Glucagon-like peptide-1 protects against ischemic left ventricular dysfunction during hyperglycemia in patients with coronary artery disease and type 2 diabetes mellitus.

BACKGROUND: Enhancement of myocardial glucose uptake may reduce fatty acid oxidation and improve tolerance to ischemia. Hyperglycemia, in association with hyperinsulinemia, stimulates this metabolic change but may have deleterious effects on left ventricular (LV) function. The incretin hormone, glucagon-like peptide-1 (GLP-1), also has favorable cardiovascular effects, and has emerged as an alternative method of altering myocardial substrate utilization. In patients with coronary artery disease (CAD), we investigated: (1) the effect of a hyperinsulinemic hyperglycemic clamp (HHC) on myocardial performance during dobutamine stress echocardiography (DSE), and (2) whether an infusion of GLP-1(7-36) at the time of HHC protects against ischemic LV dysfunction during DSE in patients with type 2 diabetes mellitus (T2DM). METHODS: In study 1, twelve patients underwent two DSEs with tissue Doppler imaging (TDI)-one during the steady-state phase of a HHC. In study 2, ten patients with T2DM underwent two DSEs with TDI during the steady-state phase of a HHC. GLP-1(7-36) was infused intravenously at 1.2 pmol/kg/min during one of the scans. In both studies, global LV function was assessed by ejection fraction and mitral annular systolic velocity, and regional wall LV function was assessed using peak systolic velocity, strain and strain rate from 12 paired non-apical segments. RESULTS: In study 1, the HHC (compared with control) increased glucose (13.0 ± 1.9 versus 4.8 ± 0.5 mmol/l, p < 0.0001) and insulin (1,212 ± 514 versus 114 ± 47 pmol/l, p = 0.01) concentrations, and reduced FFA levels (249 ± 175 versus 1,001 ± 333 µmol/l, p < 0.0001), but had no net effect on either global or regional LV function. In study 2, GLP-1 enhanced both global (ejection fraction, 77.5 ± 5.0 versus 71.3 ± 4.3%, p = 0.004) and regional (peak systolic strain -18.1 ± 6.6 versus -15.5 ± 5.4%, p < 0.0001) myocardial performance at peak stress and at 30 min recovery. These effects were predominantly driven by a reduction in contractile dysfunction in regions subject to demand ischemia. CONCLUSIONS: In patients with CAD, hyperinsulinemic hyperglycemia has a neutral effect on LV function during DSE. However, GLP-1 at the time of hyperglycemia improves myocardial tolerance to demand ischemia in patients with T2DM. TRIAL REGISTRATION: http://www.isrctn.org . Unique identifier ISRCTN69686930.

Direct stenting is an independent predictor of improved survival in patients undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction.

AIMS: Randomised trials have shown that direct stenting (DS) is associated with improved markers of reperfusion during primary percutaneous coronary intervention (PPCI) for ST elevation myocardial infarction (STEMI). However, data evaluating its impact on long-term clinical outcomes are lacking. We set out to evaluate the effect of DS on mortality in a contemporary population of patients undergoing PPCI for STEMI. METHODS: Consecutive patients undergoing PPCI for STEMI at two high-volume UK heart attack centres between September 2008- December 2010 (n=1562) were included in the analysis. Local databases were analysed for patient demographics, as well as details on PPCI strategy, including use of DS versus predilatation (PD) followed by stenting, manual thrombus aspiration (MT) and glycoprotein IIb/IIIa inhibitors (GPIs). National databases were interrogated for in-hospital, 30-day and one-year mortality. To determine the impact of PPCI strategy on one-year survival, multivariate logistic analysis was performed. RESULTS: Altogether 489 patients underwent DS (31.3%) and 1073 (68.7%) received PD prior to stenting. Patients receiving DS had reduced mortality at 30 days (2.04 versus 4.66%, p=0.01) and one year (3.27 versus 8.48%, p=0.0001). After multivariate adjustment, PD remained an independent predictor of one-year mortality (odds ratio 2.42, 95% confidence interval 1.08-5.45, p=0.032) along with age, cardiogenic shock, number of diseased vessels, and left main or proximal left anterior descending artery intervention. However, neither GPI use nor MT improved survival in either univariate or multivariate analyses. CONCLUSIONS: In a contemporary, unselected population of patients undergoing PPCI for STEMI, DS - when compared with stenting after PD - is independently predictive of improved 30-day and one-year survival.

Chronic dipeptidyl peptidase-4 inhibition with sitagliptin is associated with sustained protection against ischemic left ventricular dysfunction in a pilot study of patients with type 2 diabetes mellitus and coronary artery disease.

BACKGROUND: The incretin hormone, glucagon-like peptide-1, promotes myocardial glucose uptake and may improve myocardial tolerance to ischemia. Endogenous glucagon-like peptide-1 (7-36) is augmented by pharmacological inhibition of dipeptidyl peptidase-4. We investigated whether chronic dipeptidyl peptidase-4 inhibition by sitagliptin protected against ischemic left ventricular dysfunction during dobutamine stress in patients with type 2 diabetes mellitus and coronary artery disease. METHODS AND RESULTS: A total of 19 patients with type 2 diabetes mellitus underwent dobutamine stress echocardiography with tissue Doppler imaging on 2 separate occasions: the first (control) while receiving oral hypoglycemic agents, and the second after the addition of sitagliptin (100 mg once daily) for ≈4 weeks. Sitagliptin increased plasma glucagon-like peptide-1 (7-36) levels and, at peak stress, enhanced both global (ejection fraction, 70.5±7.0 versus 65.7±8.0%; P<0.0001; mitral annular systolic velocity, 11.7±2.6 versus 10.9±2.3 cm/s; P=0.01) and regional left ventricular function, assessed by peak systolic velocity and strain rate in 12 paired, nonapical segments. This was predominantly because of a cardioprotective effect on ischemic segments (strain rate in ischemic segments, -2.27±0.65 versus -1.98±0.58 s(-1); P=0.001), whereas no effect was seen in nonischemic segments (-2.19±0.48 versus -2.18±0.54 s(-1); P=0.87). At 30 minutes recovery, dipeptidyl peptidase-4 inhibition mitigated the postischemic stunning seen in the control scan. CONCLUSIONS: The addition of dipeptidyl peptidase-4 inhibitor therapy with sitagliptin to the treatment regime of patients with type 2 diabetes mellitus and coronary artery disease is associated with a sustained improvement in myocardial performance during dobutamine stress and a reduction in postischemic stunning. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.org. Unique identifier ISRCTN61646154.