HFrEF Learning Center

Reduced cardiac contractility is central to heart failure with reduced ejection fraction (HFrEF) manifestation and progression


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Disruption of contractility is at the core of dysfunction in HFrEF.1

Heart muscle function is dependent on the key contractile proteins of the sarcomere: actin and myosin.5,8
Click here to learn more about actin-myosin interaction.

Contractility drives performance, and the actin-myosin interaction drives contractility.5,8

The sarcomere is the basic contractile unit of the myocyte. Cardiac sarcomeres consist of long, fibrous proteins that form a thick filament made of the contractile protein myosin, and a thin filament made of actin.23 Directly affecting the contractile proteins of the myocardium is referred to as myotropy.8

Myosin acts as a molecular motor that converts energy stored as adenosine triphosphate (ATP) into a contractile force.8

Myosin heads that productively attach to actin filament and produce force contribute to myocyte contraction. Troponin and tropomyosin are associated with the actin filament and regulate the actin-myosin interaction.5,8,23

Intracellular Ca2+ shifts facilitate the actin-myosin interaction via troponin and tropomyosin.5,8,23

Cardiac contraction is executed through the "sliding" of actin and myosin past each other.5,23

This movement is dependent on Ca2+ fluxes and energy production (ATP).5,8,23

The actin-myosin interaction is also ATP dependent.5,8,23

Production of a forceful power stroke:8,26

  1. Myosin catabolizes ATP hydrolysis to become adenosine diphosphate (ADP) + orthophosphate (Pi), and flexion or cocking of the myosin head occurs (weak interaction with actin)
  2. Pi released high-affinity actin-myosin interaction
  3. ADP is released, and extension of myosin head is initiated
  4. Power stroke is completed (moves actin ~ 10 nm)
  5. ATP binds to myosin; myosin dissociates from actin filament

The substantial ATP quantity used for ventricular systole is provided by the mitochondria of the cardiac myocytes. This process is again upregulated by increased Ca2+ concentrations, among other stimuli, including elevated intracellular ADP.8

Ca2+, ATP, troponin, and tropomyocin together drive the actin-myosin interaction, which is the bedrock of myocardial contractility.5,8,23 Converting a greater number of actin-myosin interactions into effective power strokes results in greater contractility.34

Energy production and use within the cell, including ATP, are required for contraction, as well as system reset.6,8

Failing hearts undergo pathologic remodeling, producing inefficiencies that increase demand of ATP while decreasing capacity for ATP.6,35

The cycling of Ca2+ governs exposure of the actin-binding site for myosin attachment.8

There is Ca2+ dysregulation in the failing heart.36,37

Cardiac calcitropy, also known as "traditional inotropy," results in myocardial force augmentation by increasing intracellular Ca2+ concentration.8,38

Ca2+ is toxic at high levels in the myocardium. Elevated Ca2+ increases energy utilization and myocardial oxygen demand, as well as arrhythmogenicity, which can lead to increased morbidity and mortality.39,40

Despite many currently available therapies, further work is needed to improve patient outcomes in HFrEF.

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