Integrative Clinical–Molecular Modeling Identifies <i>LRRN4CL</i> as a Determinant of Structural and Functional Myocardial Improvement

bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-26

ABSTRACT Background Mechanical ventricular unloading and systemic circulatory support with left ventricular assist devices (LVADs) enable myocardial recovery in a subset of advanced heart failure (HF) patients, but predictors and mechanisms of recovery are not well understood. Integrating clinical and molecular data may improve identification of patients most likely to recover and uncover biologically relevant targets in HF. Methods We collected and analyzed left ventricular apical myocardial tissue and clinical data from 208 patients undergoing LVAD implantation across five centers. Pre-implant transcriptomic profiles (22,373 mRNA transcripts) were integrated with 59 clinical variables using supervised machine learning with repeated cross-validation to identify and prioritize features associated with myocardial recovery, defined as a binary outcome based on improvement in left ventricular ejection fraction (LVEF ≥40%) and left ventricular end-diastolic diameter (LVEDD ≤5.9 cm). We also modeled functional (LVEF) and structural (LVEDD) improvement as a continuous outcome without any predefined LVEF and LVEDD pathological thresholds. Feature prioritization was followed by validation in human myocardial tissue and mechanistic interrogation in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Results Integrative models achieved modest discrimination for myocardial recovery as a binary categorical outcome (maximum mean cross-validated area under the curve 0.73±0.15), identifying clinical features such as HF duration, LVEDD, HF pharmacologic therapy, and device configuration. Leucine-rich repeat neuronal 4C-like ( LRRN4CL ), measured in human myocardium, consistently emerged as a top transcriptomic predictor across both binary and continuous metric models (functional and structural). Higher pre-LVAD LRRN4CL expression was associated with reduced likelihood of myocardial recovery and localized primarily to cardiomyocytes. In iPSC-CMs, LRRN4CL overexpression localized to the sarcoplasmic reticulum, induced transcriptional remodeling characterized by suppression of contractile pathways and activation of stress programs, impaired calcium handling, impaired contraction–relaxation kinetics, and diminished mitochondrial respiratory reserve capacity. Conclusions Integration of clinical and myocardial transcriptomic data identifies LRRN4CL as a novel marker associated with impaired myocardial recovery following LVAD-mediated ventricular unloading and systemic circulatory support. These findings move beyond predictive modeling, linking integrative computational discovery to cardiomyocyte dysfunction and providing a translational framework for biologically informed risk stratification and therapeutic targeting for myocardial recovery. CLINICAL PERSPECTIVE What Is New? Integrative clinical and myocardial transcriptomic modeling identifies LRRN4CL as a novel molecular determinant of structural and functional changes after LVAD-mediated ventricular unloading and enhanced systemic circulatory support. Elevated LRRN4CL expression is associated with adverse remodeling signatures, impaired calcium handling, and stress responses in human iPSC-derived cardiomyocytes. Experimental overexpression of LRRN4CL directly disrupts calcium cycling, contractile performance, and mitochondrial respiration linking molecular signature to functional phenotype. What Are the Clinical Implications? Identification of LRRN4CL as a marker associated with impaired myocardial recovery supports future efforts toward biologically informed risk stratification for patients undergoing LVAD therapy. LRRN4CL as a marker of cardiac improvement potential may extend beyond advanced HF to earlier stage disease patients and inform prognosis, risk stratification, and response to medical therapies. These findings highlight LRRN4CL -associated pathways as potential therapeutic targets and demonstrate how integrative clinical–transcriptomic approaches can move beyond clinical prediction toward identification of new biologically precise therapeutic targets in HF following a bedside to bench and back approach.

Supplemental Table 1 from New-Onset Diabetes after an Obesity-Related Cancer Diagnosis and Survival Outcomes in the Women's Health Initiative

2025-11-26

&lt;p&gt;Supplemental Table 1 provides demographic characteristics for the included and excluded participants in the study.&lt;/p&gt;

Muscle‐specific Keap1 deletion enhances force production but does not prevent inactivity‐induced muscle atrophy in mice

The FASEB Journal · 2025-03-14 · 1 citations

Immobilization-associated muscle atrophy and weakness appear to be driven in part by oxidative stress. Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) is a critical redox rheostat that regulates oxidative stress responses, and its deletion is known to accelerate muscle atrophy and weakness during aging (sarcopenia) or denervation. Conversely, pharmacologic activation of NRF2 extends mouse lifespan and attenuates sarcopenia. Similarly, deletion of Kelch-like ECH-associated Protein 1 (Keap1), a negative regulator of NRF2, enhances exercise capacity. The purpose of this study was to determine whether muscle-specific Keap1 deletion is sufficient to prevent muscle atrophy and weakness in mice following 7 days of hindlimb unloading (HU). To test this hypothesis, control (Ctrl) and tamoxifen-inducible, muscle-specific Keap1 knockout (mKO) mice were subjected to either normal housing (Sham) or HU for 7 days. Activation of NRF2 in muscle was confirmed by increased mRNA of NRF2 targets thioredoxin 1 (Txn1) and NAD(P)H quinone dehydrogenase 1 (NQO1) in mKO mice. Keap1 deletion had an effect to increase force-generating capacity at baseline. However, muscle masses, cross-sectional area, and ex vivo force were not different between mKO and Ctrl HU mice. In addition, muscle 4-hydroxynonenal-modified proteins and protein carbonyls were unaffected by Keap1 deletion. These data suggest that NRF2 activation improves muscle force production during ambulatory conditions but is not sufficient to prevent muscle atrophy or weakness following 7 days of HU.

The role of sphingolipids in heart failure

European Heart Journal Open · 2025-04-30 · 1 citations

Advanced heart failure (HF) is characterized by changes in the structure, function, and metabolism of cardiac muscle. As the disease progresses, cardiomyocytes shift their ATP production from fatty acid oxidation to glycolysis. This shift results in an accumulation of lipid metabolites, particularly sphingolipids, which can disrupt normal cellular function and contribute to cardiac dysfunction. In animal models of obesity, accumulation of toxic sphingolipid metabolites in the heart has been described as cardiac lipotoxicity. In humans, HF is classified into two groups based on ejection fraction (EF): HF with reduced EF of less than 40% (HFrEF) and HF with preserved EF of greater than 50% (HFpEF). Despite shared risk factors and comorbidities, the structural and cellular differences between HFrEF and HFpEF distinguish them as separate conditions. Ceramides (Cer), a type of sphingolipid, have gained significant attention for their involvement in the development and prognosis of atherosclerotic disease and myocardial infarction, while sphingosine-1-phosphate, a downstream product of Cer, has shown cardioprotective properties. The aim of this review is to describe the role of sphingolipids in HF with reduced and preserved EF. By understanding the role of sphingolipids through animal and human studies, this review aims to pave the way for developing strategies that target abnormal signalling pathways in the failing heart, ultimately bridging the gap between scientific research and clinical applications.

Supplemental Table 3 from New-Onset Diabetes after an Obesity-Related Cancer Diagnosis and Survival Outcomes in the Women's Health Initiative

2025-11-26

&lt;p&gt;Supplemental Table 3 provides effect estimates for the association of incident diabetes and all-cause mortality among obesity-related cancer survivors and cancer-free individuals, stratified by covariates that did not meet PH assumptions.&lt;/p&gt;

Supplemental Table 7 from Metabolic Phenotype and Risk of Obesity-Related Cancers in the Women’s Health Initiative

2025-02-03

&lt;p&gt;Supplemental Table 7. Association between metabolic phenotypes defined by Wildman criteria with obesity-related cancer (ORC) risk after excluding participants diagnosed with ORC within the first three years of follow-up in the Women’s Health Initiative cohort (N= 20,320).&lt;/p&gt;

Therapeutic remodeling of the ceramide backbone prevents kidney injury

Cell Metabolism · 2025-11-12 · 2 citations

Supplemental Table 7 from New-Onset Diabetes after an Obesity-Related Cancer Diagnosis and Survival Outcomes in the Women's Health Initiative

2025-11-26

&lt;p&gt;Supplemental Table 7 provides results for the 6 months lag analysis.&lt;/p&gt;

Loss of hepatic autophagy induces α‐cell proliferation through impaired glutamine‐dependent gluconeogenesis

Physiological Reports · 2025-05-01

Abstract Autophagy, the highly conserved process of protein and organelle degradation, is suppressed in the liver by obesity and metabolic dysfunction‐associated fatty liver disease and associated with the development of insulin resistance. We generated adult liver‐inducible ATG3 knockout mice ( Atg3 iLKO ) to characterize pathways linking hepatic autophagy with metabolic homeostasis. Genetic loss of hepatic autophagy leads to a reduction in 16‐h fasted glucose levels, a decrease in endogenous glucose production rates, and an increase in serum amino acids across the fed and fasted states. These changes collectively reflect a loss of hepatic gluconeogenic enzyme activity and not a general inability to degrade amino acids in the liver. Increased circulating glutamine levels resulting from this are associated with an induction of α‐cell hyperplasia, leading to constitutively elevated glucagon levels. However, the loss of hepatic gluconeogenesis renders these animals highly glucagon resistant. Collectively, our data demonstrate that loss of hepatic autophagy is sufficient to activate the hepatic α‐islet cell axis, leading to hyperglucagonemia with impaired glucose production.

A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice

Science Advances · 2025-09-19 · 14 citations

Ketogenic diets (KDs)-very-low-carbohydrate and very-high-fat diets-have gained popularity as therapeutic against obesity and type 2 diabetes. However, their long-term effects on metabolic health remain understudied. Here, we show that, in male and female mice, a KD protects against weight gain and induces weight loss but over time leads to the development of hyperlipidemia, hepatic steatosis, and severe glucose intolerance. Unlike mice on conventional high-fat diet, KD-fed mice remain insulin sensitive and display low-insulin levels. Hyperglycemic clamp and ex vivo glucose-stimulated insulin secretion assays revealed systemic and cell-intrinsic impairments in insulin secretion. Transcriptomic profiling of islets from KD-fed mice indicated endoplasmic reticulum (ER)/Golgi stress and disrupted ER-Golgi protein trafficking, which were confirmed by electron microscopy showing a dilated Golgi network consistent with defective insulin granule trafficking and secretion. Together, these results suggest that long-term KD leads to multiple aberrations of metabolic parameters that caution their systematic use as a health-promoting dietary intervention.