Daily Cardiology Research Analysis
Analyzed 167 papers and selected 3 impactful papers.
Summary
Analyzed 167 papers and selected 3 impactful articles.
Selected Articles
1. Breast tumour-secreted ADAM10 mediates atrial fibrogenesis and fibrillation.
Before any therapy, women with breast cancer had a markedly higher AF prevalence and ECG markers of atrial remodeling than matched controls. Mechanistically, tumor-secreted soluble ADAM10 cleaved EphrinB2 in atrial fibroblasts to drive fibrosis and AF; pharmacologic or genetic inhibition of ADAM10/EphrinB2 signaling attenuated AF in mice.
Impact: This study uncovers a direct tumor–heart axis whereby breast cancer biochemically induces AF via sADAM10-EphrinB2 signaling, redefining AF risk in oncology beyond treatment cardiotoxicity and revealing a druggable pathway.
Clinical Implications: Pre-treatment AF screening and rhythm surveillance should be considered in breast cancer, with potential biomarker risk stratification using sADAM10/sEphrinB2. Targeting sADAM10 could emerge as a cardio-oncology therapeutic strategy.
Key Findings
- AF prevalence was higher in treatment-naïve breast cancer (6.41%) vs controls (0.90%), with more abnormal P-wave terminal force.
- Orthotopic breast cancer and tumor-conditioned media induced atrial fibrosis and increased AF susceptibility in mice.
- Tumor-secreted sADAM10 cleaved EphrinB2 in atrial fibroblasts; inhibiting ADAM10 or knocking down EphrinB2 reduced fibrosis and AF; plasma sADAM10 correlated with sEphrinB2 (R2=0.67).
Methodological Strengths
- Integrated human propensity-matched cohort with multi-species mechanistic validation (mouse models, cell assays).
- Use of targeted pharmacologic inhibitor and fibroblast-specific genetic knockdown to test causality.
Limitations
- Observational human data limit causal inference; residual confounding is possible.
- Generalizability beyond breast cancer and to clinical intervention remains unproven.
Future Directions: Prospective AF screening studies in oncology cohorts, validation of sADAM10/sEphrinB2 as risk biomarkers, and early-phase trials of ADAM10 inhibitors to prevent AF.
BACKGROUND AND AIMS: Breast cancer (BC)-related atrial fibrillation (AF) contributes to an overall poor prognosis and raises great concerns. However, beyond cancer treatment-related AF, it is unknown whether BC itself is sufficient to directly induce AF. This study aimed to explore the role of BC in the development of AF, focusing on the tumour itself rather than therapy-related cardiotoxicity. METHODS: A retrospective analysis was conducted on 1224 female BC patients before therapy and 18 159 healthy female participants. The prevalence of AF was assessed, and markers of atrial remodelling, including P-wave indices on electrocardiogram (ECG), were measured. An orthotopic BC model was established by implanting E0771 cells to mammary fat pads of female C57BL/6 mice. An electrophysiological study was employed to assess atrial arrhythmia vulnerability. Masson's trichrome staining, coculture assays and molecular biological techniques were used to determine the mechanisms of BC-induced AF. RESULTS: BC patients (n = 1217) were individually matched 1:1 to non-cancer female controls (n = 1217) by propensity score matching. Even before treatment, BC patients had a significantly higher prevalence of AF (6.41%) than controls (0.90%). BC patients exhibited more marked atrial remodelling evaluated by abnormal P-wave terminal force in ECG lead V1 (7.37% vs 3.90%, P < .001), compared to non-cancer female controls. Similarly, BC mice, as well as mice administered with tumour-conditioned media or plasma from BC mice, developed atrial fibrosis and had increased AF susceptibility. After screening tumour-secreted factors, both BC patients with AF and BC mice displayed elevated levels of soluble ADAM10 (sADAM10) in tumour tissue and plasma. Moreover, sADAM10 promoted the cleavage of Ephrin B2 into soluble Ephrin B2 (sEphrin B2) in atrial cardiofibroblasts (ACFs), which then bound with EphB3 and EphB4 receptors and activated the atrial fibrosis pathway. Cardiac fibroblast-specific knockdown of Ephrin B2 suppressed AF development in BC mice. The plasma levels of sEphrin B2 were especially higher in pre-treatment breast cancer patients with AF compared to controls, in parallel with increasing sADAM10 levels (R2 = 0.67, P < .0001). The inhibition of tumour-originated sADAM10 with its specific inhibitor (GI254023X) or its shRNA attenuated atrial fibrosis and AF susceptibility in BC mice. CONCLUSIONS: BC patients before treatment present a significantly higher prevalence of AF and atrial remodelling, which correlate with elevated levels of tumour-originated sADAM10 and ACF-secreted sEphrin B2. Tumour-originated sADAM10 directly promotes AF pathogenesis by inducing atrial fibrosis, independent of cancer treatment. These findings imply that the inhibition of sADAM10 represents a potentially new therapeutic option for BC-associated AF.
2. Nuclear AGO2 exacerbates heart failure with preserved ejection fraction through myocardial ketogenesis.
Nuclear (but not cytosolic) AGO2 activates HMGCS2 transcription, driving myocardial ketogenesis and a lipotoxicity–ketone toxicity loop that worsens HFD-induced diastolic dysfunction. Genetic suppression of AGO2 or HMGCS2 protected mice from HFpEF-like phenotypes and identified ATP5MG and UQCR10 as downstream effectors.
Impact: The study defines a nuclear AGO2–HMGCS2 axis as a master switch linking cardiac lipid excess to maladaptive ketogenesis in HFpEF, nominating tractable metabolic targets for a prevalent, therapy-resistant phenotype.
Clinical Implications: Although preclinical, targeting AGO2/HMGCS2-driven ketogenesis and β-OHB toxicity may offer novel therapeutics for metabolic HFpEF; β-OHB or pathway components could serve as biomarkers for phenotyping and treatment response.
Key Findings
- Cardiac AGO2 knockdown attenuated HFD-induced diastolic dysfunction; nuclear AGO2 overexpression exacerbated dysfunction.
- AGO2 directly activated HMGCS2 transcription; knockdown of AGO2 or HMGCS2 protected against HFD-induced dysfunction.
- High-throughput profiling identified ATP5MG and UQCR10 as downstream mediators of β-OHB overproduction; a PKCα–ERK–EGR1–AGO2–HMGCS2 axis was delineated.
Methodological Strengths
- Comprehensive multi-omics and functional assays (ChIP, luciferase, Seahorse, proteomics) with in vivo AAV9 manipulation.
- Subcellular localization dissection distinguishing nuclear vs cytosolic AGO2 roles.
Limitations
- Preclinical mouse model; human validation of the pathway and translatability remain to be established.
- No clinical pharmacologic inhibition data; off-target metabolic effects of pathway modulation are unknown.
Future Directions: Validate AGO2/HMGCS2 activation and β-OHB signatures in human HFpEF tissue; develop selective nuclear AGO2 modulators or HMGCS2 inhibitors; test metabolic combination therapies.
BACKGROUND AND AIMS: With the prevalence of Western-style high-fat diet (HFD), the incidence of heart failure with preserved ejection fraction (HFpEF) is gradually increasing. Recent studies suggested that microRNAs (miRNAs) located in different subcellular organelles could regulate lipid metabolism and cardiac function. However, the functional property of subcellular argonaute 2 (AGO2), the core member of miRNA machinery, remained elusive in HFD-related HFpEF. METHODS: The causal role of nuclear AGO2 in inducing cardiac dysfunction was revealed with a recombinant adeno-associated virus (serotype 9) vector. The underlying mechanisms were explored with echocardiography, catheter manometer system, proteomics analyses, chromatin immunoprecipitation assays, luciferase assays, Western blotting, immunofluorescence, seahorse assays, β-hydroxybutyrate (β-OHB), and ATP measurements. RESULTS: Knockdown of AGO2 attenuated HFD-induced cardiac dysfunction. Mechanistically, AGO2 could activate the transcription of HMGCS2. Knockdown of either cardiac AGO2 or HMGCS2 protected against HFD-induced cardiac dysfunction. Subsequent high-through profiling further identified ATP5MG and UQCR10 as the key downstream targets for AGO2/HMGCS2 mediated β-OHB over-production, and a feed forward loop involving lipo-toxicity and ketone-toxicity was discovered. Furthermore, a PKCα-ERK-EGR1-AGO2-HMGCS2 axis in the initiation of fatty acid-induced cardiomyocyte dysfunction was revealed. Importantly, overexpressing of nuclear AGO2 rather than cytosolic AGO2 exacerbated the HFD-induced cardiac dysfunction in mice. CONCLUSIONS: These findings uncover that long-term Western-style HFD treatment captures some critical characteristics of HFpEF, characterized by diastolic dysfunction with left ventricular ejection fraction >50%. AGO2/HMGCS2 pathway links lipo-toxicity to ketone-toxicity in the heart, which provides new mechanistic insights and suggests a potential strategy to develop treatments against metabolism disorder-related HFpEF.
3. Association of Guideline-Concordant Echocardiographic Surveillance With Mortality and Aortic Valve Replacement in US Adults With Aortic Stenosis.
In 20,571 AS patients, adherence to ACC/AHA-recommended echo surveillance intervals was associated with lower adjusted all-cause mortality (notably in ≥moderate AS) and higher AVR rates across all severities, yet real-world concordance was only ~50% in moderate–severe and severe AS.
Impact: This large real-world analysis links guideline-concordant imaging follow-up to survival and timely intervention in AS, spotlighting a modifiable systems-level gap in care.
Clinical Implications: Health systems should implement EHR-based recall and monitoring to ensure guideline-timed echocardiography in AS; improving surveillance may reduce mortality and facilitate timely AVR referral.
Key Findings
- Guideline-concordant surveillance was achieved in 74% (mild) but only ~49–63% for moderate to severe AS in real-world practice.
- Concordance associated with lower adjusted all-cause death in ≥moderate AS (e.g., severe AS aHR 0.62) and higher AVR rates across all severities.
- Male sex, younger age, and cardiologist involvement predicted better concordance.
Methodological Strengths
- Very large integrated health system cohort with validated NLP to classify surveillance intervals.
- Multivariable Cox modeling with long median follow-up (5.2 years).
Limitations
- Observational design; residual confounding and healthy adherer bias cannot be excluded.
- Surveillance classification relies on report NLP and may misclassify severity changes over time.
Future Directions: Test EHR-driven recall and navigator interventions to raise surveillance concordance; evaluate impacts on time-to-AVR and mortality in pragmatic trials.
BACKGROUND: Consensus-based clinical practice guidelines recommend echocardiographic surveillance intervals based on aortic stenosis (AS) severity; however, real-world surveillance practices and associated outcomes remain poorly characterized. METHODS: We evaluated AS echocardiographic surveillance patterns using validated natural language processing algorithms applied to echocardiogram reports from Kaiser Permanente Northern California between January 1, 2008, and September 30, 2017. Patients with prior aortic valve replacement (AVR) were excluded. Guideline concordance was based on the American College of Cardiology/American Heart Association (ACC/AHA) recommendations for surveillance frequency of patients with mild, moderate, and severe AS. Mild-moderate and moderate-severe AS were assigned to follow surveillance intervals of the more severe AS classification. We used multivariable Cox proportional hazards regression to examine associations between guideline concordance and all-cause death and receipt of AVR. RESULTS: Among 20 571 patients with AS (mean age 75.7±11.2 years, 48% women), rates of guideline concordance were 74% for mild AS, 51% for mild-moderate AS, 63% for moderate AS, 51% for moderate-severe AS, and 49% for severe AS. Male sex, younger age, having a cardiologist, and certain comorbid conditions were positively associated with guideline concordance. During median follow-up of 5.2 (interquartile range, 3.0-7.4) years, patients who were guideline concordant experienced 1929 (28.8%) deaths and 1783 (26.6%) AVRs, while those not concordant experienced 3683 (42.2%) deaths and 1266 (14.5%) AVRs. Guideline concordance was associated with lower adjusted all-cause death for those with at least moderate AS (moderate: adjusted hazard ratio [aHR], 0.76 [95% CI, 0.68-0.85]; moderate-severe: aHR, 0.70 [0.54-0.91]; severe: aHR, 0.62 [0.51-0.76]), and higher rates of AVR across all AS severity levels (mild: aHR, 2.23 [1.93-2.57]; mild-moderate: aHR, 1.56 [1.22-1.99]; moderate: aHR, 1.45 [1.28-1.64]; moderate-severe: aHR, 2.09 [1.62-2.69]; severe: aHR, 1.95 [1.60-2.36]). CONCLUSIONS: Implementation of the current American College of Cardiology/American Heart Association guideline-recommended echocardiographic surveillance frequency in adults with AS is associated with improved outcomes yet remains suboptimal in real-world settings.