Treatments for heart failure with reduced ejection fraction

SOC treatment isn't always optimized

For patients with symptomatic heart failure, use of all 4 pillars of guideline-directed medical therapy (GDMT)* was estimated to significantly reduce all-cause mortality. However, target doses can rarely be achieved in patients with HFrEF and may not be well tolerated when they are. This can limit the ability to slow disease progression, which may lead to worsening heart failure.1-3

Patients with signs and symptoms of worsening heart failure, even with SOC treatment, need something more to reduce hospitalizations.2,4
The 4 treatment pillars of GDMT are RAASi/ARNI, beta blockers, MRA, and SGLT2i

Most current therapeutic options are designed to treat the neurohormonal implications of heart failure5

Current SOC treatments that target neurohormonal pathways are rarely titrated to optimal doses in patients with HFrEF due to side effects and tolerability issues

  • These include declining renal function, higher risk of hyperkalemia, and hypotension3,6

Treatments may directly impact the contractile function of the heart7

Inotropic subclassifications are based on 3 myocardial mechanisms7:
  • Mitotropes focus on myocardial energetics
  • Calcitropes are traditional inotropic agents that modulate calcium signaling
  • Myotropes act upon the physical sarcomere

The role of calcitropes in treating HFrEF

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 failure with reduced ejection fraction (HFrEF).7

  • With continued use, calcitropes detrimentally alter myocardial energetics, decrease the ATP/ADP ratio, and have been associated with poor clinical outcomes, including malignant arrhythmias7

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.7
  • Mitotropes target the energy dependence of myocardial contraction and the metabolic deficiencies present in the myocardium of patients with HFrEF7
  • Myotropes target the sarcomere’s contractility via myosin, actin, and associated regulatory proteins through calcium-independent mechanisms7

Myotropes were shown to increase contractility without worsening cardiac energetics, raising diastolic pressure, or heart rate5,7

Myotropes’ effect on cardiac energy5

Chart showing how in a failing heart, calcitropes improve contractility but deplete cardiac energy; myotropes avoid this and maintain cardiac energetics
Since SOC treatments for HFrEF act on neurohormonal pathways, another MOA that targets the sarcomere directly to improve contractility may complement the treatment effects of current SOC5,7
See the therapeutic potential of contractility
See the therapeutic
potential of contractility

*Standard GDMT included ACE inhibitors, ARBs, ARN inhibitors, beta-blockers, mineralocorticoid-receptor antagonists, and SGLT2 inhibitors.

ADP, adenosine diphosphate; ATP, adenosine triphosphate; GDMT, guideline-directed medical therapy; HFrEF, heart failure with reduced ejection fraction; IV, intravenous; LVAD, left ventricular assist device; SOC, standard of care.

References: 1. Heidenreich PA et al. J Am Coll Cardiol. 2022;79(17):e2-e159. 2. Butler J et al. J Am Coll Cardiol. 2019;73(8):935-944. 3. Fiuzat Met al. J Am Coll Cardiol. 2022;79(5):504-510. 4. Greene et al. Eur J Heart Fail. 2019;21(1)121-124. 5. He H et al. Circ Heart Fail. 2022;15(3):e009195. 6. Verhestraeten C et al. Heart Fail Rev. 2021;26(6):1359-1370. 7. Psotka MA et al. J Am Coll Cardiol. 2019;73:2345-2353.