Focusing on cardiac contractility is an intuitive complement to neurohormonal therapy1

Limitations of therapy that are active on neurohormonal pathways

SOC therapies typically target the neurohormonal pathways.1,2

As HF worsens, compensatory neurohormonal mechanisms activate to preserve cardiac output and systemic blood pressure; however, although neurohormonal activation can provide some benefit by compensating for cardiac dysfunction, it can also lead to progressive damage and worsening heart failure.1,3
  • Increased plasma levels of several neurohormones have been associated with increased morbidity and mortality over time1,2
Graphic showing examples of compensatory neurohormonal mechanisms as they activate and interact with the heart and kidneys

Why improvements to contractility may be a viable alternative to treating heart failure with reduced ejection fraction (HFrEF)2

Sarcomeric contractility in a healthy heart2

Graphic showing a calcium ion binding to the calcium binding site on troponin. Two free myosin heads are below the actin filament

Fluxes in intracellular Ca2+ reveal myosin binding sites on the actin filament

Graphic showing ATP binding to a myosin head

Myosin acts as a molecular motor that converts energy stored as ATP into a contractile force

Graphic showing the myosin head attached to the actin filament. The myosin head pulls the actin filament to the right. One of the myosin heads is bound to the actin filament and one is free

Myosin and actin bind to create a crossbridge. Crossbridge cycling allows many myosin heads to work together to cause the sarcomere to contract

The potential for novel therapies that target contractility

In HFrEF, abnormalities in crossbridge cycling result in fewer myosin heads interacting with actin, which diminishes the force of contraction.4,5

Traditional inotropic agents (ie, calcitropes) alter calcium signaling in the myocardium.2

Novel inotropes are being developed to target the sarcomere directly, without activating neurohormonal systems.2

  • Myotropes target the sarcomere’s contractility via myosin, actin, and associated regulatory proteins2
  • Mitotropes target the energy dependence of myocardial contraction and the metabolic deficiencies present in the myocardium of patients with HFrEF2

An important treatment goal is to reduce the number of heart failure events and symptoms, which can in turn improve quality of life1

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HFrEF, heart failure with reduced ejection fraction; QoL, quality of life; SOC, standard of care.

References: 1. He H et al. Circ Heart Fail. 2022;15(3):e009195. 2. Psotka MA et al. J Am Coll Cardiol. 2019;73:2345-2353. 3. Hartupee et al. Nat Rev Cardiol. 2017;14(1):30-38. 4. Spudich JA. Biophys J. 2014;106:1236-1249. 5. Planelles-Herrero VJ et al. Nat Commun. 2017;8:190.