ArticleCirculation. Heart failure2022
Novel Small-Molecule Troponin Activator Increases Cardiac Contractile Function Without Negative Impact on Energetics.
Article in Circulation. Heart failure, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 25 citations in OpenAlex.
- Predicting Cardiac Magnetic Resonance-Derived Ejection Fraction from Echocardiogram Via Deep Learning Approach in Tetralogy of Fallot.Pediatric cardiology · 2026Article
- Danicamtiv reduces myosin's working stroke but activates the thin filament by accelerating actomyosin attachment.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- ATP directly modulates thick filament structure and function in porcine myocardium.Biophysical journal · 2025Article
- Focus on cardiac troponin complex: From gene expression to cardiomyopathy.Genes & diseases · 2024Review
- Danicamtiv reduces myosin's working stroke but enhances contraction by activating the thin filament.bioRxiv : the preprint server for biology · 2024Article
- Discovery of Nelutroctiv (CK-136), a Selective Cardiac Troponin Activator for the Treatment of Cardiovascular Diseases Associated with Reduced Cardiac Contractility.Journal of medicinal chemistry · 2024Article
- Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies.Biomedicines · 2024Review
- Synthesis and Biophysical Characterization of Fingolimod Derivatives as Cardiac Troponin Antagonists.ACS medicinal chemistry letters · 2024Article
- Assessing Cardiac Contractility From Single Molecules to Whole Hearts.JACC. Basic to translational science · 2024Review
- The carbon monoxide prodrug oCOm-21 increases CaPhysiological reports · 2024Article
- Differentiating Cardiac Troponin Levels During Cardiac Myosin Inhibition or Cardiac Myosin Activation Treatments: Drug Effect or the Canary in the Coal Mine?Current heart failure reports · 2023Review
- Single-molecule mechanics and kinetics of cardiac myosin interacting with regulated thin filaments.Biophysical journal · 2023Article
- Discovery of novel cardiac troponin activators using fluorescence polarization-based high throughput screening assays.Scientific reports · 2023Article
- Functional assays reveal the pathogenic mechanism of a de novo tropomyosin variant identified in patient with dilated cardiomyopathy.Journal of molecular and cellular cardiology · 2023Article
- Distinct Mechanisms for Increased Cardiac Contraction Through Selective Alteration of Either Myosin or Troponin Activity.JACC. Basic to translational science · 2022Article
- L-2-Hydroxyglutarate Protects Against Cardiac Injury via Metabolic Remodeling.Circulation research · 2022Article
- Targeting the sarcomere in inherited cardiomyopathies.Nature reviews. Cardiology · 2022Review
- Small Molecule RPI-194 Stabilizes Activated Troponin to Increase the Calcium Sensitivity of Striated Muscle Contraction.Frontiers in physiology · 2022Article
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Authors and funding
15 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundCurrent heart failure therapies unload the failing heart without targeting the underlying problem of reduced cardiac contractility. Traditional inotropes (ie, calcitropes) stimulate contractility via energetically costly augmentation of calcium cycling and worsen patient survival. A new class of agents-myotropes-activates the sarcomere directly, independent of calcium. We hypothesize that a novel myotrope TA1 increases contractility without the deleterious myocardial energetic impact of a calcitrope dobutamine.
methodsWe determined the effect of TA1 in bovine cardiac myofibrils and human cardiac microtissues, ex vivo in mouse cardiac fibers and in vivo in anesthetized normal rats. Effects of increasing concentrations of TA1 or dobutamine on contractile function, phosphocreatine and ATP concentrations, and ATP production were assessed by
resultsTA1 increased the rate of myosin ATPase activity in isolated bovine myofibrils and calcium sensitivity in intact mouse papillary fibers. Contractility increased dose dependently in human cardiac microtissues and in vivo in rats as assessed by echocardiography. In isolated rat hearts, TA1 and dobutamine similarly increased the rate-pressure product. Dobutamine increased both developed pressure and heart rate accompanied by decreased phosphocreatine-to-ATP ratio and decreased free energy of ATP hydrolysis (ΔG
conclusionsNovel myotrope TA1 increased myocardial contractility by sensitizing the sarcomere to calcium without impairing diastolic function or depleting the cardiac energy reserve. Since energetic depletion negatively correlates with long-term survival, myotropes may represent a superior alternative to traditional inotropes in heart failure management.
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