How do phosphodiesterase (PDE) inhibitors improve heart failure symptoms?

Phosphodiesterase Inhibitors in Heart Failure: Mechanism and Clinical Impact

Phosphodiesterase (PDE) inhibitors improve heart failure by inhibiting the breakdown of cyclic AMP, resulting in increased myocardial contractility and peripheral vasodilation, which together improve cardiac output and reduce pulmonary wedge pressure. 1

Mechanism of Action

• PDE inhibitors (such as milrinone and enoximone) work by inhibiting type III phosphodiesterase, preventing the breakdown of cyclic AMP in cardiac and vascular muscle 1
• The increased intracellular cyclic AMP leads to:
  • Enhanced calcium-mediated contractility in cardiac muscle 2
  • Improved diastolic relaxation through cAMP-dependent contractile protein phosphorylation 2
  • Vasodilation in vascular smooth muscle 1
• Unlike beta-adrenergic agonists, PDE inhibitors work at a site distal to beta-adrenergic receptors, allowing them to maintain effectiveness during concomitant beta-blocker therapy 1

Hemodynamic Effects

• PDE inhibitors produce significant inotropic and peripheral vasodilating effects, resulting in 1:
  • Increased cardiac output and stroke volume
  • Decreased pulmonary artery pressure
  • Reduced pulmonary wedge pressure
  • Lowered systemic and pulmonary vascular resistance
• The hemodynamic profile is intermediate between a pure vasodilator and a predominant inotropic agent 1
• Milrinone improves both systolic pump function and impaired diastolic relaxation of the failing heart 3

Clinical Applications

• PDE inhibitors are indicated for patients with evidence of peripheral hypoperfusion with or without congestion refractory to diuretics and vasodilators at optimal doses 1
• They may be preferred to dobutamine in patients on concomitant beta-blocker therapy due to their ability to maintain effects despite beta-blockade 1
• Milrinone is administered as a 25-75 μg/kg bolus over 10-20 minutes, followed by a continuous infusion at 0.375-0.75 μg/kg/min 1
• Enoximone is given as a bolus of 0.25-0.75 mg/kg followed by a continuous infusion at 1.25-7.5 μg/kg/min 1

Advantages Compared to Other Inotropes

• Compared to dobutamine in postoperative low cardiac output, PDE inhibitors cause:
  • Less pronounced increase in heart rate 1
  • Decreased likelihood of arrhythmias 1
  • Lower incidence of postoperative myocardial infarction (0% with amrinone vs. 40% with dobutamine) 1
• PDE inhibitors decrease left ventricular wall tension without increasing myocardial oxygen consumption, unlike catecholamines 1

Limitations and Cautions

• Long-term oral PDE inhibitor therapy increases mortality in patients with heart failure 1, 4
• The PROMISE study showed that oral milrinone increased mortality by 28% compared to placebo in severe chronic heart failure 4
• Common side effects include hypotension (especially in patients with low filling pressures) and thrombocytopenia (uncommon with both milrinone and enoximone) 1
• PDE inhibitors should be used with caution in patients with coronary artery disease as they may increase medium-term mortality 1
• They are contraindicated in patients with heart failure due to their association with increased mortality 1

Comparison with Other Inotropes

• Levosimendan, a calcium sensitizer with mild PDE inhibitory action, may offer advantages over pure PDE inhibitors:
  • Improves cardiac contractility by binding to troponin-C 5
  • Provides significant vasodilation through ATP-sensitive potassium channels 5
  • Has shown decreased incidence of postoperative atrial fibrillation, myocardial infarction, and ICU length of stay compared to dobutamine 1, 5

Current Recommendations

• PDE inhibitors have a Class IIb recommendation (may be considered) with level of evidence B for use in acute heart failure 1
• They are primarily indicated for short-term use in hospitalized patients with decompensated heart failure rather than for chronic therapy 1
• PDE inhibitors should be avoided in patients with heart failure and preserved systolic blood pressure 1

In conclusion, while PDE inhibitors provide effective short-term hemodynamic improvement in acute heart failure through their dual inotropic and vasodilator effects, their use must be carefully considered due to potential adverse effects on long-term outcomes, particularly when used orally for extended periods.