Clonal haematopoiesis of indeterminate potential predicts incident cardiac arrhythmias.

BACKGROUND AND AIMS: Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion of blood cells with preleukemic mutations, is associated with atherosclerotic cardiovascular disease and heart failure. This study aimed to test the association of CHIP with new-onset arrhythmias. METHODS: UK Biobank participants without prevalent arrhythmias were included. Co-primary study outcomes were supraventricular arrhythmias, bradyarrhythmias, and ventricular arrhythmias. Secondary outcomes were cardiac arrest, atrial fibrillation, and any arrhythmia. Associations of any CHIP [variant allele fraction (VAF) ≥ 2%], large CHIP (VAF ≥10%), and gene-specific CHIP subtypes with incident arrhythmias were evaluated using multivariable-adjusted Cox regression. Associations of CHIP with myocardial interstitial fibrosis [T1 measured using cardiac magnetic resonance (CMR)] were also tested. RESULTS: This study included 410 702 participants [CHIP: n = 13 892 (3.4%); large CHIP: n = 9191 (2.2%)]. Any and large CHIP were associated with multi-variable-adjusted hazard ratios of 1.11 [95% confidence interval (CI) 1.04-1.18; P = .001] and 1.13 (95% CI 1.05-1.22; P = .001) for supraventricular arrhythmias, 1.09 (95% CI 1.01-1.19; P = .031) and 1.13 (95% CI 1.03-1.25; P = .011) for bradyarrhythmias, and 1.16 (95% CI, 1.00-1.34; P = .049) and 1.22 (95% CI 1.03-1.45; P = .021) for ventricular arrhythmias, respectively. Associations were independent of coronary artery disease and heart failure. Associations were also heterogeneous across arrhythmia subtypes and strongest for cardiac arrest. Gene-specific analyses revealed an increased risk of arrhythmias across driver genes other than DNMT3A. Large CHIP was associated with 1.31-fold odds (95% CI 1.07-1.59; P = .009) of being in the top quintile of myocardial fibrosis by CMR. CONCLUSIONS: CHIP may represent a novel risk factor for incident arrhythmias, indicating a potential target for modulation towards arrhythmia prevention and treatment.

Noninvasive assessment of organ-specific and shared pathways in multi-organ fibrosis using T1 mapping.

Fibrotic diseases affect multiple organs and are associated with morbidity and mortality. To examine organ-specific and shared biologic mechanisms that underlie fibrosis in different organs, we developed machine learning models to quantify T1 time, a marker of interstitial fibrosis, in the liver, pancreas, heart and kidney among 43,881 UK Biobank participants who underwent magnetic resonance imaging. In phenome-wide association analyses, we demonstrate the association of increased organ-specific T1 time, reflecting increased interstitial fibrosis, with prevalent diseases across multiple organ systems. In genome-wide association analyses, we identified 27, 18, 11 and 10 independent genetic loci associated with liver, pancreas, myocardial and renal cortex T1 time, respectively. There was a modest genetic correlation between the examined organs. Several loci overlapped across the examined organs implicating genes involved in a myriad of biologic pathways including metal ion transport (SLC39A8, HFE and TMPRSS6), glucose metabolism (PCK2), blood group antigens (ABO and FUT2), immune function (BANK1 and PPP3CA), inflammation (NFKB1) and mitosis (CENPE). Finally, we found that an increasing number of organs with T1 time falling in the top quintile was associated with increased mortality in the population. Individuals with a high burden of fibrosis in ≥3 organs had a 3-fold increase in mortality compared to those with a low burden of fibrosis across all examined organs in multivariable-adjusted analysis (hazard ratio = 3.31, 95% confidence interval 1.77-6.19; P = 1.78 × 10-4). By leveraging machine learning to quantify T1 time across multiple organs at scale, we uncovered new organ-specific and shared biologic pathways underlying fibrosis that may provide therapeutic targets.

BMI-adjusted adipose tissue volumes exhibit depot-specific and divergent associations with cardiometabolic diseases.

For any given body mass index (BMI), individuals vary substantially in fat distribution, and this variation may have important implications for cardiometabolic risk. Here, we study disease associations with BMI-independent variation in visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) fat depots in 40,032 individuals of the UK Biobank with body MRI. We apply deep learning models based on two-dimensional body MRI projections to enable near-perfect estimation of fat depot volumes (R2 in heldout dataset = 0.978-0.991 for VAT, ASAT, and GFAT). Next, we derive BMI-adjusted metrics for each fat depot (e.g. VAT adjusted for BMI, VATadjBMI) to quantify local adiposity burden. VATadjBMI is associated with increased risk of type 2 diabetes and coronary artery disease, ASATadjBMI is largely neutral, and GFATadjBMI is associated with reduced risk. These results - describing three metabolically distinct fat depots at scale - clarify the cardiometabolic impact of BMI-independent differences in body fat distribution.

Genetics of myocardial interstitial fibrosis in the human heart and association with disease.

Myocardial interstitial fibrosis is associated with cardiovascular disease and adverse prognosis. Here, to investigate the biological pathways that underlie fibrosis in the human heart, we developed a machine learning model to measure native myocardial T1 time, a marker of myocardial fibrosis, in 41,505 UK Biobank participants who underwent cardiac magnetic resonance imaging. Greater T1 time was associated with diabetes mellitus, renal disease, aortic stenosis, cardiomyopathy, heart failure, atrial fibrillation, conduction disease and rheumatoid arthritis. Genome-wide association analysis identified 11 independent loci associated with T1 time. The identified loci implicated genes involved in glucose transport (SLC2A12), iron homeostasis (HFE, TMPRSS6), tissue repair (ADAMTSL1, VEGFC), oxidative stress (SOD2), cardiac hypertrophy (MYH7B) and calcium signaling (CAMK2D). Using a transforming growth factor ß1-mediated cardiac fibroblast activation assay, we found that 9 of the 11 loci consisted of genes that exhibited temporal changes in expression or open chromatin conformation supporting their biological relevance to myofibroblast cell state acquisition. By harnessing machine learning to perform large-scale quantification of myocardial interstitial fibrosis using cardiac imaging, we validate associations between cardiac fibrosis and disease, and identify new biologically relevant pathways underlying fibrosis.

Silhouette images enable estimation of body fat distribution and associated cardiometabolic risk.

Inter-individual variation in fat distribution is increasingly recognized as clinically important but is not routinely assessed in clinical practice, in part because medical imaging has not been practical to deploy at scale for this task. Here, we report a deep learning model trained on an individual's body shape outline-or "silhouette" -that enables accurate estimation of specific fat depots of interest, including visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) adipose tissue volumes, and VAT/ASAT ratio. Two-dimensional coronal and sagittal silhouettes are constructed from whole-body magnetic resonance images in 40,032 participants of the UK Biobank and used as inputs for a convolutional neural network to predict each of these quantities. Mean age of the study participants is 65 years and 51% are female. A cross-validated deep learning model trained on silhouettes enables accurate estimation of VAT, ASAT, and GFAT volumes (R2: 0.88, 0.93, and 0.93, respectively), outperforming a comparator model combining anthropometric and bioimpedance measures (ΔR2 = 0.05-0.13). Next, we study VAT/ASAT ratio, a nearly body-mass index (BMI)-and waist circumference-independent marker of metabolically unhealthy fat distribution. While the comparator model poorly predicts VAT/ASAT ratio (R2: 0.17-0.26), a silhouette-based model enables significant improvement (R2: 0.50-0.55). Increased silhouette-predicted VAT/ASAT ratio is associated with increased risk of prevalent and incident type 2 diabetes and coronary artery disease independent of BMI and waist circumference. These results demonstrate that body silhouette images can estimate important measures of fat distribution, laying the scientific foundation for scalable population-based assessment.

Inherited basis of visceral, abdominal subcutaneous and gluteofemoral fat depots.

For any given level of overall adiposity, individuals vary considerably in fat distribution. The inherited basis of fat distribution in the general population is not fully understood. Here, we study up to 38,965 UK Biobank participants with MRI-derived visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) adipose tissue volumes. Because these fat depot volumes are highly correlated with BMI, we additionally study six local adiposity traits: VAT adjusted for BMI and height (VATadj), ASATadj, GFATadj, VAT/ASAT, VAT/GFAT, and ASAT/GFAT. We identify 250 independent common variants (39 newly-identified) associated with at least one trait, with many associations more pronounced in female participants. Rare variant association studies extend prior evidence for PDE3B as an important modulator of fat distribution. Local adiposity traits (1) highlight depot-specific genetic architecture and (2) enable construction of depot-specific polygenic scores that have divergent associations with type 2 diabetes and coronary artery disease. These results - using MRI-derived, BMI-independent measures of local adiposity - confirm fat distribution as a highly heritable trait with important implications for cardiometabolic health outcomes.

Genetic analysis of right heart structure and function in 40,000 people.

Congenital heart diseases often involve maldevelopment of the evolutionarily recent right heart chamber. To gain insight into right heart structure and function, we fine-tuned deep learning models to recognize the right atrium, right ventricle and pulmonary artery, measuring right heart structures in 40,000 individuals from the UK Biobank with magnetic resonance imaging. Genome-wide association studies identified 130 distinct loci associated with at least one right heart measurement, of which 72 were not associated with left heart structures. Loci were found near genes previously linked with congenital heart disease, including NKX2-5, TBX5/TBX3, WNT9B and GATA4. A genome-wide polygenic predictor of right ventricular ejection fraction was associated with incident dilated cardiomyopathy (hazard ratio, 1.33 per standard deviation; P = 7.1 × 10-13) and remained significant after accounting for a left ventricular polygenic score. Harnessing deep learning to perform large-scale cardiac phenotyping, our results yield insights into the genetic determinants of right heart structure and function.

Cohort design and natural language processing to reduce bias in electronic health records research.

Electronic health record (EHR) datasets are statistically powerful but are subject to ascertainment bias and missingness. Using the Mass General Brigham multi-institutional EHR, we approximated a community-based cohort by sampling patients receiving longitudinal primary care between 2001-2018 (Community Care Cohort Project [C3PO], n = 520,868). We utilized natural language processing (NLP) to recover vital signs from unstructured notes. We assessed the validity of C3PO by deploying established risk models for myocardial infarction/stroke and atrial fibrillation. We then compared C3PO to Convenience Samples including all individuals from the same EHR with complete data, but without a longitudinal primary care requirement. NLP reduced the missingness of vital signs by 31%. NLP-recovered vital signs were highly correlated with values derived from structured fields (Pearson r range 0.95-0.99). Atrial fibrillation and myocardial infarction/stroke incidence were lower and risk models were better calibrated in C3PO as opposed to the Convenience Samples (calibration error range for myocardial infarction/stroke: 0.012-0.030 in C3PO vs. 0.028-0.046 in Convenience Samples; calibration error for atrial fibrillation 0.028 in C3PO vs. 0.036 in Convenience Samples). Sampling patients receiving regular primary care and using NLP to recover missing data may reduce bias and maximize generalizability of EHR research.

Selection of 51 predictors from 13,782 candidate multimodal features using machine learning improves coronary artery disease prediction.

Current cardiovascular risk assessment tools use a small number of predictors. Here, we study how machine learning might: (1) enable principled selection from a large multimodal set of candidate variables and (2) improve prediction of incident coronary artery disease (CAD) events. An elastic net-based Cox model (ML4HEN-COX) trained and evaluated in 173,274 UK Biobank participants selected 51 predictors from 13,782 candidates. Beyond most traditional risk factors, ML4HEN-COX selected a polygenic score, waist circumference, socioeconomic deprivation, and several hematologic indices. A more than 30-fold gradient in 10-year risk estimates was noted across ML4HEN-COX quintiles, ranging from 0.25% to 7.8%. ML4HEN-COX improved discrimination of incident CAD (C-statistic = 0.796) compared with the Framingham risk score, pooled cohort equations, and QRISK3 (range 0.754-0.761). This approach to variable selection and model assessment is readily generalizable to a broad range of complex datasets and disease endpoints.

Regulation of Nuclear Hormone Receptors by MYCN-Driven miRNAs Impacts Neural Differentiation and Survival in Neuroblastoma Patients.

MYCN amplification and MYC signaling are associated with high-risk neuroblastoma with poor prognosis. Treating these tumors remains challenging, although therapeutic approaches stimulating differentiation have generated considerable interest. We have previously shown that the MYCN-regulated miR-17∼92 cluster inhibits neuroblastoma differentiation by repressing estrogen receptor alpha. Here, we demonstrate that this microRNA (miRNA) cluster selectively targets several members of the nuclear hormone receptor (NHR) superfamily, and we present a unique NHR signature associated with the survival of neuroblastoma patients. We found that suppressing glucocorticoid receptor (GR) expression in MYCN-driven patient and mouse tumors was associated with an undifferentiated phenotype and decreased survival. Importantly, MYCN inhibition and subsequent reactivation of GR signaling promotes neural differentiation and reduces tumor burden. Our findings reveal a key role for the miR-17∼92-regulated NHRs in neuroblastoma biology, thereby providing a potential differentiation approach for treating neuroblastoma patients.