DPP-4 Inhibition by Sitagliptin Improves the Myocardial Response to Dobutamine Stress and Mitigates Stunning in a Pilot Study of Patients With Coronary Artery Disease
DPP-4 Inhibition by Sitagliptin Improves the Myocardial Response to Dobutamine Stress and Mitigates Stunning in a Pilot Study of Patients With Coronary Artery Disease
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DOI：
10.1161/circimaging.109.899377
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发表时间：
2010-03-01
影响因子：
7.5
通讯作者：
Dutka, David P.
中科院分区：
文献类型：
--
作者：
Read, Philip A.;Khan, Fakhar Z.;Dutka, David P.
背景胰高血糖素样肽-1（GLP-1）是一种餐后分泌的肠促胰岛素激素，可促进心肌葡萄糖摄取。活性酰胺GLP-1（7-36）被酶DPP-4降解，抑制这种酶的药物（如西格列汀）已被引入治疗2型糖尿病。我们评估的假设，增加血浆中的GLP-1的DPP-4抑制剂浓度将保护心脏缺血性左心室（LV）功能障碍多巴酚丁胺负荷超声心动图在冠心病patients.Methods和Results-Fourteen冠心病患者和保存左心室功能等待血运重建进行了研究。在单次给予100 mg西格列汀或安慰剂后，口服75 g葡萄糖以促进GLP-1分泌，并在静息、峰值负荷和30分钟时进行多巴酚丁胺负荷超声心动图和组织多普勒成像。西格列汀给药后，血浆GLP-1（7-36）在峰值应力时升高（16.5 +/- 10.7 vs 9.7 +/- 8.7 pg/mL; P = 0.003）和恢复期（12.4 +/- 5.5 vs 9.0 +/- 5.5 pg/mL; P = 0.01），左室对应激的反应增强（射血分数，72.6 ± 7.2 vs 63.9 ± 7.9%，P = 0.0001;二尖瓣环收缩期流速，12.54 ± 3.18 vs 11.49 ± 2.52 cm/s; P = 0.0006）。DPP-4抑制还改善了12对非心尖段的LV局部功能，通过收缩期峰值组织多普勒评估（速度，10.56 +/- 4.49 vs 9.81 +/- 4.26 cm/s，P = 0.002;应变，-15.9 +/- 6.3 vs-14.6 +/-6.6%，P = 0.01;应变率，-2.04 +/- 1.04对比-1.75 +/- 0.98 s（-1），P = 0.0003）。这主要是由于对缺血节段的心脏保护作用（缺血节段的血流速度，9.77 ± 4.18 vs 8.74 ± 3.87，P = 0.007;非缺血节段的血流速度，11.51 ± 4.70 vs 11.14 ± 4.38，P = 0.14）。在恢复期，西格列汀减弱了对照研究后观察到的缺血后顿抑。结论-GLP-1（7-36）的增强通过抑制DPP-4改善了全球和区域LV性能，以应对压力，并减轻了缺血后顿抑在冠状动脉疾病的人。
Background-Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted postprandially that promotes myocardial glucose uptake. The active amide GLP-1 (7-36) is degraded by the enzyme DPP-4, and drugs that inhibit this enzyme (such as sitagliptin) have been introduced to treat type 2 diabetes. We assessed the hypothesis that increasing the plasma concentration of GLP-1 by DPP-4 inhibition would protect the heart from ischemic left ventricular (LV) dysfunction during dobutamine stress echocardiography in patients with coronary artery disease.Methods and Results-Fourteen patients with coronary artery disease and preserved LV function awaiting revascularization were studied. After either a single dose of 100 mg sitagliptin or placebo, 75 g of glucose was given orally to promote GLP-1 secretion and dobutamine stress echocardiography was conducted with tissue Doppler imaging at rest, peak stress, and 30 minutes. After sitagliptin, plasma GLP-1 (7-36) was increased at peak stress (16.5 +/- 10.7 versus 9.7 +/- 8.7 pg/mL; P = 0.003) and in recovery (12.4 +/- 5.5 versus 9.0 +/- 5.5 pg/mL; P = 0.01), and the LV response to stress was enhanced (ejection fraction, 72.6 +/- 7.2 versus 63.9 +/- 7.9%, P = 0.0001; mitral annular systolic velocity, 12.54 +/- 3.18 versus 11.49 +/- 2.52 cm/s; P = 0.0006). DPP-4 inhibition also improved LV regional function in the 12 paired nonapical segments assessed by peak systolic tissue Doppler (velocity, 10.56 +/- 4.49 versus 9.81 +/- 4.26 cm/s, P = 0.002; strain, -15.9 +/- 6.3 versus -14.6 +/- 6.6%, P = 0.01; strain rate, -2.04 +/- 1.04 versus -1.75 +/- 0.98 s(-1), P = 0.0003). This was predominantly due to a cardioprotective effect on ischemic segments (velocity in ischemic segments, 9.77 +/- 4.18 versus 8.74 +/- 3.87, P = 0.007; velocity in nonischemic segments, 11.51 +/- 4.70 versus 11.14 +/- 4.38, P = 0.14). In recovery, sitagliptin attenuated the postischemic stunning seen after the control study.Conclusions-The augmentation of GLP-1 (7-36) by inhibition of DPP-4 improves global and regional LV performance in response to stress and mitigates postischemic stunning in humans with coronary artery disease.