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Effects of chronic tachycardia-induced cardiomyopathy on the beta-adrenergic receptor system
S A Burchell1, F G Spinale, F A Crawford
1Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29425.
Insights
Chronic supraventricular tachycardia causes heart muscle disease. This study found that while beta-receptors didn't change, their response to agonists was blunted, suggesting a pathway uncoupling. This impacts treatment strategies for tachycardia-induced cardiomyopathy.
Area of Science:
- Cardiology
- Physiology
- Pharmacology
Background:
- Chronic supraventricular tachycardia (SVT) can lead to dilated cardiomyopathy.
- The exact mechanisms driving SVT-induced cardiomyopathy are not fully understood.
- The role of the beta-adrenergic system in this condition requires further investigation.
Purpose of the Study:
- To investigate the relationship between left ventricular function, plasma norepinephrine levels, beta-receptor characteristics, and the response to beta-agonist stimulation in SVT-induced cardiomyopathy.
- To test the hypothesis that chronic SVT is associated with alterations in the beta-adrenergic system.
Main Methods:
- Eight control pigs and eight pigs with induced SVT (240 bpm for 3 weeks) were studied.
- Left ventricular function was assessed via echocardiography and catheterization.
- Plasma norepinephrine levels, beta-receptor number/affinity, and response to isoproterenol infusion were measured.
Main Results:
- SVT pigs showed increased left ventricular dimensions and pressure, and decreased fractional shortening compared to controls.
- Plasma norepinephrine levels were significantly higher in SVT pigs.
- Despite unchanged beta-receptor number/affinity, the contractile response to isoproterenol was blunted in SVT pigs.
Conclusions:
- Chronic SVT leads to impaired left ventricular function and increased norepinephrine levels.
- The findings suggest an uncoupling of the beta-adrenergic receptor from intracellular signaling pathways in SVT-induced cardiomyopathy.
- Treatment strategies may need to consider agents not reliant on the beta-adrenergic pathway.
Abstract:
Chronic supraventricular (or ventricular) tachycardia causes a dilated cardiomyopathy. Effective treatment requires ablation of the tachycardia using antiarrhythmic agents, cryoablation, electroablation, or surgical interruption/excision. However, the underlying pathophysiologic mechanisms responsible for the development of supraventricular tachycardia-induced cardiomyopathy have not been fully identified. We hypothesized that chronic supraventricular tachycardia is associated with significant changes in the beta-adrenergic system that may have implications for the pathophysiology and treatment of supraventricular tachycardia-induced cardiomyopathy. Accordingly, we examined the relationship between left ventricular function, plasma norepinephrine level, beta-receptor number and affinity, and response to a beta-agonist (isoproterenol) infusion in eight control pigs and eight pigs subjected to supraventricular pacing-induced tachycardia (240 beats/min for 3 weeks). Left ventricular function was measured using simultaneous echocardiography and catheterization. Left ventricular end-diastolic dimension and pressure increased in pigs with supraventricular tachycardia (5.1 +/- 0.4 cm and 27 +/- 2 mm Hg) versus control pigs (3.8 +/- 0.3 cm and 8 +/- 2 mm Hg), p < 0.05. Left ventricular fractional shortening decreased in supraventricular tachycardia (10 +/- 1%) versus control pigs (34 +/- 1%), p < 0.05. In addition, in the pigs with supraventricular tachycardia the fractional shortening versus left ventricular end-systolic stress relationship fell below the control relationship. Plasma norepinephrine level (measured by high-performance liquid chromatography) increased in pigs with supraventricular tachycardia (3592 +/- 1606 pg/ml plasma) versus control pigs (323 +/- 74 pg/ml plasma), p < 0.05. beta-Receptor number and affinity (measured by [3H]dihydroalprenolol binding) did not change in supraventricular tachycardia (98.6 +/- 11.5 fmol/mg protein and 7.2 +/- 1.1 nmol) versus control pigs (99.1 +/- 9.4 fmol/mg protein and 6.8 +/- 0.5 nmol). The response to isoproterenol infusion (10 micrograms/kg) in supraventricular tachycardia was blunted: the absolute increase in left ventricular peak (+)dP/dt was reduced in supraventricular tachycardia (833 +/- 233 mm Hg/sec) versus control pigs (2180 +/- 139 mm Hg/sec), p < 0.05. Chronic supraventricular tachycardia caused a decreased contractile state, increased plasma norepinephrine level, and caused no change in beta-receptor number or affinity; however, the response to beta-agonist infusion was blunted. These results suggest that chronic supraventricular tachycardia is associated with uncoupling of the beta-receptor from subsequent intracellular components of the beta-adrenergic system. Therefore medical management of chronic supraventricular tachycardia-induced cardiomyopathy before and immediately after definitive ablation may require use of pharmacologic agents whose actions do not depend on an intact beta-adrenergic pathway.