Euan Ashley

• Stanford University

Background: Individuals with neuromuscular diseases (NMDs) have low physical activity levels and an increased risk of cardiovascular and pulmonary diseases. Respiratory gas kinetics obtained during cardiopulmonary exercise testing (CPET) may provide valuable insights into disease mechanisms and cardiorespiratory fitness in individuals with NMD. Rec...

Background: An estimated 1 in 500 people live with hypertrophic cardiomyopathy (HCM), a disease for which genetic diagnosis can identify family members at risk, and increasingly guide therapy. Mutations in the myosin binding protein C3 (MYBPC3) gene account for a significant proportion of HCM cases. However, many of these variants are classified as...

Aims Deep learning methods have shown impressive performance in detecting a range of diseases from electrocardiogram (ECG) waveforms, but the breadth of diseases that can be detected with high accuracy remains unknown, and in many cases the changes to the ECG allowing these classifications are also opaque. In this study, we aim to determine the ful...

Rare structural variants (SVs)—insertions, deletions, and complex rearrangements—can cause Mendelian disease, yet they remain difficult to accurately detect and interpret. We sequenced and analyzed Oxford Nanopore Technologies long-read genomes of 68 individuals from the undiagnosed disease network (UDN) with no previously identified diagnostic mut...

Personalized, smartphone-based coaching improves physical activity but relies on static, human-crafted messages. We introduce My Heart Counts (MHC)-Coach, a large language model fine-tuned on the Transtheoretical Model of Change. MHC-Coach generates messages tailored to an individual's psychology (their "stage of change"), providing personalized su...

Importance Filamin C truncating variants (FLNCtv) are a rare cause of cardiomyopathy with heterogeneous phenotypic presentations. Despite a high incidence of life-threatening ventricular arrhythmias and sudden cardiac death (SCD), reliable risk predictors to stratify carriers of FLNCtv are lacking. Objective To determine factors predictive of SCD/...

Aims Cardiorespiratory fitness (CRF), measured by peak oxygen uptake (VO2peak), is a strong predictor of mortality. Despite its widespread clinical use, current reference equations for VO2peak show distorted calibration in obese individuals. Using data from the Fitness Registry and the Importance of Exercise National Database (FRIEND), we sought to...

BACKGROUND Females with hypertrophic cardiomyopathy present at a more advanced stage of the disease and have a higher risk of heart failure and death. The factors behind these differences are unclear. We aimed to investigate sex-related differences in clinical and genetic factors affecting adverse outcomes in the Sarcomeric Human Cardiomyopathy Reg...

Background The mechanistic pathways that give rise to the extreme symptoms exhibited by rare disease patients are complex, heterogeneous, and difficult to discern. Understanding these mechanisms is critical for developing treatments that address the underlying causes of diseases rather than merely the presenting symptoms. Moreover, the same dysfunc...

Cardiac wall motion abnormalities (WMA) are strong predictors of mortality, but current screening methods using Q waves from electrocardiograms (ECGs) have limited accuracy and vary across racial and ethnic groups. This study aimed to identify novel ECG features using deep learning to enhance WMA detection, referencing echocardiography as the gold...

Background: Polygenic risk scores (PRS) have demonstrated predictive validity across a range of cohorts and diseases, but quantifying their clinical utility remains a challenge. As PRS can be derived from a single biological sample and remain stable throughout life, we explore the potential of PRS to optimize existing screening programs. Methods: U...

The rapid advances in genomics over the last decade have come to fruition amid intense public discussions of justice in medicine and health care. While much emphasis has been placed on increasing diversity in genomics research participation, an overly narrow focus on recruitment eschews recognition of the disparities in health care that will ultima...

BACKGROUND Septal reduction therapy (SRT) provides substantial symptomatic improvement in patients with obstructive hypertrophic cardiomyopathy (HCM). However, long-term disease course after SRT and predictors of adverse outcomes have not been systematically examined. METHODS Data from 13 high clinical volume HCM centers from the international SHA...

The scarcity of subspecialist medical expertise, particularly in rare, complex and life-threatening diseases, poses a significant challenge for healthcare delivery. This issue is particularly acute in cardiology where timely, accurate management determines outcomes. We explored the potential of AMIE (Articulate Medical Intelligence Explorer), a lar...

Mavacamten is a first-in-class cardiac myosin ATPase inhibitor, approved by the United States Food and Drug Administration for the treatment of hypertrophic cardiomyopathy with obstructive physiology (oHCM). Here, we present the real-world use of mavacamten in 50 patients with oHCM at a tertiary care referral center. In both our highlighted case an...

CSF1R-related disorder (CSF1R-RD) is a neurodegenerative condition that predominantly affects white matter due to genetic alterations in the CSF1R gene, which is expressed by microglia. We studied an elderly man with a hereditary, progressive dementing disorder of unclear etiology. Standard genetic testing for leukodystrophy and other neurodegenera...

Physical activity plays a fundamental role in human health and disease. Exercise has been shown to improve a wide variety of disease states, and the scientific community is committed to understanding the precise molecular mechanisms that underlie the exquisite benefits. This review provides an overview of molecular responses to acute exercise and c...

Long-read sequencing technology has enabled variant detection in difficult-to-map regions of the genome and enabled rapid genetic diagnosis in clinical settings. Rapidly evolving third-generation sequencing platforms like Pacific Biosciences (PacBio) and Oxford Nanopore Technologies (ONT) are introducing newer platforms and data types. It has been...

Background One of the major hurdles in clinical genetics is interpreting the clinical consequences associated with germline missense variants in humans. Recent significant advances have leveraged natural variation observed in large-scale human populations to uncover genes or genomic regions that show a depletion of natural variation, indicative of...

Purpose Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 and has not been implicated in human disease. Methods We identify 5 unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and 2...

The six-minute walk test (6MWT) is a sub-maximal exercise test used clinically as a measure of functional capacity. With the emergence of advanced sensors, 6MWTs were commonly performed remotely via smartphones and other devices. The My Heart Counts Cardiovascular Health Study is a smartphone application that serves as a digital platform for studie...

Though some controversy remains regarding the place of the 12 lead Electrocardiogram (ECG) in the routine screening of young athletes and how and where the pre-participation examination should be performed, studies continue to support the ECG and properly organized mass screening. The purpose of this paper is to provide brief historical perspective...

Background With increasing numbers of patients and novel drugs for distinct causes of systolic and diastolic heart failure, automated assessment of cardiac function is important. We aimed to provide a non-invasive method to predict diagnosis of patients undergoing cardiac MRI (cMRI) and to obtain left ventricular end-diastolic pressure (LVEDP).

Endurance exercise training is known to reduce risk for a range of complex diseases. However, the molecular basis of this effect has been challenging to study and largely restricted to analyses of either few or easily biopsied tissues. Extensive transcriptome data collected across 15 tissues during exercise training in rats as part of the Molecular...

Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood 1–3 . Here, the Molecular Transducers of Physical Activity Consortium ⁴ profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome...

Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training (ExT) and sex on its molecular landscape is not fully established. Utilizing an integrative multi-omics approach, and leveraging data generated by the Molecular Transducers of Physical...

Aims Deep learning methods have recently gained success in detecting left ventricular systolic dysfunction (LVSD) from electrocardiogram waveforms. Despite their impressive accuracy, they are difficult to interpret and deploy broadly in the clinical setting. We set out to determine whether simpler models based on standard electrocardiogram measurem...

BACKGROUND: Cardiorespiratory fitness (CRF), measured by peak oxygen uptake (VO2peak), is a strong predictor of mortality. Despite its widespread clinical use, current reference equations for VO2peak show distorted calibration in obese individuals. Using data from the Fitness Registry and the Importance of Exercise National Database (FRIEND), we so...

Long read sequencing offers benefits for the detection of structural variation in Mendelian disease. Here, we applied a new technology that generates contiguous long reads via tagmentation and sequencing by synthesis to a small cohort of patients with undiagnosed disease from the Undiagnosed Diseases Network. We first compare sequencing from the HG...

Rare structural variants (SVs) – insertions, deletions, and complex rearrangements – can cause Mendelian disease, yet they remain difficult to accurately detect and interpret. We sequenced and analyzed Oxford Nanopore long-read genomes of 68 individuals from the Undiagnosed Disease Network (UDN) with no previously identified diagnostic mutations fr...

BACKGROUND To realize the potential of genome engineering therapeutics, tractable strategies must be identified that balance personalized therapy with the need for off-the-shelf availability. We hypothesized that regional clustering of pathogenic variants can inform the design of rational prime editing therapeutics to treat the majority of genetic...

Background and Aims Early identification of cardiac structural abnormalities indicative of heart failure is crucial to improving patient outcomes. Chest X-rays (CXRs) are routinely conducted on a broad population of patients, presenting an opportunity to build scalable screening tools for structural abnormalities indicative of Stage B or worse hear...

The goal of this study is to quantify the assumptions associated with the Wasserman‐Hansen (WH) and Fitness Registry and the Importance of Exercise: A National Database (FRIEND) predictive peak oxygen consumption (pVO 2 ) equations across body mass index (BMI). Assumptions in pVO 2 for both equations were first determined using a simulation and the...

Pharmacogenomics has the potential to inform drug dosing and selection, reduce adverse events, and improve medication efficacy; however, provider knowledge of pharmacogenomic testing varies across provider types and specialties. Given that many actionable pharmacogenomic genes are implicated in cardiovascular medication response variability, this s...

Importance Deep learning methods have recently gained success in detecting left ventricular systolic dysfunction (LVSD) from electrocardiogram waveforms. Despite their impressive accuracy, they are difficult to interpret and deploy broadly in the clinical setting. Objective To determine whether simpler models based on standard electrocardiogram me...

The Rab family of guanosine triphosphatases (GTPases) includes key regulators of intracellular transport and membrane trafficking targeting specific steps in exocytic, endocytic, and recycling pathways. DENND5B (Rab6-interacting Protein 1B-like protein, R6IP1B) is the longest isoform of DENND5, an evolutionarily conserved DENN domain-containing gua...

Previous studies have associated COVID-19 symptoms severity with levels of physical activity. We therefore investigated longitudinal trajectories of COVID-19 symptoms in a cohort of healthcare workers (HCWs) with non-hospitalised COVID-19 and their real-world physical activity. 121 HCWs with a history of COVID-19 infection who had symptoms monitore...

BACKGROUND Deep learning models may combat widening racial disparities in heart failure outcomes through early identification of individuals at high risk. However, demographic biases in the performance of these models have not been well-studied. METHODS This retrospective analysis used 12-lead ECGs taken between 2008 and 2018 from 326 518 patient...

Cardiac blood flow is a critical determinant of human health. However, the definition of its genetic architecture is limited by the technical challenge of capturing dynamic flow volumes from cardiac imaging at scale. We present DeepFlow, a deep-learning system to extract cardiac flow and volumes from phase-contrast cardiac magnetic resonance imagin...

We describe real-world use of mavacamten in 50 patients with oHCM. Consistent with EXPLORER-HCM and VALOR-HCM, we report significant improvement in wall thickness, mitral regurgitation, left ventricular outflow tract obstruction and NYHA class. Moreover, in our center’s experience, neither arrhythmia burden, nor contractility have worsened in the v...

Background Long term outcome after septal reduction therapies SRT in HCM patients is largely unresolved, since most available studies report post-operative results up to 1 year. Purpose To evaluate the long term outcome and its predictors in patients with HCM from the SHaRe Registry (Sarcomeric Human Cardiomyopathy Registry) Registry. Methods Dat...

The combinatorial effect of genetic variants is often assumed to be additive. Although genetic variation can clearly interact non-additively, methods to uncover epistatic relationships remain in their infancy. We develop low-signal signed iterative random forests to elucidate the complex genetic architecture of cardiac hypertrophy. We derive deep l...

Background: Cardiac wall motion abnormalities (WMA) independently predict mortality and other adverse events beyond ejection fraction. Clinical screening relies on detection of ECG Q waves yet has poor predictive accuracy. Hypothesis: We hypothesized that ECG features beyond the Q wave could be identified by deep learning to improve WMA detection o...

Background: Cardiac wall motion abnormalities (WMA) independently predict mortality and other adverse events beyond ejection fraction. The impact on mortality and ejection fraction has not been studied in large cohorts with long term follow up. Aim: We aimed to describe the relationship of specific regional cardiac WMAs with ejection fraction and m...

Introduction: Cardiac wall motion abnormalities (WMA) are key prognostic indicators for major cardiovascular events and mortality, yet they are poorly detected by current ECG screening tools such as Q waves. Deep learning (DL) models have improved analysis of complex data and novel tools may provide interpretation of these models. Hypothesis: ECG f...

Background: Approximately 40% of cases of dilated (DCM) and arrhythmogenic cardiomyopathy (AC) are caused by rare genetic variants of large-effect. Sex-based differences in the penetrance of genetic DCM and AC have been described, however, findings have been inconsistent. Age at the time of diagnosis can be used as an indicator of age-related penet...

Introduction: Cardiac wall motion abnormalities (WMA) are key prognostic indicators for major cardiovascular events and mortality (MACE), yet poorly detected by current ECG screening such as for Q waves. Given that race and gender impact the ECG, it is also unknown if ECG screening for WMA could be applied broadly. We hypothesized that deep learnin...

The combinatorial effect of genetic variants is often assumed to be additive. Although genetic variation can clearly interact non-additively, methods to uncover epistatic relationships remain in their infancy. We develop low-signal signed iterative random forests to elucidate the complex genetic architecture of cardiac hypertrophy. We derive deep l...

Two KCNA2 variants (p.H310Y and p.H310R) were discovered in paediatric patients with epilepsy and developmental delay. KCNA2 encodes KV1.2‐channel subunits, which regulate neuronal excitability. Both gain and loss of KV1.2 function cause epilepsy, precluding the prediction of variant effects; and while H310 is conserved throughout the KV‐channel su...

BACKGROUND Hypercontractility and arrhythmia are key pathophysiologic features of hypertrophic cardiomyopathy (HCM), the most common inherited heart disease. β-Adrenergic receptor antagonists (β-blockers) are the first-line therapy for HCM. However, β-blockers commonly selected for this disease are often poorly tolerated in patients, where heart-ra...

Background Mobile health (mHealth) interventions are increasingly being used for cardiovascular research and physical activity promotion. Objectives As a result, the authors aimed to evaluate which features facilitate and impede routine engagement with mobile fitness applications. Methods We distributed a pan-Canadian online questionnaire via the...

Long-read sequencing technology has enabled variant detection in difficult-to-map regions of the genome and enabled rapid genetic diagnosis in clinical settings. Rapidly evolving third-generation sequencing platforms like Pacific Biosciences (PacBio) and Oxford nanopore technologies (ONT) are introducing newer platforms and data types. It has been...

The electrocardiogram (ECG) is the most frequently performed cardiovascular diagnostic test, but it is unclear how much information resting ECGs contain about long term cardiovascular risk. Here we report that a deep convolutional neural network can accurately predict the long-term risk of cardiovascular mortality and disease based on a resting ECG...

Background and aims: Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA). This study aimed to better characterise the cardiac complic...

Introduction Left ventricular hypertrophy (LVH) detection techniques on by electrocardiogram (ECG) are cumbersome to remember with modest performance. This study validated a rapid technique for LVH detection and measured its performance against other techniques. Methods This was a retrospective cohort study of patients at Stanford Health Care who...

Aims Physical activity is associated with decreased incidence of the chronic diseases associated with aging. We previously demonstrated that digital interventions delivered through a smartphone app can increase short-term physical activity. Methods and results We offered enrolment to community-living iPhone-using adults aged ≥18 years in the USA,...

Rationale: Right ventricular (RV) dysfunction is common among patients hospitalized with COVID-19; however, its epidemiology may depend on the echocardiographic parameters used to define it. Objective: To evaluate the prevalence of abnormalities in three common echocardiographic parameters of RV function among COVID-19 patients admitted to the i...

Phosphoinositides (PIs) are membrane phospholipids produced through the local activity of PI kinases and phosphatases that selectively add or remove phosphate groups from the inositol head group. PIs control membrane composition and play key roles in many cellular processes including actin dynamics, endosomal trafficking, autophagy, and nuclear fun...

Background: Cardiopulmonary Exercise Testing (CPX) is essential for the assessment of exercise capacity for patients with Chronic Heart Failure (CHF). Respiratory gas and hemodynamic parameters such as Ventilatory Efficiency (VE/VCO2 slope), peak oxygen uptake (peak VO2), and heart rate recovery are established diagnostic and prognostic markers fo...

Background: Women with HCM present at a more advanced stage of the disease and have a higher risk of heart failure and death. The factors contributing to these differences are unclear. Objectives: We aimed to investigate sex differences in clinical and genetic factors associated with adverse outcomes in the Sarcomeric Human Cardiomyopathy Registry...

Objective: To explore the perspectives of parents of undiagnosed children enrolled in genomic diagnosis research regarding their motivations for enrolling their children, their understanding of the potential burdens and benefits, and the extent to which their experiences ultimately aligned with or diverged from their original expectations. Study...

Background: The development of left ventricular systolic dysfunction (LVSD) in hypertrophic cardiomyopathy (HCM) is rare but serious and associated with poor outcomes in adults. Little is known about the prevalence, predictors, and prognosis of LVSD in patients diagnosed with HCM as children. Methods: Data from patients with HCM in the internati...

Background Deep learning models may combat widening racial disparities in heart failure outcomes through early identification of individuals at high risk. However, demographic biases in the performance of these models have not been well studied. Methods This retrospective analysis used 12-lead ECGs taken between 2008 - 2018 from 290,252 patients r...

Large-language models have recently demonstrated impressive zero-shot capabilities in a variety of natural language tasks such as summarization, dialogue generation, and question-answering. Despite many promising applications in clinical medicine, adoption of these models in real-world settings has been largely limited by their tendency to generate...

Background: Physical activity is strongly protective against the development of chronic diseases associated with aging. We previously demonstrated that digital interventions delivered through a smartphone app can increase short-term physical activity. Our randomized crossover trial has continued to digitally enroll participants, allowing increasing...

Introduction The Undiagnosed Diseases Network (UDN), a clinical research study funded by the National Institutes of Health, aims to provide answers for patients with undiagnosed conditions and generate knowledge about underlying disease mechanisms. UDN evaluations involve collaboration between clinicians and researchers and go beyond what is possib...

The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutatio...

Background Patients with neuromuscular disease (NMD) have progressive muscle weakness and limited mobility that contributes to a sedentary lifestyle. A sedentary lifestyle often leads to deconditioning and decreases cardiorespiratory fitness (CRF). Cardiopulmonary exercise testing (CPX) is the gold standard for the evaluation of CRF but has not bee...

As genomic technologies rapidly develop, polygenic scores (PGS) are entering into a growing conversation on how to improve precision in public health and prevent chronic disease. While the integration of PGS into public health and clinical services raises potential benefits, it also introduces potential harms. In particular, there is a high level o...

While genetic testing is becoming mainstream in the management of patients with potentially inherited cardiovascular disease, the prevalence of uncertain results severely limits its utility. One promising approach is to generate variant effect maps that report the function of all possible variants in a gene prospectively. The proactive clinical app...

What is this plain language summary about? This plain language summary describes the results of a study looking at the effects of a medicine called ARRY-371797 (also known as PF-07265803) in people with dilated cardiomyopathy (DCM for short) caused by a faulty LMNA gene. This condition is called LMNA-related DCM. DCM happens when the heart becomes...

BACKGROUND Standard of care for patients with neuromuscular disease (NMD) includes exercise testing and exercise therapy. The focus of exercise in this group is to respond to muscular skeletal pathologies related to NMD, improve general health and fitness and health related quality of life. Cardiopulmonary exercise testing CPX is the gold standard...

Mitochondria are adaptable organelles with diverse cellular functions critical to whole-body metabolic homeostasis. While chronic endurance exercise training is known to alter mitochondrial activity, these adaptations have not yet been systematically characterized. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) mapped the...

The “diagnostic odyssey” describes the process those with undiagnosed conditions undergo to identify a diagnosis. Throughout this process, families of children with undiagnosed conditions have multiple opportunities to decide whether to continue or stop their search for a diagnosis and accept the lack of a diagnostic label. Previous studies identif...

Dilated cardiomyopathies (DCM) are one of the main causes of heart failure as one ages. BAG3 is a chaperone protein that is heavily implicated in the development of DCM and speed of progression toward heart failure. Here we generate two human iPSC lines from individuals with mutations in exon 3 of BAG3 and provide validation of their pluripotency a...

Background: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. Methods: Individuals wi...

BACKGROUND Lamin A/C gene ( LMNA )-related dilated cardiomyopathy is a serious and life-threatening condition with a high unmet medical need. This phase 2 study assessed the effects of the oral selective p38 mitogen-activated protein kinase inhibitor ARRY-371797 on functional capacity and cardiac function in patients with LMNA -related dilated card...