Focusing on cardiac contractility is an intuitive complement to neurohormonal therapy1

Limitations of therapy that are active on neurohormonal pathways

GDMTs typically target the neurohormonal pathways.1,2

As heart failure 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

The role of calcitropes in treating heart failure with reduced ejection fraction (HFrEF)

Calcitropes improve contractility but at the risk of side effects, such as worsening energetics or malignant arrhythmias.2
Calcitropes are a class of traditional inotropes that are generally reserved for advanced heart failure as treatment for cardiogenic shock, bridge to LVAD or transplant, or as palliative therapy because long-term use is associated with increased mortality in patients with heart HFrEF.2

The promise of myotropes and mitotropes

In contrast to calcitropes, myotropes and mitotropes may improve long-term myocardial contractility and mortality without increasing cardiomyocyte calcium fluxes or adverse events such as worsening cardiac energetics, raising diastolic pressure, or heart rate.2
Myotropes’ effect on cardiac energy1
Chart showing how in a failing heart, calcitropes improve contractility but deplete cardiac energy; myotropes avoid this and maintain cardiac energetics
  • Mitotropes target the energy dependence of myocardial contraction and the metabolic deficiencies present in the myocardium of patients with HFrEF2
  • Myotropes target the sarcomere’s contractility via myosin, actin, and associated regulatory proteins through calcium-independent mechanisms2

Why improving contractility, a core issue in HF, may be useful in treating HFrEF2

Sarcomeric contractility in a healthy heart2

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

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

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 contraction4,5
  • Traditional inotropic agents (ie, calcitropes) alter calcium signaling in the myocardium2
  • Novel inotropes are being developed to target the sarcomere directly, without activating neurohormonal systems2

An important treatment goal is to reduce the number of heart failure events and symptoms

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor-neprilysin inhibitor; ATP, adenosine triphosphate; GDMT, guideline-directed medical therapy; LVAD, left ventricular assistance device; MRA, mineralocorticoid receptor antagonists; NEPi, neprilysin inhibitor; QoL, quality of life; sGC, soluble guanylate cyclase; SGLT2i, sodium/glucose cotransporter-2 inhibitors.

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. Planelles-Herrero VJ et al. Nat Commun. 2017;8:190. 5. Spudich JA. Biophys J. 2014;106:1236-1249.