Background-The failing heart demonstrates a preference for glucose as its metabolic substrate. Whether enhancing myocardial glucose uptake favorably influences left ventricular (LV) contractile performance in heart failure remains uncertain. Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with potent insulinotropic effects the action of which is attenuated when glucose levels fall below 4 mmol. We examined the impact of recombinant GLP-1 (rGLP-1) on LV and systemic hemodynamics and myocardial substrate uptake in conscious dogs with advanced dilated cardiomyopathy (DCM) as a mechanism for overcoming myocardial insulin resistance and enhancing myocardial glucose uptake. Methods and Results-Thirty-five dogs were instrumented and studied in the fully conscious state. Advanced DCM was induced by 28 days of rapid pacing. Sixteen dogs with advanced DCM received a 48-hour infusion of rGLP-1 (1.5 pmol · kg

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We have recently demonstrated the benefits of glucagon-like peptide-1 (GLP-1) in enhancing regional and global myocardial function after reperfusion in the clinical setting of acute myocardial infarction. We hypothesized that GLP-1 facilitates recovery from myocardial stunning after an ischemic event. To investigate this, we administered GLP-1 (1.5 pmol/kg/min) to six dogs undergoing 10-min occlusion of the left circumflex coronary artery, followed by 24-h reperfusion. We compared the responses of coronary blood flow and regional thickening of the posterior wall with a group of eight vehicle-treated dogs undergoing the same occlusion-reperfusion protocol. Although recovery of coronary blood flow was identical, regional wall motion recovery occurred significantly (*p Ͻ 0.05) earlier (92 Ϯ 4 versus 57 Ϯ 5%* at 15 min) and was complete in the GLP-1-treated dogs, whereas residual contractile dysfunction persisted in the control group (99 Ϯ 4 versus 78 Ϯ 3%* at 24 h). This phenomenon was independent of changes in systemic hemodynamics or global systolic function. However, isovolumic left ventricular relaxation improved significantly in GLP-1-treated dogs. GLP-1 caused an insulinotropic effect, but no hypoglycemia. We conclude that GLP-1 enhances recovery from ischemic myocardial stunning after successful reperfusion.

Background-ACE inhibitors have been used extensively in heart failure, where they induce systemic vasodilatation. ACE inhibitors have also been shown to reduce ischemic events after myocardial infarction, although their mechanisms of action on the coronary circulation are less well understood. The purpose of the present study was to determine the effects and the mechanism of action of the ACE inhibitor enalaprilat and the AT 1 antagonist losartan on regional myocardial perfusion and coronary flow and vasodilator reserve in conscious dogs with pacing-induced dilated cardiomyopathy (DCM). Methods and Results-Twenty-seven conscious, chronically instrumented dogs were studied during advanced stages of dilated cardiomyopathy, which was induced by rapid pacing. Enalaprilat (1.25 mg IV) improved transmural distribution (endocardial/epicardial ratio) at rest (baseline, 0.91Ϯ0.11; enalaprilat, 1.02Ϯ0.07 mL/min per g; PϽ0.05) and during atrial pacing (baseline, 0.82Ϯ0.11; enalaprilat, 0.98Ϯ0.07; PϽ0.05). Enalaprilat also restored subendocardial coronary flow reserve (CFR) (baseline CFR, 1.89Ϯ0.11; enalaprilat CFR, 2.74Ϯ0.33; PϽ0.05) in DCM. These effects were abolished by pretreatment with the NO synthase inhibitor nitro-L-arginine. The effects were recapitulated by the bradykinin 2 receptor agonist cereport but not by the AT 1 antagonist losartan. Conclusions-The ACE inhibitor enalaprilat improves transmural myocardial perfusion at rest and after chronotropic stress and restores impaired subendocardial coronary flow and vasodilator reserve in DCM. The effects of enalaprilat were bradykinin mediated and NO dependent and were not recapitulated by losartan. These data suggest beneficial effects of ACE inhibitors on the coronary circulation in DCM that are not shared by AT 1 receptor antagonists.

Incessant tachycardia induces dilated cardiomyopathy in humans and experimental models; mechanisms are incompletely understood. We hypothesized that excessive chronotropic demands require compensatory contractility reductions to balance metabolic requirements. We studied 24 conscious dogs during rapid right ventricular (RV) pacing over 4 wk. We measured hemodynamic, coronary blood flow (CBF), myocardial O(2) consumption (MVO(2)) responses, myocardial nitric oxide (NO) production, and substrate utilization. Early pacing (6 h) resulted in decreased heart rate (HR)-adjusted coronary blood flow (CBF), MVO(2) (CBF/beat: 0.33 +/- 0.02 to 0.19 +/- 0.01 ml, P < 0.001, MVO(2)/beat: 0.031 +/- 0.002 to 0.016 +/- 0.001 ml O(2), P < 0.001), and contractility [left ventricular (LV) first derivative pressure (dP/dt)/LV end-diastolic diameter (EDD): 65 +/- 4 to 44 +/- 3 mmHg x s(-1) x mm(-1), P < 0.01], consistent with flow-metabolism-function coupling, which persisted over the first 72 h of pacing (CBF/beat: 0.15 +/- 0.01 ml, MVO(2)/beat: 0.013 +/- 0.001 ml O(2), P < 0.001). Thereafter, CBF per beat and MVO(2) per beat increased (CBF/beat: 0.25 +/- 0.01 ml, MVO(2)/beat: 0.021 +/- 0.001 ml O(2) at 28 days, P < 0.01 vs. 72 h). Contractility declined [(LV dP/dt)/LVEDD: 19 +/- 2 mmHg x s(-1) x mm(-1), P < 0.0001], signifying flow-function mismatch. Cardiac NO production, endothelial NO synthase expression, and fatty acid utilization decreased in late phase, whereas glycogen content and lactate uptake increased. Incessant tachycardia induces contractile, metabolic, and flow abnormalities reflecting flow-function matching early, but progresses to LV dysfunction late, despite restoration of flow and metabolism. The shift to flow-function mismatch is associated with impaired myocardial NO production.

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.

Our results indicate differences in the use of PA in the elderly and African-Americans. These differences are not explained by severity of illness and suggest that interventions and standard therapies may be withheld from those who may benefit most.