Background

The improvement in left ventricular ejection fraction (LVEF) in response to β -blockers is heterogeneous in patients with heart failure due to ischaemic heart disease. This possibly indicates variations in the myocardial substrate (ranging from myocardial scar, through viable myocardium with contractile failure, intermittent myocardial ischemia, and finally remodelled myocardium with preserved systolic function) underlying left ventricular dysfunction.

Aim

To investigate whether improvement in LVEF in response to carvedilol treatment in patients with heart failure and LV dysfunction secondary to ischaemic heart disease (IHD), is associated with volume of hibernating myocardium.

Study groups

Carvedilol (initial dose 3.125 mg twice daily) vs. placebo
Target dose: 25 mg twice daily or 50 mg twice daily (in patients with > 85 kg weight)

Study Duration

6 months

Patients

387 patients with stable, chronic heart failure (NYHA class I - III) with LV systolic dysfunction due to coronary artery disease (CAD) (approximate ejection fraction < 40%).

Primary endpoint

Change in LVEF, in hibernators versus non-hibernators (designated according to volume of hibernating myocardium), on carvedilol compared to placebo.

Results

1. Carvedilol showed significant increase in LVEF unlike placebo in hibernators as well as non-hibernators
   
   
2. The mean number of segments with resting sestamibi uptake of 50% or less rose on placebo but was unchanged on carvedilol while the number with more than 60% uptake declined on placebo and increased on carvedilol. This suggests that carvedilol might stabilize or improve myocardial perfusion and viability.
   
   
   
   
3. The volume of myocardium affected by hibernation, ischaemia, or both is an important determinant of the increase in LVEF on carvedilol. This implies that pharmacological treatment of ischaemic or hibernating myocardium could mediate much of the improvement in LVEF seen with carvedilol.
   
4. Carvedilol significantly reduced heart rate as compared to placebo.

Conclusion

The myocardial substrate underlying LV systolic dysfunction due to CAD is complex and might account for the heterogeneity in response of LVEF to carvedilol. However, since -blockers can also exert clinical benefit by reducing acute coronary events and arrhythmias, they should now be used routinely, unless contraindicated, for all patients with heart failure due to LV systolic dysfunction. Medical treatment might be an important adjunct or alternative to revascularization for patients with hibernating myocardium.

Lancet 2003; 362: 7-13

Carvedilol could improve function in hibernating segments in following ways:

a. Slowing of the heart rate conserves myocardial energy and might improve cardiac myocyte efficiency, thereby offsetting the direct negative effects of -blockade on myocardial contractility.

b. Slowing the heart rate will also enhance the time for diastolic blood flow. Reduction of the myocardial oxygen requirements of contracting myocardium and increasing diastolic flow could redistribute blood flow to areas of contractile dysfunction, and should protect against recurrent myocardial ischaemia leading to stunning.

c. β-blockers may also switch the energy substrate of the failing myocardium away from free fatty acids and towards glucose, which is more efficient. This effect could be especially important in myocardium affected by hibernation.

d. The antioxidant effects of carvedilol could also contribute to improvement of ventricular function by protecting ischaemic myocardium.

e. Carvedilol might delay or prevent death of cardiac myocytes (apoptosis).

Lancet 2003; 362: 14-21

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