. Our proposed approach captures the intricate patterns of hypertensive disease state without resorting to the complex measures, which is hard to obtain in practical settings. It generates a numeric score between 0 and 1 of multi-organ damage, as well as provides an estimate of the overall uncertainty. The performance of our models is evaluated in different experimental settings and compared against the reference model. The results consistently demonstrate that the proposed approach can effectively model the multi-organ phenotypical changes from simple clinical measures with high performance (best-performing model MAE=0.108, MSE=0.019, variance=0.0005), and underscores its feasibility for potential clinical use.
Exercise Improves Myocardial Deformation But Not Cardiac Structure in Preterm-Born Adults: A Randomized Clinical Trial.
BACKGROUND: People born preterm (<37 weeks' gestation) have a potentially adverse cardiac phenotype that progresses with blood pressure elevation. OBJECTIVES: The authors investigated whether preterm-born and term-born adults exhibit similar cardiac structural and functional remodeling following a 16-week aerobic exercise intervention. METHODS: We conducted a randomized controlled trial in 203 adults (aged 18-35 years) with elevated blood pressure or stage 1 hypertension. Participants were randomized 1:1 to a 16-week aerobic exercise intervention or to a control group. In a prespecified cardiovascular magnetic resonance imaging (CMR) substudy, CMR was performed at 3.0-Tesla to assess left and right ventricular (LV and RV) structure and function before and after intervention. RESULTS: A total of 100 participants completed CMR scans at baseline and after the 16-week intervention, with n = 47 in the exercise intervention group (n = 26 term-born; n = 21 preterm-born) and n = 53 controls (n = 32 term-born; n = 21 preterm-born). In term-born participants, LV mass to end-diastolic volume ratio decreased (-3.43; 95% CI: -6.29 to -0.56; interaction P = 0.027) and RV stroke volume index increased (5.53 mL/m2; 95% CI: 2.60, 8.47; interaction P = 0.076) for those in the exercise intervention group vs controls. No significant effects were observed for cardiac structural indices in preterm-born participants. In preterm-born participants, LV basal- and mid-ventricular circumferential strain increased (-1.33; 95% CI: -2.07 to -0.60; interaction P = 0.057 and -1.54; 95% CI: -2.46 to -0.63; interaction P = 0.046, respectively) and RV global longitudinal strain increased (1.99%; 95% CI: -3.12 to -0.87; interaction P = 0.053) in the exercise intervention group vs controls. No significant effects were observed for myocardial deformation parameters in term-born participants. CONCLUSIONS: Aerobic exercise training induces improved myocardial function but not cardiac structure in preterm-born adults.
Multiorgan Imaging for Interorgan Crosstalk in Cardiometabolic Diseases
Cardiometabolic diseases encompass a group of conditions characterized by metabolic and inflammatory abnormalities that increase the risk of diabetes and cardiovascular disease. These syndromes involve multiple organs, including the heart, arterial system, brain, skeletal muscle, adipose tissue, hematopoietic system, liver, kidneys, and pancreas. The crosstalk between these organs contributes to the development of disease. Advances in imaging techniques, such as magnetic resonance imaging, magnetic resonance spectroscopy, computed tomography, and positron emission tomography, have revolutionized the evaluation of these conditions. Hybrid imaging modalities, such as positron emission tomography/computed tomography and positron emission tomography/magnetic resonance imaging, provide unique insights into the anatomy and metabolic alterations occurring in response to cardiometabolic risk factors. These methods are particularly valuable for assessing multisystemic involvement and interorgan crosstalk, revealing critical interactions such as the brain-heart axis, the heart-liver axis, and the fat-muscle-heart dynamics. This review discusses the role of state-of-the-art imaging techniques in evaluating the pathophysiological mechanisms underlying these complex syndromes and the clinical applications of the different imaging techniques in the assessment of cardiometabolic diseases.
Roadmap for alleviating the manifestations of ageing in the cardiovascular system.
Ageing of the cardiovascular system is associated with frailty and various life-threatening diseases. As global populations grow older, age-related conditions increasingly determine healthspan and lifespan. The circulatory system not only supplies nutrients and oxygen to all tissues of the human body and removes by-products but also builds the largest interorgan communication network, thereby serving as a gatekeeper for healthy ageing. Therefore, elucidating organ-specific and cell-specific ageing mechanisms that compromise circulatory system functions could have the potential to prevent or ameliorate age-related cardiovascular diseases. In support of this concept, emerging evidence suggests that targeting the circulatory system might restore organ function. In this Roadmap, we delve into the organ-specific and cell-specific mechanisms that underlie ageing-related changes in the cardiovascular system. We raise unanswered questions regarding the optimal design of clinical trials, in which markers of biological ageing in humans could be assessed. We provide guidance for the development of gerotherapeutics, which will rely on the technological progress of the diagnostic toolbox to measure residual risk in elderly individuals. A major challenge in the quest to discover interventions that delay age-related conditions in humans is to identify molecular switches that can delay the onset of ageing changes. To overcome this roadblock, future clinical trials need to provide evidence that gerotherapeutics directly affect one or several hallmarks of ageing in such a manner as to delay, prevent, alleviate or treat age-associated dysfunction and diseases.
Association of short-term air pollution with risk of major adverse cardiovascular event mortality and modification effects of lifestyle in Chinese adults.
BACKGROUND: Previous evidence showed that ambient air pollution and cardiovascular mortality are related. However, there is a lack of evidence towards the modification effect of long-term lifestyle on the association between short-term ambient air pollution and death from cardiovascular events. METHOD: A total of 14,609 death from major adverse cardiovascular events (MACE) were identified among the China Kadoorie Biobank participants from 2013 to 2018. Ambient air pollution exposure including particulate matter 2.5 (PM2.5), SO2, NO2, CO, and O3 from the same period were obtained from space-time model reconstructions based on remote sensing data. Case-crossover design and conditional logistic regression was applied to estimate the effect of short-term exposure to air pollutants on MACE mortality. RESULTS: We found MACE mortality was significantly associated with PM2.5 (relative percent increase 2.91% per 10 µg/m3 increase, 95% CI 1.32-4.53), NO2 (5.37% per 10 µg/m3 increase, 95% CI 1.56-9.33), SO2 (6.82% per 10 µg/m3 increase, 95% CI 2.99-10.80), and CO (2.24% per 0.1 mg/m3 increase, 95% CI 1.02-3.48). Stratified analyses indicated that drinking was associated with elevated risk of MACE mortality with NO2 and SO2 exposure; physical inactivity was associated with higher risk of death from MACE when exposed to PM2.5; and people who had balanced diet had lower risk of MACE mortality when exposed to CO and NO2. CONCLUSIONS: The study results showed that short-term exposure to ambient PM2.5, NO2, SO2, and CO would aggravate the risk of cardiovascular mortality, yet healthy lifestyle conduct might mitigate such negative impact to some extent.
Rational design, synthesis, and evaluation of novel polypharmacological compounds targeting NaV1.5, KV1.5, and K2P channels for atrial fibrillation.
Atrial fibrillation (AF) involves electrical remodeling of the atria, with ion channels such as Na<sub>V</sub>1.5, K<sub>V</sub>1.5, and TASK-1 playing crucial roles. This study investigates acetamide-based compounds designed as multi-target inhibitors of these ion channels to address AF. Compound 6f emerged as the most potent in the series, demonstrating a strong inhibition of TASK-1 (IC<sub>50</sub> ∼ 0.3 μM), a moderate inhibition of Na<sub>V</sub>1.5 (IC<sub>50</sub> ∼ 21.2 μM) and a subtle inhibition of K<sub>V</sub>1.5 (IC<sub>50</sub> ∼ 81.5 μM), alongside unexpected activation of TASK-4 (∼ 40% at 100 μM). Functional assays on human atrial cardiomyocytes from sinus rhythm (SR) and patients with AF revealed that 6f reduced action potential amplitude in SR (indicating Na<sub>V</sub>1.5 block), while in AF it increased action potential duration (APD), reflecting high affinity for TASK-1. Additionally, 6f caused hyperpolarization of the resting membrane potential in AF cardiomyocytes, consistent with the observed TASK-4 activation. Mathematical modeling further validated its efficacy in reducing AF burden. Pharmacokinetic analyses suggest favorable absorption and low toxicity. These findings identify 6f as a promising multi-target therapeutic candidate for AF management.
Prospective in silico trials identify combined SK and K2P channel block as an effective strategy for atrial fibrillation cardioversion.
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 through in silico trials, including single and combined SK and K<sub>2</sub>P channel block. AF and pharmacological action were assessed in a large cohort of 1000 virtual patients, through 2962 multiscale simulations. Extensive calibration and validation with experimental and clinical data support their credibility. Sustained AF was observed in 654 virtual patients. In this cohort, cardioversion efficacy increased to 82% (535 of 654) through combined SK+K<sub>2</sub>P channel block, from 33% (213 of 654) and 43% (278 of 654) for single SK and K<sub>2</sub>P blocks, respectively. Drug-induced prolongation of tissue refractoriness, dependent on the virtual patient's ionic current profile, explained cardioversion efficacy (atrial refractory period increase: 133.0 ± 48.4 ms for combined vs. 45.2 ± 43.0 and 71.0 ± 55.3 ms for single SK and K<sub>2</sub>P block, respectively). Virtual patients cardioverted by SK channel block presented lower K<sub>2</sub>P densities, while lower SK densities favoured the success of K<sub>2</sub>P channel inhibition. Both ionic currents had a crucial role on atrial repolarization, and thus a synergism resulted from the multichannel block. All three strategies, including the multichannel block, preserved atrial electrophysiological function (i.e. conduction velocity and calcium transient dynamics) and thus its contractile properties (safety). In silico trials identify key factors determining treatment success and the combined SK+K<sub>2</sub>P channel block as a promising strategy for AF management. KEY POINTS: This is a large-scale in silico trial study involving 2962 multiscale simulations. A population of 1000 virtual patients underwent three treatments for atrial fibrillation. Single and combined SK+K<sub>2</sub>P channel block were assessed prospectively. The multi-ion channel inhibition resulted in 82% cardioversion efficacy. In silico trials have broad implications for precision medicine.
Harnessing 12-lead ECG and MRI data to personalise repolarisation profiles in cardiac digital twin models for enhanced virtual drug testing.
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 cohorts to fast-track therapy development. Here, we present an open-source automated pipeline for personalising ventricular electrophysiological function based on routinely acquired magnetic resonance imaging (MRI) data and the standard 12-lead electrocardiogram (ECG). Using MRI-based anatomical models, a sequential Monte-Carlo approximate Bayesian computational inference method is extended to infer electrical activation and repolarisation characteristics from the ECG. Fast simulations are conducted with a reaction-Eikonal model, including the Purkinje network and biophysically-detailed subcellular ionic current dynamics for repolarisation. For each patient, parameter uncertainty is represented by inferring an envelope of plausible ventricular models rather than a single one, which means that parameter uncertainty can be propagated to therapy evaluation. Furthermore, we have developed techniques for translating from reaction-Eikonal to monodomain simulations, which allows more realistic simulations of cardiac electrophysiology. The pipeline is demonstrated in three healthy subjects, where our inferred pseudo-diffusion reaction-Eikonal models reproduced the patient's ECG with a median Pearson's correlation coefficient of 0.9, and then translated to monodomain simulations with a median correlation coefficient of 0.84 across all subjects. We then demonstrate our digital twins for virtual evaluation of Dofetilide with uncertainty quantification. These evaluations using our cardiac digital twins reproduced dose-dependent QTc and T peak to T end prolongations that are in keeping with large population drug response data. The methodologies for cardiac digital twinning presented here are a step towards personalised virtual therapy testing and can be scaled to generate virtual populations for clinical trials to fast-track therapy evaluation. The tools developed for this paper are open-source, documented, and made publicly available.
Molnupiravir or nirmatrelvir-ritonavir plus usual care versus usual care alone in patients admitted to hospital with COVID-19: a randomised, controlled, open-label, platform trial (RECOVERY)
Background: Molnupiravir and nirmatrelvir-ritonavir (Paxlovid) are oral antivirals that were assessed in separate treatment comparisons in the RECOVERY trial, a randomised, controlled, open-label, adaptive platform trial evaluating treatments for patients hospitalised with COVID-19 pneumonia. Methods: Adult participants could join the molnupiravir comparison, the nirmatrelvir-ritonavir comparison, or both. In each comparison, they were randomly allocated in a 1:1 ratio to the relevant antiviral (five days of molnupiravir 800mg twice daily or nirmatrelvir-ritonavir 300mg/100mg twice daily) in addition to usual care, or to usual care alone. The primary outcome was 28-day mortality, and secondary outcomes were time to discharge alive from hospital, and progression to invasive ventilation or death. Analysis was by intention-to-treat. Both comparisons were stopped because of low recruitment. ISRCTN50189673; clinicaltrials.gov NCT04381936. Findings: From January 2022 to May 2023, 923 patients were recruited to the molnupiravir comparison (445 allocated molnupiravir and 478 allocated usual care), and from March 2022 to May 2023, 137 patients were recruited to the nirmatrelvir-ritonavir comparison (68 allocated nirmatrelvir-ritonavir and 69 allocated usual care). Over three-quarters of the patients were vaccinated and had anti-spike antibodies at randomisation, and over two-thirds were receiving other SARS-CoV-2 antivirals. In the molnupiravir comparison, 74 (17%) patients allocated molnupiravir and 79 (17%) patients allocated usual care died within 28 days (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.68-1.28; p=0.66). In the nirmatrelvir-ritonavir comparison, 13 (19%) patients allocated nirmatrelvir-ritonavir and 13 (19%) patients allocated usual care died within 28 days (HR 1.02; 95% CI 0.47-2.23; p=0.96). In neither comparison was there evidence of any difference in the duration of hospitalisation or the proportion of patients progressing to invasive ventilation or death. Interpretation: Adding molnupiravir or nirmatrelvir-ritonavir to usual care was not associated with improvements in clinical outcomes. However, limited recruitment meant a clinically meaningful benefit of treatment could not be ruled-out, particularly for nirmatrelvir-ritonavir.
Dopamine D2 receptor upregulation in dorsal striatum in the LRRK2-R1441C rat model of early Parkinson's disease revealed by in vivo PET imaging.
We conducted PET imaging with [18F]FDOPA and dopamine D2/3 receptor ligand [18F]fallypride in aged transgenic rats carrying human pathogenic LRRK2 R1441C or G2019S mutations. These rats have mild age-dependent deficits in dopamine release restricted to dorsal striatum despite no overt loss of dopamine neurons or dopamine content and demonstrate L-DOPA-responsive movement deficits.LRRK2 mutant rats displayed no deficit in [18F]FDOPA uptake, consistent with intact dopamine synthesis in striatal axons. However, LRRK2-R1441C rats demonstrated greater binding of [18F]fallypride than LRRK2-G2019S or non-transgenic controls, from a regionally selective increase in dorsal striatum. Immunocytochemical labelling post-mortem confirmed a greater density of D2 receptors in LRRK2-R1441C than other genotypes restricted to dorsal striatum, consistent with upregulation of D2-receptors as a compensatory response to the greater dopamine release deficit previously demonstrated in this genotype.These results show that [18F]fallypride PET imaging is sensitive to dysregulation of dopamine signalling in the LRRK2-R1441C rat, revealing upregulation of D2 receptors that parallels observations in human putamen in early sporadic PD. Future studies of candidate therapies could exploit this non-invasive approach to assess treatment efficacy.