Department of Physiology, VU University Medical Center Amsterdam, Van der Boechorststraat 7,1081BT Amsterdam, The Netherlands.
Circulation. 2011 Sep 6;124(10):1151-9. doi: 10.1161/CIRCULATIONAHA.111.025270. Epub 2011 Aug 15.
Aortic stenosis (AS) and diabetes mellitus (DM) are frequent comorbidities in aging populations. In heart failure, DM worsens diastolic left ventricular (LV) dysfunction, thereby adversely affecting symptoms and prognosis. Effects of DM on diastolic LV function were therefore assessed in aortic stenosis, and underlying myocardial mechanisms were identified.
Patients referred for aortic valve replacement were subdivided into patients with AS and no DM (AS; n=46) and patients with AS and DM (AS-DM; n=16). Preoperative Doppler echocardiography and hemodynamics were implemented with perioperative LV biopsies. Histomorphometry and immunohistochemistry quantified myocardial collagen volume fraction and myocardial advanced glycation end product deposition. Isolated cardiomyocytes were stretched to 2.2-μm sarcomere length to measure resting tension (F(passive)). Expression and phosphorylation of titin isoforms were analyzed with gel electrophoresis with ProQ Diamond and SYPRO Ruby stains. Reduced LV end-diastolic distensibility in AS-DM was evident from higher LV end-diastolic pressure (21±1 mm Hg for AS versus 28±4 mm Hg for AS-DM; P=0.04) at comparable LV end-diastolic volume index and attributed to higher myocardial collagen volume fraction (AS, 12.9±1.1% versus AS-DM, 18.2±2.6%; P<0.001), more advanced glycation end product deposition in arterioles, venules, and capillaries (AS, 14.4±2.1 score per 1 mm(2) versus AS-DM, 31.4±6.1 score per 1 mm2; P=0.03), and higher F(passive) (AS, 3.5±1.7 kN/m2 versus AS-DM, 5.1±0.7 kN/m2; P=0.04). Significant hypophosphorylation of the stiff N2B titin isoform in AS-DM explained the higher F(passive) and normalization of F(passive) after in vitro treatment with protein kinase A.
Worse diastolic LV dysfunction in AS-DM predisposes to heart failure and results from more myocardial fibrosis, more intramyocardial vascular advanced glycation end product deposition, and higher cardiomyocyte F(passive), which was related to hypophosphorylation of the N2B titin isoform.
主动脉瓣狭窄（AS）和糖尿病（DM）是老龄化人群中常见的合并症。在心力衰竭中，DM 会加重左心室（LV）舒张功能障碍，从而对症状和预后产生不利影响。因此，在主动脉瓣狭窄中评估了 DM 对舒张 LV 功能的影响，并确定了潜在的心肌机制。
将接受主动脉瓣置换的患者分为无 DM 的 AS 患者（AS；n=46）和 AS-DM 患者（AS-DM；n=16）。进行术前多普勒超声心动图和血流动力学检查，并进行围手术期 LV 活检。组织形态计量学和免疫组织化学定量心肌胶原容积分数和心肌晚期糖基化终产物沉积。将分离的心肌细胞拉伸至 2.2-μm 肌节长度以测量静息张力（F（被动））。用 ProQ Diamond 和 SYPRO Ruby 染色进行凝胶电泳分析肌球蛋白重链同工型的表达和磷酸化。AS-DM 的 LV 舒张末期顺应性降低，表现为更高的 LV 舒张末期压力（AS 为 21±1mmHg，AS-DM 为 28±4mmHg；P=0.04），在可比的 LV 舒张末期容量指数下，归因于更高的心肌胶原容积分数（AS 为 12.9±1.1%，AS-DM 为 18.2±2.6%；P<0.001），在小动脉、小静脉和毛细血管中的晚期糖基化终产物沉积更多（AS 为 14.4±2.1 分/1mm²，AS-DM 为 31.4±6.1 分/1mm²；P=0.03），以及更高的 F（被动）（AS 为 3.5±1.7 kN/m²，AS-DM 为 5.1±0.7 kN/m²；P=0.04）。AS-DM 中僵硬的 N2B 肌球蛋白重链同工型的显著低磷酸化解释了 F（被动）较高的原因，并通过体外用蛋白激酶 A 治疗后 F（被动）恢复正常。
AS-DM 中更严重的舒张 LV 功能障碍易导致心力衰竭，这是由于心肌纤维化更多、心肌内血管晚期糖基化终产物沉积更多以及心肌细胞 F（被动）更高所致，这与 N2B 肌球蛋白重链同工型的低磷酸化有关。
