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Related Concept Videos

Heart Failure Drugs: Inotropic Agents01:26

Heart Failure Drugs: Inotropic Agents

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Positive inotropic agents are commonly used as the first line of treatment for heart failure. One such agent is digoxin, derived from the genus Digitalis, which has been known for centuries but effectively utilized since 1785. However, these cardiac glycosides can have potentially toxic effects due to their mechanism of action, which involves inhibiting Na+/K+-ATPase and increasing contractility. Digoxin is absorbed orally and distributed in various tissues, including the CNS. It has a long...
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Heart Failure Drugs: Inhibitors of Renin-Angiotensin System01:26

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The activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) contributes to cardiac remodeling, and inhibiting the RAAS is a pharmacological target in heart failure management. As a result, neurohumoral modulation is a crucial treatment principle for managing heart failure. This approach involves using medications like ACE inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers, mineralocorticoid receptor antagonists (MRAs), and neutral...
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Updated: May 7, 2025

Delayed Intramyocardial Delivery of Stem Cells after Ischemia Reperfusion Injury in a Murine Model
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Novel Selective Cardiac Myosin-Targeted Inhibitors Alleviate Myocardial Ischaemia-Reperfusion Injury.

Nur Liyana Mohammed Yusof1,2, Derek M Yellon1, Sean M Davidson3

  • 1The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.

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|January 4, 2025
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Summary

Cardiac myosin-targeted inhibitors (CMIs) show promise in reducing heart damage after ischemia and reperfusion (IR) injury. These drugs limit cardiomyocyte hypercontraction, offering potential cardioprotection in IR settings.

Keywords:
AficamtenHypercontractureIschaemiaMavacamtenMyocardial infarctionReperfusion

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Area of Science:

  • Cardiology
  • Pharmacology
  • Cell Biology

Background:

  • Reperfusion is crucial for limiting myocardial infarction but can induce cardiomyocyte hypercontracture.
  • Cardiac myosin-targeted inhibitors (CMIs), like Mavacamten (MYK-461) and Aficamten (CK-274), are approved for cardiac hypercontractility and are safe in clinical trials.

Purpose of the Study:

  • To investigate the cardioprotective potential of CMIs in reducing hypercontracture and infarct size during ischemia-reperfusion (IR) injury.
  • To test the hypothesis that CMIs can mitigate IR-induced cardiac damage by limiting cardiomyocyte hypercontraction.

Main Methods:

  • Adult rat cardiomyocytes (ARVC) were used to assess CMI inhibition of hypercontracture in vitro after ATP depletion.
  • In vivo studies involved anesthetized rats subjected to 30 min coronary artery ligation followed by 2 h reperfusion, with CMI or vehicle administration prior to reperfusion.
  • Infarct size was quantified using tetrazolium chloride staining, and hypercontracture was assessed via histological staining. Ischemic preconditioning (IPC) served as a positive control.

Main Results:

  • CMIs effectively inhibited ARVC hypercontracture in vitro.
  • Both MYK-461 and CK-274 significantly reduced infarct size in vivo compared to vehicle treatment.
  • While IPC reduced contraction band necrosis, CMIs did not, potentially due to assay limitations. Inhibition of PI3Kα with GDC-0326 abrogated CK-274-mediated protection and reduced AKT phosphorylation.

Conclusions:

  • CMIs demonstrate novel cardioprotective effects in the context of IR injury.
  • This study highlights CMIs as potential therapeutic agents for mitigating reperfusion injury in the heart.