AIM Cardiovascular complications, including cardiac arrhythmias, result in high morbidity and mortality in patients with type-2 diabetes mellitus (T2DM). Clinical and experimental data suggest electrophysiological impairment of the natural pacemaker of the diabetic heart. The present study examined sinoatrial node (SAN) arrhythmias in a mouse model of T2DM and physiologically probed their underlying cause. METHODS Electrocardiograms were obtained from conscious diabetic db/db and lean control db/+ mice. In vivo SAN function was probed through pharmacological autonomic modulation with isoprenaline, atropine and carbachol. Blood pressure stability and heart rate variability (HRV) were evaluated. Intrinsic SAN function was evaluated through ex vivo imaging of spontaneous Ca2+ transients in isolated SAN preparations. RESULTS While lean control mice showed constant RR intervals during isoprenaline challenge, the diabetic mice experienced SAN arrhythmias with large RR fluctuations in a dose-dependent manner. These arrhythmias were completely abolished by atropine pre-treatment, while carbachol pretreatment significantly increased SAN arrhythmia frequency in the diabetic mice. Blood pressure and HRV were comparable in db/db and db/+ mice, suggesting that neither augmented baroreceptor feedback nor autonomic neuropathy is a likely arrhythmia mechanism. Cycle length response to isoprenaline was comparable in isolated SAN preparations from db/db and db/+ mice; however, Ca2+ spark frequency was significantly increased in db/db mice compared to db/+ at baseline and after isoprenaline. CONCLUSION Our results demonstrate a dysfunction of cardiac pacemaking in an animal model of T2DM upon challenge with a β-adrenergic agonist. Ex vivo, higher Ca2+ spark frequency is present in diabetic mice, which may be directly linked to in vivo arrhythmias.

中文翻译：

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β-肾上腺素刺激过程中窦房结异常放电会导致糖尿病小鼠心律不齐。

AIM心血管并发症，包括心律不齐，导致2型糖尿病（T2DM）患者的高发病率和高死亡率。临床和实验数据表明，糖尿病心脏天然起搏器的电生理损伤。本研究检查了T2DM小鼠模型中的窦房结（SAN）心律失常，并从生理角度探讨了其潜在原因。方法从有意识的糖尿病db / db和瘦对照组db / +小鼠获得心电图。通过异丙肾上腺素，阿托品和卡巴胆碱的药理自主调节来探索体内SAN功能。评估血压稳定性和心率变异性（HRV）。通过离体成像在分离的SAN制剂中自发的Ca2 +瞬变来评估SAN的固有功能。结果瘦对照小鼠在异丙肾上腺素攻击过程中显示出恒定的RR间隔，而糖尿病小鼠则出现SAN心律失常，且RR波动较大，且呈剂量依赖性。阿托品预处理可完全消除这些心律不齐，而卡巴胆碱预处理可显着增加糖尿病小鼠的SAN心律失常频率。在db / db和db / +小鼠中，血压和HRV相当，这表明增强的压力感受器反馈和自主神经病变均不是心律失常的可能机制。在来自db / db和db / +小鼠的分离的SAN制剂中，对异丙肾上腺素的周期长度响应相当。但是，与基线时和异丙肾上腺素后的db / +相比，db / db小鼠中的Ca2 +火花频率显着增加。结论我们的结果表明，在用β-肾上腺素能激动剂激发的T2DM动物模型中，心脏起搏功能异常。离体时，糖尿病小鼠中存在较高的Ca 2+火花频率，这可能与体内心律不齐直接相关。