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.
BACKGROUND: Cardiac fibrosis is a major determinant of adverse clinical outcomes of many heart diseases; currently, therapeutic strategy directly targeting fibroblasts is lacking. Nitric oxide-mediated nitrosative stress is associated with cardiac injury, and excessive nitric oxide can trigger S-nitrosylation (SNO) to specific cysteine thiol. This study aims to investigate the role of SNO in cardiac fibrosis and to identify potential therapeutic target. METHODS: SNO proteomic analysis was performed in cardiac tissue isolated from both mice subjected to transverse aortic constriction and spontaneous hypertensive rats. Elevated SNO of pyruvate kinase M2 (PKM2) was identified in cardiac fibroblasts, which was merely detected in cardiomyocytes. Cardiac fibroblast-specific PKM2 knockout mice and mice transfected with wild-type or SNO-resistant PKM2 mutant were used to determine the involvement of SNO of PKM2 (SNO-PKM2) in cardiac fibrosis. Unbiased proteomics and coimmunoprecipitation combined with mass spectrometry analysis were conducted to explore effectors mediating SNO-PKM2-induced activation of cardiac fibroblasts. A recently approved drug for rare blood disorder, mitapivat, was shown to dose-dependently relieve cardiac fibrosis. RESULTS: SNO of PKM2 at cysteine 49 and 326 increased in the heart tissue of patients with heart failure, heart tissue of murine cardiac fibrosis models, and cardiac fibroblasts stimulated with angiotensin II. SNO-PKM2 reduced pyruvate kinase activity and tetramerization of PKM2, and cardiac fibroblast-specific PKM2 knockout aggravated cardiac fibrosis, whereas cardiac fibroblast-specific PKM2 knockout mice transfected with SNO-resistant mutant rather than wild-type PKM2 had cardiac function. Mechanistically, SNO-PKM2 drove excessive mitochondrial fission and mitochondrial dysfunction through interfering with its interaction with actin regulatory protein gelsolin. TEPP-46, a pharmacological PKM2 activator, alleviated mitochondrial fission and cardiac fibrosis. Moreover, the US Food and Drug Administration-approved drug mitapivat showed preventive and therapeutical effects on cardiac fibrosis through activating PKM2. CONCLUSIONS: SNO-PKM2 specifically increases in cardiac fibroblasts and activated cardiac fibroblasts by inducing excessive mitochondrial fission through a gelsolin-dependent manner. Mitapivat is a potential therapeutic option for attenuating cardiac fibrosis.
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.
BACKGROUND: Stabilizers/silencers limit new transthyretin amyloid formation, whereas emerging agents aim to clear existing deposits. Cardiovascular magnetic resonance (CMR) extracellular volume (ECV) reflects myocardial amyloid and may provide a quantitative framework for therapeutic planning OBJECTIVES: The aim was to define calibrated ECV thresholds, evaluate their diagnostic and prognostic value, and explore how CMR-ECV could provide a quantitative framework for disease staging and therapeutic planning. METHODS: We studied 1,541 subjects undergoing CMR for transthyretin amyloidosis (ATTR) classified as TTR-variant carriers (n = 123), extracardiac ATTR (n = 41), early-stage ATTR-CM (n = 70), or overt ATTR-CM (n = 1,308). The endpoint was all-cause mortality. RESULTS: ECV was similar in carriers and extracardiac ATTR but rose from early-stage to ATTR-cardiomyopathy (CM). Associations with biomarkers, National Amyloidosis Centre (NAC) stage, Perugini grade, and echocardiographic measures were modest, with wide overlap. Diagnostic performance was excellent: ECV <30% excluded and ≥40% confirmed cardiac involvement, whereas 30% to 39% indicated early infiltration. Over a median follow-up of 2.8 years (IQR: 1.4-4.3 years), 612 patients (40%) died. Prognostically, ECV independently predicted mortality (HR: 1.22 per 10% increase; 95% CI: 1.10-1.34 per 10% increase; P < 0.001) after multivariable analysist. Stratifying patients by ECV categories (degree of infiltration: none <30%; mild = 30%-39%; moderate = 40%-49%; moderate-to-severe = 50%-59%; severe ≥60%) showed monotonic risk increase across categories. ECV retained prognostic value across hs-troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) strata, Perugini grades 1 to 3, and left ventricular mass index (LVMI) tertiles, with steeper gradients in low-biomarker/low-LVMI strata. CONCLUSIONS: ECV directly quantifies myocardial amyloid load and, for the first time, defines reproducible thresholds that stratify burden and refine risk prediction beyond stage, biomarkers, and imaging, providing a quantitative framework for staging and therapeutic planning in ATTR amyloidosis.
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.
BACKGROUND: The PR interval is a ubiquitous parameter available to all clinicians. Studies on associated risk have been conflicting, often limited by sample sizes and one ECG per individual. The study aimed to investigate the association between the PR interval and its temporal changes with cardiac events in a nationwide cohort. METHODS: Nationwide hospital ECGs were linked with Danish national registries. Associations between index-PR interval and absolute temporal changes in PR interval (ΔPR), and cardiac events were modelled with multivariable cause-specific Cox models. RESULTS: A total of 9 020 051 ECGs (n=2 234 492; 53% female) were available, with 1 213 073 patients having >1 ECG. Median follow-up was 7.1 years. Median index-PR interval was 158 ms. PR interval <120 or >200 ms was found in 2.9% and 7.4%, respectively. Prevalence of prolonged PR interval increased with age. Median ΔPR was 10 ms and highest among the oldest. Cox models between the index-PR interval and events showed the following HR patterns: U-shaped for risk of atrial fibrillation/flutter, heart failure and ventricular arrhythmias (HR 1.03-1.24, 1.04-1.11, 1.08-1.16, respectively, p<0.05); stepwise increase at PR interval ≥170 ms for syncope (HR 1.08-1.36, p<0.001); linear increasing at PR intervals >160 ms (HR 1.07-2.11, p<0.05) for high-degree atrioventricular block/cardiac device implantation; J-shaped with moderate and marginal increases among the shortest (HR 1.44, p<0.001) and longest PR intervals (HR 1.03, p<0.001), respectively, for all-cause mortality. Models on ΔPR showed stepwise increases in HR for all events. CONCLUSION: Prevalence of PR prolongation and temporal PR changes increased with age. Short, long and temporal changes in the PR interval were all associated with increased risk of cardiac events and all-cause mortality.