Leveraging Signaling Pathways to Treat Heart Failure With Reduced Ejection Fraction

Circ Res. 2019 May 24;124(11):1618-1632. doi: 10.1161/CIRCRESAHA.119.313682.


Advances in the treatment of heart failure with reduced ejection fraction due to systolic dysfunction are engaging an ever-expanding compendium of molecular signaling targets. Well established approaches modifying hemodynamics and cell biology by neurohumoral receptor blockade are evolving, exploring the role and impact of modulating intracellular signaling pathways with more direct myocardial effects. Even well-tread avenues are being reconsidered with new insights into the signaling engaged and thus opportunity to treat underlying myocardial disease. This review explores therapies that have proven successful, those that have not, those that are moving into the clinic but whose utility remains to be confirmed, and those that remain in the experimental realm. The emphasis is on signaling pathways that are tractable for therapeutic manipulation. Of the approaches yet to be tested in humans, we chose those with a well-established experimental history, where clinical translation may be around the corner. The breadth of opportunities bodes well for the next generation of heart failure therapeutics.

Keywords: G-coupled protein receptor; cardiomyopathy; inotrope; kinase; metabolism; phosphodiesterase; therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cardiovascular Agents / adverse effects
  • Cardiovascular Agents / therapeutic use*
  • Drug Design
  • Heart Failure / drug therapy*
  • Heart Failure / metabolism
  • Heart Failure / physiopathology
  • Humans
  • Molecular Targeted Therapy
  • Myocardium / metabolism*
  • Recovery of Function
  • Signal Transduction / drug effects*
  • Stroke Volume / drug effects*
  • Treatment Outcome
  • Ventricular Function, Left / drug effects*


  • Cardiovascular Agents