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Increased beta-receptor density and improved hemodynamic response to catecholamine stimulation during long-term
S M Heilbrunn1, P Shah, M R Bristow
1Cardiology Division, Stanford University School of Medicine, CA.
Insights
Long-term metoprolol therapy in severe heart failure patients significantly improved cardiac function. This beta-blocker treatment increased beta-adrenergic receptors, enhancing the heart
Area of Science:
- Cardiology
- Pharmacology
Background:
- Severe heart failure is linked to reduced myocardial beta-adrenergic receptor density.
- Impaired contractile response to catecholamines is characteristic of heart failure.
Purpose of the Study:
- To investigate the effects of 6-month metoprolol therapy on beta-adrenergic receptor density and cardiac function in dilated cardiomyopathy patients.
- To assess if metoprolol improves myocardial beta-receptor density and contractile response to catecholamines.
Main Methods:
- 14 patients with dilated cardiomyopathy received metoprolol for 6 months (mean dose 105 mg/day).
- Myocardial beta-receptor density, resting hemodynamics, and dobutamine response were measured before and after therapy.
- Hemodynamic studies were conducted during ongoing metoprolol treatment.
Main Results:
- Myocardial beta-receptor density increased significantly (39 to 80 fmol/mg).
- Resting hemodynamic output improved, with stroke work index rising (27 to 43 g/m/m2) and ejection fraction increasing (0.26 to 0.39).
- Dobutamine-induced increase in peak positive left ventricular dP/dt improved from 21% to 74% during metoprolol therapy.
Conclusions:
- Long-term metoprolol therapy up-regulates myocardial beta-adrenergic receptors.
- Metoprolol significantly improves resting cardiac hemodynamics and contractile response to catecholamines in heart failure.
- These findings suggest restoration of beta-adrenergic sensitivity with metoprolol treatment.
Abstract:
Severe heart failure is associated with a reduction in myocardial beta-adrenergic receptor density and an impaired contractile response to catecholamine stimulation. Metoprolol was administered during a 6-month period to 14 patients with dilated cardiomyopathy to examine its effects on these abnormalities. The mean daily dose of metoprolol for the group was 105 mg (range, 75-150 mg). Myocardial beta-receptor density, resting hemodynamic output, and peak left ventricular dP/dt response to dobutamine infusions were compared in 9, 14, and 7 patients, respectively, before and after 6 months of metoprolol therapy while the patients were on therapy. The second hemodynamic study was performed 1-2 hours after the morning dose of metoprolol had been given. Myocardial beta-receptor density increased from 39 +/- 7 to 80 +/- 12 fmol/mg (p less than 0.05). Resting hemodynamic output showed a rise in stroke work index from 27 +/- 4 to 43 +/- 3 g/m/m2, p less than 0.05, and ejection fraction rose from 0.26 +/- 0.03 to 0.39 +/- 0.03 after 6 months of metoprolol therapy, p less than 0.05. Before metoprolol therapy, dobutamine caused a 21 +/- 4% increase in peak positive left ventricular dP/dt; during metoprolol therapy, the same dobutamine infusion rate increased peak positive dP/dt by 74 +/- 18% (p less than 0.05). Thus, long-term metoprolol therapy is associated with an increase in myocardial beta-receptor density, significant improvement in resting hemodynamic output, and improved contractile response to catecholamine stimulation. These changes indicate a restoration of beta-adrenergic sensitivity associated with metoprolol therapy, possibly related to the observed up-regulation of beta-adrenergic receptors.