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Catecholamine stimulation is associated with impaired myocardial O(2) utilization in heart failure
Lazaros A Nikolaidis1, Teresa Hentosz, Aaron Doverspike
1Department of Medicine, Allegheny General Hospital, MCP-Hahneman University School of Medicine, 320 E. North Avenue, Pittsburgh, PA 15212, USA.
Insights
In dilated cardiomyopathy (DCM), alpha or beta-1 adrenergic receptor stimulation impairs oxygen extraction and shifts metabolism to glycolysis. Beta-2 receptor stimulation increases oxygen demand and fatty acid oxidation, potentially harming the heart.
Area of Science:
- Cardiology
- Pharmacology
- Physiology
Background:
- Dilated cardiomyopathy (DCM) is characterized by impaired cardiac function.
- Adrenergic receptors (ARs) play a crucial role in regulating cardiovascular function.
- Understanding the metabolic effects of AR stimulation in DCM is vital for therapeutic strategies.
Purpose of the Study:
- To investigate the impact of alpha, beta-1, and beta-2 adrenergic receptor (AR) stimulation on coronary hemodynamics.
- To assess myocardial oxygen consumption (M(v)O(2)) and metabolic substrate preference in advanced DCM.
- To elucidate the differential effects of various AR agonists in a canine model of DCM.
Main Methods:
- Utilized a pacing-induced canine model of advanced dilated cardiomyopathy (DCM).
- Administered adrenergic agonists: norepinephrine, dobutamine, phenylephrine, and isoproterenol (alone or with metoprolol).
- Evaluated systemic and coronary hemodynamics, M(v)O(2), and myocardial substrate preference (RQ).
Main Results:
- Alpha or beta-1 AR stimulation in DCM led to desensitized contractile responses and reduced M(v)O(2) per beat.
- Impaired transmyocardial oxygen extraction, not reduced coronary blood flow, explained decreased M(v)O(2) per beat.
- Beta-1/beta-2 or beta-2 AR stimulation increased M(v)O(2) per beat and favored fatty acid oxidation.
Conclusions:
- Contractile dysfunction in DCM is linked to impaired myocardial oxygen extraction and a shift towards glycolysis.
- Beta-2 AR stimulation in DCM promotes fatty acid oxidation, increasing M(v)O(2) requirements.
- Beta-2 AR stimulation may have deleterious metabolic effects in DCM.
Objectives:
To investigate the effect of alpha,beta(1) and beta(2) adrenergic receptor (AR) stimulation on coronary hemodynamics, myocardial oxygen consumption (M(v)O(2)) and metabolic substrate preference in advanced dilated cardiomyopathy (DCM).
Methods:
We studied 19 conscious, instrumented dogs with pacing-induced DCM. We evaluated systemic, coronary hemodynamics and M(v)O(2) in response to norepinephrine (NOR, 0.05-0.4 microg/kg per min), dobutamine (DOB, 1-10 microg/kg per min), phenylephrine (PHE, 1-5 microg/kg per min) and isoproterenol (ISO, 0.05-0.4 microg/kg per min) alone or in the presence of metoprolol (ISO+MET). Experiments were conducted in control state and in advanced DCM, 4-5 weeks after the initiation of pacing.
Results:
Contractile responses (LV dP/dt) to catecholamines were desensitized and accompanied by a parallel decrease in heart rate-adjusted myocardial O(2) consumption (M(v)O(2/beat)), when alpha(PHE) or beta(1) (DOB) or both alpha/beta(1) (NOR) AR were stimulated in DCM. This was due to impaired transmyocardial (Ao-Cs) O(2) extraction rather than limitations in CBF responses. There was an associated shift in myocardial metabolism, evidenced by an increased preference for glycolytic substrates (Respiratory Quotient) following administration of any of these three adrenergic agonists in DCM. Combined beta(1)/beta(2) stimulation with ISO or beta(2)-AR stimulation (ISO+MET) in DCM resulted in greater M(v)O(2/beat), [(Ao-Cs) O(2)] extraction, and decreases in myocardial RQ consistent with a shift toward oxidation of FFA.
Conclusions:
The impairment in contractile responses to dobutamine and norepinephrine in DCM is associated with impaired myocardial O(2) extraction, and a shift toward a preference for glycolysis. A different myocardial metabolic pattern suggestive of increased oxidation of FFA with increased myocardial O(2) extraction was observed in the presence of combined beta(1)/beta(2) stimulation with isoproterenol or beta(2) stimulation (ISO+MET). These data suggest that beta(2)-AR stimulation in DCM shifts substrate preference toward FFA oxidation associated with greater M(v)O(2) requirements. These findings identify a putative metabolic effect of beta(2) -AR in DCM that may be deleterious.