Norton G R, Candy G, Woodiwiss A J
Department of Physiology, University of Witwatersrand, Johannesburg, South Africa.
Circulation. 1996 May 15;93(10):1905-12. doi: 10.1161/01.cir.93.10.1905.
A decreased cardiac compliance is a major feature of the cardiomyopathy of diabetes mellitus. Either an increase in the resistance afterload to the LV or an increase in collagen cross-linking induced by the formation of advanced glycosylation end products (AGEs) of collagen may be responsible for the stiff myocardium. To evaluate these hypotheses, we examined the effect of captopril, an afterload-reducing agent, and aminoguanidine, a nucleophilic hydrazine that prevents the accumulation of collagen AGEs, on left ventricular end-diastolic (LVED) compliance after 4 months of streptozotocin (0.26 mmol/kg)-induced diabetes mellitus in rats.
Diabetes mellitus produced a decrease in LV chamber compliance as a result of an increased myocardial stiffness (slope of the linearized LVED stress-LVED strain relation [unitless]: diabetes mellitus, 47+/-4; control, 27+/-3; P<.001) and an increase in blood pressure as a result of an elevated vascular resistance. LV end-systolic elastance was unaltered by diabetes mellitus. The stiff myocardium was not associated with changes in the myocardial collagen volume fraction or total hydroxyproline concentration but was associated with an increased myocardial collagen fluorescence (fluorescence units/microg hydroxyproline) (diabetes mellitus, 11+/-1.1; control, 6.6+/-0.7; P<.01). Captopril therapy (0.22 mmol x kg(-1) x d(-1)), despite producing a decrease in blood pressure through alterations in vascular resistance, failed to decrease myocardial stiffness in rats with diabetes mellitus. Alternatively, administration of aminoguanidine (7.35 mmol x kg(-1) x d(-1)) prevented both the enhanced myocardial collagen fluorescence (7.1+/-1.2) and the increased slope of the linearized LVED stress-LVED strain relation (29+/-2) but did not change markers of blood glucose control.
These results demonstrate that diabetes mellitus can produce a stiff myocardium before the development of myocardial fibrosis. The stiff myocardium in the early stages of the development of the cardiomyopathy of diabetes mellitus is not a consequence of an increase in ventricular resistance afterload and in these circumstances is associated with the formation of collagen AGEs.
心脏顺应性降低是糖尿病心肌病的主要特征。左心室后负荷阻力增加或胶原晚期糖基化终末产物（AGEs）形成所诱导的胶原交联增加，可能是心肌僵硬的原因。为了评估这些假说，我们研究了卡托普利（一种降低后负荷的药物）和氨基胍（一种亲核肼，可防止胶原AGEs的积累）对链脲佐菌素（0.26 mmol/kg）诱导的大鼠糖尿病4个月后左心室舒张末期（LVED）顺应性的影响。
糖尿病导致LV腔顺应性降低，原因是心肌僵硬度增加（线性化LVED应力-LVED应变关系的斜率[无量纲]：糖尿病组，47±4；对照组，27±3；P<0.001）以及血管阻力升高导致血压升高。糖尿病对LV收缩末期弹性无影响。僵硬的心肌与心肌胶原容积分数或总羟脯氨酸浓度的变化无关，但与心肌胶原荧光增加（荧光单位/μg羟脯氨酸）有关（糖尿病组，11±1.1；对照组，6.6±0.7；P<0.01）。卡托普利治疗（0.22 mmol·kg⁻¹·d⁻¹）尽管通过改变血管阻力使血压降低，但未能降低糖尿病大鼠的心肌僵硬度。相反，给予氨基胍（7.35 mmol·kg⁻¹·d⁻¹）可防止心肌胶原荧光增强（7.1±1.2）和线性化LVED应力-LVED应变关系斜率增加（29±2），但未改变血糖控制指标。
这些结果表明，糖尿病在心肌纤维化发生之前即可导致心肌僵硬。糖尿病心肌病发展早期的心肌僵硬并非心室阻力后负荷增加的结果，在这些情况下与胶原AGEs的形成有关。
