Daily Cardiology Research Analysis
Three standout cardiology studies advance mechanisms, risk stratification, and imaging-based staging. A Circulation paper identifies S-nitrosylated PKM2 as a fibroblast-specific driver of cardiac fibrosis and demonstrates antifibrotic benefit with PKM2 activators including the FDA-approved mitapivat. A nationwide Heart cohort links both baseline and temporal changes in PR interval to multiple cardiac events and mortality. A JACC study calibrates CMR-ECV thresholds to stage myocardial amyloid bur
Summary
Three standout cardiology studies advance mechanisms, risk stratification, and imaging-based staging. A Circulation paper identifies S-nitrosylated PKM2 as a fibroblast-specific driver of cardiac fibrosis and demonstrates antifibrotic benefit with PKM2 activators including the FDA-approved mitapivat. A nationwide Heart cohort links both baseline and temporal changes in PR interval to multiple cardiac events and mortality. A JACC study calibrates CMR-ECV thresholds to stage myocardial amyloid burden in ATTR and independently predict mortality.
Research Themes
- Redox-metabolic control of cardiac fibrosis via S-nitrosylated PKM2 and therapeutic repurposing
- Population-scale ECG phenotypes: PR interval levels and trajectories predicting cardiac outcomes
- Quantitative CMR extracellular volume thresholds for staging and prognostication in ATTR cardiomyopathy
Selected Articles
1. S-Nitrosylation of Pyruvate Kinase Isoform 2 Drives Cardiac Fibrosis by Promoting Mitochondrial Fission.
This study identifies S-nitrosylated PKM2 as a fibroblast-specific driver of cardiac fibrosis via gelsolin-dependent promotion of mitochondrial fission. Pharmacologic activation of PKM2 (TEPP-46 and the FDA-approved mitapivat) reversed mitochondrial fission and attenuated fibrosis across preclinical models, suggesting repurposing potential for antifibrotic therapy.
Impact: Reveals a previously unrecognized redox-metabolic mechanism of fibrosis and provides an actionable, human-approved drug (mitapivat) as a translational candidate. This bridges mechanistic discovery with therapeutic intervention in a major unmet need.
Clinical Implications: PKM2 activation may represent a novel antifibrotic strategy for heart failure; mitapivat could be evaluated in early-phase cardiofibrosis trials with biomarker-guided selection (e.g., SNO-PKM2 signature).
Key Findings
- S-nitrosylation of PKM2 (Cys49/326) is elevated in cardiac fibroblasts from human HF and multiple fibrosis models.
- SNO-PKM2 reduces PKM2 activity/tetramerization and drives gelsolin-dependent mitochondrial fission, promoting fibroblast activation and fibrosis.
- PKM2 activators (TEPP-46, mitapivat) attenuate mitochondrial fission and cardiac fibrosis in preclinical models.
Methodological Strengths
- Multi-system validation: human HF tissue, murine TAC/SHR models, and fibroblast-specific genetic manipulations
- Orthogonal approaches: SNO-proteomics, co-IP/MS interactome, genetics (SNO-resistant PKM2), and pharmacologic rescue
Limitations
- Preclinical study; human sample sizes and clinical generalizability are not defined
- Dosing, safety, and cardiac-specific delivery of PKM2 activators for antifibrotic purposes require clinical evaluation
Future Directions: Early-phase trials testing mitapivat/PKM2 activation in HF with fibrosis; develop fibroblast-targeted delivery; validate SNO-PKM2 as a biomarker; explore combination with RAAS/SGTL2i therapy.
2. Myocardial Amyloid Burden in Transthyretin Amyloidosis.
In 1,541 ATTR participants, calibrated CMR-ECV thresholds provided strong diagnostic discrimination (<30% excludes, ≥40% confirms cardiac involvement) and stratified mortality risk in a graded fashion. ECV independently predicted death across biomarker and imaging strata, supporting its use for staging and therapeutic planning as disease-modifying agents expand.
Impact: Provides reproducible, quantitative thresholds that may standardize diagnosis and staging of ATTR-CM and refine risk prediction beyond current staging systems.
Clinical Implications: Integrate ECV thresholds into diagnostic algorithms and risk stratification to guide timing and selection of stabilizers, silencers, and clearance therapies, and to monitor response.
Key Findings
- ECV <30% effectively excludes and ≥40% confirms cardiac involvement; 30–39% reflects early infiltration.
- Over median 2.8 years, ECV independently predicted mortality (HR 1.22 per 10% increase), with monotonic risk across ECV categories.
- Prognostic value persisted across biomarker strata (hs-troponin, NT-proBNP), Perugini grades 1–3, and LV mass strata.
Methodological Strengths
- Large cohort with calibrated, quantitative CMR-ECV thresholds and multivariable survival analyses
- Demonstrated additive prognostic value beyond biomarkers, nuclear grade, and echo indices
Limitations
- Observational design with potential selection bias and heterogeneity of CMR protocols across centers
- ECV thresholds may require local calibration and validation in non-ATTR infiltrative phenotypes
Future Directions: Prospective validation and incorporation into treatment algorithms; use ECV to select and monitor patients in trials of amyloid-clearing agents.
3. Natural history of the PR interval and risk of cardiac events and mortality: a nationwide study.
In a nationwide cohort linking over 9 million ECGs to outcomes, both short and long PR intervals, as well as temporal PR prolongation, were associated with higher risks of AF/flutter, HF, ventricular arrhythmias, syncope, AV block/device implantation, and all-cause mortality. Risk patterns were U- or J-shaped for several endpoints, and ΔPR conferred stepwise risk across events.
Impact: Provides population-scale evidence that both baseline PR interval and its trajectory are clinically meaningful risk markers across diverse cardiac outcomes, informing ECG-based risk stratification.
Clinical Implications: Consider PR interval level and changes over time in ECG-based surveillance and risk assessment; heightened monitoring and evaluation for conduction disease when PR ≥160–170 ms or showing progressive prolongation.
Key Findings
- Short (<120 ms) and prolonged (>200 ms) PR intervals were present in 2.9% and 7.4%, with prolongation increasing with age.
- U-shaped associations for AF/flutter, HF, and ventricular arrhythmias; stepwise risk for syncope at PR ≥170 ms; linear risk for AV block/device at PR >160 ms.
- Temporal PR changes (ΔPR) showed stepwise increases in hazard across all evaluated events and mortality.
Methodological Strengths
- Massive sample with repeated ECGs enabling both baseline and temporal (ΔPR) analyses
- Cause-specific multivariable Cox modeling across multiple clinically relevant endpoints
Limitations
- Observational design with potential residual confounding and measurement variability in routine ECGs
- Lack of ambulatory monitoring limits arrhythmia burden quantification and mechanistic inference
Future Directions: Incorporate PR level/trajectory into risk scores; prospective studies to test targeted monitoring/interventions in patients with abnormal PR dynamics.