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<p>The morbidity and mortality associated with heart failure with reduced ejection fraction (HFrEF) remain high despite significant advances in treatment. Current guideline-directed medical therapies (GDMT) primarily target neurohormonal pathways. However, traditional positive inotropes, which enhance contractility, are limited by adverse events including increased myocardial oxygen consumption and arrhythmogenesis. Omecamtiv Mecarbil (OM) is a first-in-class selective cardiac myosin activator that addresses this gap by directly targeting the cardiac sarcomere. OM binds to cardiac myosin, stabilizing it in a force-generating state, thereby prolonging systolic ejection time and improving contractility without increasing intracellular calcium or heart rate. The Phase III GALACTIC-HF trial, which enrolled over 8,200 patients with HFrEF, reported an 8% relative risk reduction in the composite endpoint of heart failure events or cardiovascular death (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.86–0.99, <i>P</i> = 0.025). This benefit was primarily driven by a reduction in heart failure hospitalizations, with no significant difference in cardiovascular mortality. Subgroup analysis revealed that the clinical benefit was most pronounced in patients with a left ventricular ejection fraction (LVEF) of ≤ 28%. OM was generally well-tolerated, with a safety profile comparable to placebo, though it possesses a narrow therapeutic window, with higher plasma concentrations associated with an increased risk of ischemic events. In summary, OM represents a novel, mechanistically distinct therapeutic option for symptomatic HFrEF patients, particularly those with severe systolic dysfunction, who remain at high risk despite optimized GDMT.</p>

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Targeting cardiac myosin in HFrEF: mechanism, clinical evidence, and the role of omecamtiv mecarbil

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月14日

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  • Eslam Abady,
  • Mandy Elewa,
  • Karrar Naem Karam,
  • Kevin Thomas Mathew,
  • Mahmoud Bedair,
  • Suleiman N. Almashaqbeh,
  • Asmaa G. Alwarraqi,
  • Hazem AbuEl-Enien,
  • Yahya Samadi,
  • Khaled Abouelmad

摘要

The morbidity and mortality associated with heart failure with reduced ejection fraction (HFrEF) remain high despite significant advances in treatment. Current guideline-directed medical therapies (GDMT) primarily target neurohormonal pathways. However, traditional positive inotropes, which enhance contractility, are limited by adverse events including increased myocardial oxygen consumption and arrhythmogenesis. Omecamtiv Mecarbil (OM) is a first-in-class selective cardiac myosin activator that addresses this gap by directly targeting the cardiac sarcomere. OM binds to cardiac myosin, stabilizing it in a force-generating state, thereby prolonging systolic ejection time and improving contractility without increasing intracellular calcium or heart rate. The Phase III GALACTIC-HF trial, which enrolled over 8,200 patients with HFrEF, reported an 8% relative risk reduction in the composite endpoint of heart failure events or cardiovascular death (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.86–0.99, P = 0.025). This benefit was primarily driven by a reduction in heart failure hospitalizations, with no significant difference in cardiovascular mortality. Subgroup analysis revealed that the clinical benefit was most pronounced in patients with a left ventricular ejection fraction (LVEF) of ≤ 28%. OM was generally well-tolerated, with a safety profile comparable to placebo, though it possesses a narrow therapeutic window, with higher plasma concentrations associated with an increased risk of ischemic events. In summary, OM represents a novel, mechanistically distinct therapeutic option for symptomatic HFrEF patients, particularly those with severe systolic dysfunction, who remain at high risk despite optimized GDMT.