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The cellular basis for the blunted response to beta-adrenergic stimulation in supraventricular tachycardia-induced
R Tanaka1, B M Fulbright, R Mukherjee
1Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29425.
Insights
Supraventricular tachycardia (SVT) induced cardiomyopathy impairs myocyte contractility and beta-adrenergic response. This is due to reduced beta-receptors, altered signaling, lower adenylate cyclase activity, and decreased contractile proteins.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Chronic tachycardia can lead to dilated cardiomyopathy, characterized by elevated catecholamines and altered beta-adrenergic responsiveness in vivo.
- The direct impact of cardiomyopathy on isolated myocyte contractile function and beta-adrenergic stimulation remains unclear.
- Understanding these cellular changes is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the effects of supraventricular tachycardia (SVT)-induced cardiomyopathy on isolated cardiac myocyte function and beta-adrenergic responsiveness.
- To determine the cellular mechanisms underlying the blunted beta-adrenergic response in SVT cardiomyopathy.
- To examine changes in beta-adrenergic receptor system components and myocyte structure.
Main Methods:
- Isolated left ventricular (LV) myocytes were obtained from control pigs and pigs with induced SVT (240 beats/min for 3 weeks).
- Myocyte contractility was assessed at baseline and in response to beta-adrenergic stimulation (isoproterenol) and forskolin.
- Cellular analyses included beta-receptor density and affinity, adenylate cyclase activity, and myocyte structure (myofibrillar content).
Main Results:
- SVT-induced cardiomyopathy significantly reduced baseline myocyte shortening and velocity compared to controls.
- The contractile response to both isoproterenol and forskolin was significantly blunted in SVT myocytes.
- Cellular investigations revealed reduced beta-receptor density, decreased basal and stimulated adenylate cyclase activity, and diminished myofibrillar content in SVT myocytes.
Conclusions:
- Tachycardia-induced cardiomyopathy depresses isolated myocyte contractile function and beta-adrenergic responsiveness.
- Key cellular factors contributing to this depression include reduced beta-receptor expression, altered signal transduction, diminished adenylate cyclase activity, and decreased myocyte contractile protein content.
- These findings highlight significant cellular dysfunctions in SVT cardiomyopathy affecting beta-adrenergic signaling pathways.
Abstract:
Chronic tachycardia-induced dilated cardiomyopathy causes increased plasma catecholamines and alterations in beta-adrenergic responsiveness in vivo. However, whether isolated myocyte contractile response to beta-stimulation is directly affected by the development of cardiomyopathy and how these changes are related to alterations in the beta-adrenergic receptor system remain unclear. Accordingly, isolated myocyte function and beta-adrenergic responsiveness were examined in two groups of 12 pigs each: sham controls, and with supraventricular tachycardia induced cardiomyopathy (SVT; pace: 240 beats/min, 3 weeks). Isolated LV myocyte percent and velocity of shortening were examined at baseline, with isoproterenol (2-100 nM), and forskolin (0.1-4 microM). Baseline percent and velocity of shortening were significantly reduced with SVT compared to controls (1.6 +/- 0.1 vs 5.4 +/- 0.2%, 56 +/- 3 vs 25 +/- 1 micron/s, respectively, P < 0.05). The maximal increase in the percent and velocity of shortening with isoproterenol was significantly blunted in the SVT myocytes compared with controls (3.2 +/- 0.4 vs 9.7 +/- 1.0%, 48.0 +/- 5.3 vs 122.6 +/- 15.5 micron/s, respectively, P < 0.05). Similarly, maximal increase in the percent and velocity of shortening with forskolin were reduced with SVT compared to controls (3.3 +/- 0.4 vs 10.5 +/- 0.6%, 50.7 +/- 6.4 vs 120.1 +/- 9.7 micron/s, respectively, P < 0.05). In order to determine the cellular basis for these changes in beta-adrenergic response, myocyte structure, sarcolemmal beta-receptor density and affinity, and adenylate cyclase activity were examined. There was a 25% reduction in beta-receptor number with SVT (P < 0.05) but no change in affinity. Basal adenylate cyclase activity was lower with SVT compared to control (46 +/- 3 vs 77 +/- 10 pmol cyclic AMP/mg/min, P < 0.05), and exhibited a blunted response with both isoproterenol (1 mM; 106 +/- 19 vs 203 +/- 26 pmol cyclic AMP/mg/min, P < 0.05) and forskolin (100 microns: 209 +/- 35 vs 378 +/- 58 pmol cyclic AMP/mg/min, P < 0.05). Finally, myofibrillar content within SVT myocytes was significantly reduced from controls (43 +/- 7 vs 63 +/- 4%, P < 0.05). In summary, the cellular basis for the depressed myocyte contractile response to beta-stimulation with tachycardia induced SVT are probably due to several factors which include: decreased expression of beta-receptors, alterations in beta-receptor transduction, reduced adenylate cyclase activity, and decreased myocyte contractile protein content.