What is the mechanism of action of Levosimendan (levosimendan) and its role in minimally invasive Coronary Artery Bypass Grafting (CABG)?

Mechanism of Action of Levosimendan and Its Role in Minimally Invasive CABG

Levosimendan is a calcium sensitizer that improves cardiac contractility by binding to troponin-C in cardiomyocytes while also providing significant vasodilation through ATP-sensitive potassium channels and mild phosphodiesterase inhibitory action, making it valuable for perioperative management in minimally invasive CABG procedures. 1

Mechanism of Action

Levosimendan works through three primary mechanisms:

• Calcium sensitization: Increases myocardial contractility by binding to cardiac troponin-C, stabilizing the calcium-bound conformation without increasing intracellular calcium concentrations 1, 2

• Vasodilation: Opens ATP-sensitive potassium channels in vascular smooth muscle, causing significant peripheral and coronary vasodilation 1, 2

• Mild PDE inhibition: Has mild phosphodiesterase III inhibitory effects, though this is less significant at therapeutic concentrations 1, 2

This unique triple mechanism distinguishes levosimendan from traditional inotropes:

• Unlike catecholamines, levosimendan increases cardiac output without substantially increasing myocardial oxygen consumption 2, 3

• The drug produces hemodynamic effects that are maintained even with concomitant beta-blocker therapy 2

• Levosimendan has an active metabolite (OR-1896) with a half-life of approximately 80 hours, allowing for prolonged hemodynamic effects after stopping infusion 2

Role in Minimally Invasive CABG

Levosimendan offers several benefits in the context of minimally invasive CABG:

Preoperative Use

• Cardioprotective effects: Pretreatment with levosimendan before cardiopulmonary bypass (CPB) has been shown to reduce postoperative troponin I concentrations, suggesting a preconditioning effect that protects against ischemia-reperfusion injury 4

• Improved outcomes: A single dose of levosimendan (24 μg/kg over 10 minutes) administered before CPB has been shown to reduce time to tracheal extubation, overall ICU length of stay, and postoperative troponin I concentrations 1

Perioperative Management

• Prevention of low cardiac output syndrome (LCOS): Perioperative administration of levosimendan should be considered to reduce the risk of LCOS in patients with reduced left ventricular ejection fraction undergoing isolated CABG 1

• Enhanced cardiac performance: Levosimendan increases cardiac output and stroke volume while decreasing systemic vascular resistance after CPB 5

• Reduced complications: Compared to dobutamine, levosimendan decreases the incidence of postoperative atrial fibrillation, myocardial infarction, ICU length of stay, acute renal dysfunction, and ventricular arrhythmias 1

Postoperative Benefits

• Improved hemodynamics: Levosimendan infusion in patients with acutely decompensated heart failure increases cardiac output and stroke volume while reducing pulmonary wedge pressure, systemic vascular resistance, and pulmonary vascular resistance 1

• Sustained effects: Due to its active metabolite, the hemodynamic effects of levosimendan are maintained for several days after stopping the infusion 2

Clinical Application in Minimally Invasive CABG

For optimal use in minimally invasive CABG, consider the following approach:

1. Patient selection: Most beneficial for patients with:

   • Reduced left ventricular ejection fraction 1
   • History of heart failure 1
   • Risk factors for developing low cardiac output syndrome 1

2. Dosing strategy:

   • Preoperative: 24 μg/kg over 10 minutes before CPB 1, 4
   • Perioperative: 0.2-0.3 μg/kg/min infusion continued for 6-24 hours 5

3. Monitoring parameters:

   • Cardiac output and stroke volume
   • Systemic and pulmonary vascular resistance
   • Heart rate and blood pressure (watch for vasodilation effects) 1, 5

Advantages Over Other Inotropes

• Hemodynamic profile: Compared to dobutamine, levosimendan produces similar increases in cardiac output but greater decreases in pulmonary capillary wedge pressure 2

• Beta-blocker compatibility: Unlike dobutamine, levosimendan's hemodynamic effects are not attenuated with concomitant beta-blocker use 2

• Myocardial oxygen balance: Levosimendan improves cardiac performance with minimal increases in oxygen consumption, unlike catecholamines 1, 3

• Reduced arrhythmogenic potential: Phosphodiesterase III inhibitors and levosimendan cause less pronounced increases in heart rate and decreased likelihood of arrhythmias compared to dobutamine 1

Potential Limitations and Side Effects

• Hypotension: Due to its vasodilatory properties, levosimendan may cause headache and hypotension 2

• Tachycardia: May increase heart rate, particularly at higher doses 5

• Evidence quality: While promising, some guidelines still classify levosimendan as a Class IIb recommendation (may be considered) for treatment of perioperative low cardiac output syndrome 1