Daily Cardiology Research Analysis
Three impactful cardiology studies emerged: an oral synthetic non-coding RNA (TY1) reversed HFpEF in mice by suppressing stress signaling; a Circulation Research study uncovered a BRISC–ABRO1–YAP–PPM1B deubiquitination axis (with liquid–liquid phase separation) driving TGF-β activation and diet-induced arterial stiffness; and AI-derived left atrial volumetry from routine CAC CT predicted atrial fibrillation and stroke comparably to MRI over 15 years.
Summary
Three impactful cardiology studies emerged: an oral synthetic non-coding RNA (TY1) reversed HFpEF in mice by suppressing stress signaling; a Circulation Research study uncovered a BRISC–ABRO1–YAP–PPM1B deubiquitination axis (with liquid–liquid phase separation) driving TGF-β activation and diet-induced arterial stiffness; and AI-derived left atrial volumetry from routine CAC CT predicted atrial fibrillation and stroke comparably to MRI over 15 years.
Research Themes
- RNA therapeutics targeting stress pathways in HFpEF
- Ubiquitin signaling and phase separation in vascular stiffness
- AI-enabled CT biomarkers for AF and stroke risk prediction
Selected Articles
1. Intravenous and oral administration of the synthetic RNA drug, TY1, reverses heart failure with preserved ejection fraction in mice.
In a two-hit obese-hypertensive mouse model, TY1 reversed HFpEF phenotypes without weight loss, suppressing myocardial MAPK stress signaling and downstream inflammatory, fibrotic, and hypertrophic pathways. Notably, an oral micellar formulation recapitulated the intravenous effects, with no evident toxicity.
Impact: Demonstrates a first-in-class synthetic ncRNA therapy that reverses HFpEF in vivo and works via oral delivery, addressing an area with no disease-modifying treatments.
Clinical Implications: If translatable, TY1 or related ncRNAs could offer a disease-modifying, potentially oral therapy for HFpEF by targeting cell stress and inflammatory signaling. This could shift management from symptomatic relief to upstream pathobiology.
Key Findings
- Intravenous TY1 reversed cardiac and systemic HFpEF manifestations in obese-hypertensive mice without inducing weight loss.
- TY1 suppressed myocardial stress-induced MAP kinase signaling and downstream inflammatory, fibrotic, and hypertrophic gene programs.
- An oral micellar formulation of TY1 reproduced the intravenous benefits, with no toxicity; effects were not seen with scrambled control RNA.
Methodological Strengths
- Use of a clinically relevant two-hit (obese-hypertensive) HFpEF model with multimodal phenotyping.
- Demonstration of efficacy via both intravenous and oral delivery with appropriate scrambled RNA controls.
Limitations
- Preclinical murine study without large-animal or human validation.
- Mechanistic dissection beyond MAPK suppression (e.g., direct cGAS/STING engagement in HFpEF) remains to be fully elucidated.
Future Directions: Evaluate pharmacokinetics, durability, and safety in large-animal models; elucidate precise upstream targets; and design early-phase clinical trials for HFpEF.
TY1, a synthetic non-coding RNA (ncRNA) bioinspired by small Y RNAs abundant in extracellular vesicles (EVs), decreases cGAS/STING activation in myocardial infarction and thereby attenuates inflammation. Motivated by the concept that heart failure with preserved ejection fraction (HFpEF) is a systemic inflammatory disease, we tested TY1 in a murine model of HFpEF. Intravenous TY1, packaged in a transfection reagent, reversed the cardiac and systemic manifestations of HFpEF in two-hit obese-hypertensive mice, without inducing weight loss. The effects of TY1 were specific, insofar as they were not reproduced by a control RNA of the same nucleotide content but in scrambled order. TY1 consistently suppressed myocardial stress-induced MAP kinase signaling, as well as downstream inflammatory, fibrotic, and hypertrophic gene pathways in heart tissue. TY1 not only prevented but actually reversed key pathological processes underlying HFpEF, with no evidence of toxicity. Most noteworthy from a practical perspective, the effects of intravenous TY1 were reproduced by feeding HFpEF mice an oral micellar formulation of TY1. As the prototype for a novel class of ncRNA drugs which target cell stress, TY1 exhibits exceptional disease-modifying bioactivity in HFpEF.
2. BRISC-Mediated PPM1B-K63 Deubiquitination and Subsequent TGF-β Pathway Activation Promote High-Fat/High-Sucrose Diet-Induced Arterial Stiffness.
The study identifies ABRO1 within the BRISC complex as a YAP-dependent partner that undergoes liquid–liquid phase separation with YAP and PPM1B to promote PPM1B K63 deubiquitination, activating TGF-β signaling and arterial stiffness under HFHSD. Smooth muscle-specific PPM1B overexpression attenuated stiffness in a K326/K63-ubiquitination–dependent manner, highlighting a druggable pathway.
Impact: Reveals a previously unrecognized LLPS-driven deubiquitination mechanism linking YAP/BRISC to TGF-β–mediated vascular stiffness, opening a new therapeutic avenue for metabolic syndrome.
Clinical Implications: Targeting the ABRO1–YAP–PPM1B–BRISC axis or modulating PPM1B K63-linked ubiquitination may reduce arterial stiffness in metabolic syndrome, suggesting strategies beyond blood pressure control.
Key Findings
- Smooth muscle cell-specific PPM1B overexpression attenuated HFHSD-induced arterial stiffness in a PPM1B K326/K63 polyubiquitination-dependent manner.
- ABRO1 directly bound YAP and underwent liquid–liquid phase separation with YAP and PPM1B to promote PPM1B K63 deubiquitination.
- PPM1B deubiquitination mechanisms were elucidated, implicating TGF-β pathway activation in HFHSD-induced arterial stiffness and nominating a therapeutic target.
Methodological Strengths
- Comprehensive mechanistic mapping using siRNA screening, mass spectrometry, protein biochemistry, and imaging.
- In vivo validation with Doppler ultrasound and telemetry in diet-induced arterial stiffness model with SMC-specific manipulations.
Limitations
- Incomplete mechanistic details in abstract and reliance on preclinical models; human validation remains to be shown.
- The specific downstream causal chain from PPM1B deubiquitination to TGF-β activation and stiffness in humans needs clinical correlation.
Future Directions: Translate findings to human tissue/biomarkers; test pharmacologic modulators of BRISC/ABRO1–YAP–PPM1B; and evaluate effects on arterial stiffness endpoints clinically.
BACKGROUND: Metabolic syndrome heightens cardiovascular disease risk primarily through increased arterial stiffness. We previously demonstrated the involvement of YAP (Yes-associated protein) in high-fat/high-sucrose diet (HFHSD)-induced arterial stiffness via modulation of PPM1B (protein phosphatase Mg METHODS: Enzymes governing PPM1B deubiquitination were identified through small interfering RNA (siRNA) screening and mass spectrometry. Glutathione S-transferase pull-down, coimmunoprecipitation, protein purification, and immunofluorescence were used to explore the mechanism underlying PPM1B deubiquitination. Doppler ultrasound was used to evaluate HFHSD-induced arterial stiffness in mice, and telemetry was used to record pulsatile (systolic and diastolic) blood pressure. RESULTS: Smooth muscle cell-specific PPM1B overexpression attenuated HFHSD-induced arterial stiffness in mice in a PPM1B-K326-K63-linked polyubiquitination-dependent manner. Mechanistically, ABRO1 (Abraxas brother 1; a core BRCC36 [BRCA1/BRCA2 (breast cancer type 1/2)-containing complex subunit 36] isopeptidase complex component) directly bound YAP and underwent liquid-liquid phase separation with YAP and PPM1B in a YAP-dependent manner, which in turn promoted PPM1B deubiquitination. Furthermore, smooth muscle cell-specific CONCLUSIONS: We elucidated the PPM1B deubiquitination mechanisms and highlighted a potential therapeutic target for metabolic syndrome-related arterial stiffness.
3. AI-Enabled CT Cardiac Chamber Volumetry Predicts Atrial Fibrillation and Stroke Comparable to MRI.
In 3,552 MESA participants followed for 15 years, AI-derived LA volume from CAC CT predicted incident AF and stroke comparably to CMRI LA volume (AUC ~0.80 for AF; ~0.76 for stroke) and improved 5-year AF risk reclassification when added to CHARGE-AF, NT-proBNP, and Agatston scores.
Impact: Enables opportunistic AF/stroke risk prediction from widely available CAC CT without dedicated CMRI, leveraging AI to extract additional prognostic value.
Clinical Implications: Radiology pipelines could incorporate AI LA volumetry on CAC scans to flag high AF/stroke risk, informing preventive strategies and closer rhythm monitoring without new imaging.
Key Findings
- AI-derived LA volume from CAC CT predicted incident AF and stroke with AUC similar to CMRI-derived LA volume (AF: 0.802 vs 0.798; stroke: 0.762 vs 0.751).
- Adding AI-CAC LA to CHARGE-AF, NT-proBNP, and Agatston scores significantly improved 5-year AF risk reclassification (positive continuous NRI).
- Long-term (15-year) outcomes confirm robustness of AI volumetry across asymptomatic, multi-ethnic cohort.
Methodological Strengths
- Large, well-characterized prospective cohort (MESA) with 15-year adjudicated outcomes and both CAC and CMRI at baseline.
- Time-dependent AUC and net reclassification analyses benchmarked against established clinical risk models and biomarkers.
Limitations
- Observational design limits causal inference; external clinical utility and workflow integration require prospective implementation studies.
- Generalizability to symptomatic populations and scanner/protocol variability needs assessment.
Future Directions: Prospective clinical deployment to test triggered monitoring/prevention strategies, calibration across scanners/vendors, and cost-effectiveness analyses.
BACKGROUND: AI-CAC provides more actionable information than the Agatston coronary artery calcium (CAC) score. We have recently shown in the MESA (Multi-Ethnic Study of Atherosclerosis) that AI-CAC automated left atrial (LA) volumetry enabled prediction of atrial fibrillation (AF) as early as 1 year. OBJECTIVES: In this study, the authors evaluated the performance of AI-CAC LA volumetry versus LA measured by human experts using cardiac magnetic resonance imaging (CMRI) for predicting incident AF and stroke and compared them with Cohorts for Heart and Aging Research in Genomic Epidemiology model for atrial fibrillation (CHARGE-AF) risk score, Agatston score, and N-terminal pro b-type natriuretic peptide (NT-proBNP). METHODS: We used 15-year outcomes data from 3,552 asymptomatic individuals (52.2% women, age 61.7 ± 10.2 years) who underwent both CAC scans and CMRI in the MESA baseline examination. CMRI LA volume was previously measured by human experts. Data on NT-proBNP, CHARGE-AF risk score, and the Agatston score were obtained from MESA. Discrimination was assessed using the time-dependent area under the curve. RESULTS: Over 15 years follow-up, 562 cases of AF and 140 cases of stroke accrued. The area under the curve for AI-CAC versus CMRI volumetry for AF (0.802 vs 0.798) and stroke (0.762 vs 0.751) were not significantly different. AI-CAC LA significantly improved the continuous net reclassification index for prediction of 5-year AF when added to CHARGE-AF risk score (0.23), NT-proBNP (0.37, 0.37), and Agatston score (0.44) ( CONCLUSIONS: AI-CAC automated LA volumetry and CMRI LA volume measured by human experts similarly predicted incident AF and stroke over 15 years. Further studies to investigate the clinical utility of AI-CAC for AF and stroke prediction are warranted.