解开糖尿病心脏的机制

糖尿病经常伴随心力衰竭（HF）和HF，可在2型糖尿病患者（T2D）中观察到高达15％的患者。然而，糖尿病和心脏之间的关系是复杂的。众所周知，糖尿病是冠状动脉疾病的重要危险因素，由此产生的心肌缺血和通往HF的呼吸缺血。但糖尿病对心肌肌肉的直接效果不太清楚。

存在非缺血性糖尿病心肌病，心肌疾病与糖尿病直接相关not due to coronary atherosclerosis，一直是辩论的长期课题。最近的EMPareg-结果研究，其中患者分配给钠葡萄糖共转运蛋白-2（SGLT-2）Empagliflozin，与HF住院的降低有关35％¹(for unclear reasons) has reignited this discussion.

Does a diabetic cardiomyopathy unrelated to atherosclerotic disease actually exist and, if so, how frequently is it responsible for the frequent HF plaguing diabetics? If it does exist, then what are the underlying mechanisms of diabetic cardiomyopathy that might be responsive to physiologically-tailored pharmacotherapies? As discussed in the recent Covance webinarThe Diabetic Heart: A Focus On Heart Failure，这些问题继续激发T2D与HF综合征之间这种复杂的连接的研究。

The History of Diabetic Cardiomyopathy

糖尿病诱导的心肌病的概念首次在20世纪50年代初期注意到Lundbæk发表了一个兰蔻刊物题为“糖尿病血管病患者的文章”.²He suggested that diabetics could have heart disease without coronary artery blockage, and later coined the term diabetic “cardiopathy” in the late 1960s.³

当Rubler报告尸检的尸检结果没有冠状动脉疾病的证据证明了4例HF的尸检结果时，在20世纪70年代注明了下一个连接。她观察了这些心灵的心室肥厚和纤维化，并提出了这些发现的代谢原因。⁴

Rubler’s observations were confirmed a few years later by Regan who performed catheterizations on patients with clean coronary arteries and HF, noting that the hearts were stiff and had increased filling pressures.⁵Biopsies also revealed an increase of fibrosis as well as triglyceride and cholesterol deposition in the ventricular walls. These observations supported Rubler’s earlier findings and align with data gathered from today’s advanced cardiac imaging techniques and hemodynamic assessments suggesting that many patients with diabetes and HF have stiff left ventricles (LVs), the main pumping chambers of the heart.

Examining the Role of Hyperglycemia-related Cardiomyopathy

糖尿病相关的HF非常普遍，并且以多种形式提供。存在日益增长的观点，即50％的一般人群HF患者保存了射血分数（HFPEF）。LV射血分数是一种原油，虽然常用，但LV收缩性指数。这些患者的弛豫和/或无源LV顺应性降低导致左心室填充压力升高，该压力升高到肺部和肺动脉电路，称为“向后失败”。在僵硬的心脏患者中，运动诱导的卒中量储备量也降低了僵硬的心脏，从而导致心脏输出和疲劳的增加，因此也有“前瞻性失败”的元素。

The precise split between HFpEF and the other form of HF where the ejection fraction is reduced (HFrEF) is unknown in diabetics but there is growing evidence, which we discuss in our blog “Exploring the Epidemiology of Diabetic Heart Failure”, that HFpEF may be even more common in diabetics than it is in non-diabetics. This concept adds further complexity to the diabetic cardiomyopathy story.

There are multiple mechanisms by which hyperglycemia and hyperinsulinemia can have direct toxic effects on the heart and cause both HFpEF and HFrEF apart from coronary artery disease. Some of these have been documented to date exclusively in animal models.

最重要的是,越来越多的意识到systemic inflammation, commonly seen with obesity and diabetes, causes increased superoxide production and reduces nitric oxide synthase levels and nitric oxide production in endothelial cells which then limits coronary vasodilatory/flow reserve. Thus, exercise-induced ischemia of the heart muscle cell (myocyte) can occur without overt evidence of atherosclerosis. In addition, chronic elevations in insulin levels present in T2D patients can induce LV hypertrophy and reduce myocyte relaxation. LV relaxation can also be impaired by hypophosphorlyation of the giant “titin” molecular spring as well as impairment of calcium signaling, the latter critical to contraction and relaxation of the heart muscle. Stiff ventricles caused by these mechanisms may lead to HFpEF and associated morbidity and mortality.

Hyperglycemia also activates the renin-angiotensin-aldosterone system leading to pleiotropic effects including an increase in reactive oxygen species, endothelial dysfunction and fibrosis. Fibrotic collagen remodeling, particularly of type 1 collagen, is found both in diabetic hearts as well as other forms of non-diabetic HFpEF. This effects both systolic and diastolic ventricular dysfunction and contributes to reduced LV passive compliance (stiffening). In addition, an increase in advanced glycation end products (AGEs) can be detected in both diabetics and the elderly. AGEs are proteins to which glucose is non-enzymatically attached (glycation). AGEs cross-linking can lead to LV stiffening and impaired production of local nitric oxide in vascular endothelial cells, again limiting exercise-associated vascular flow reserve⁶contributing to both depression of LV systolic and diastolic function.

新陈代谢和能源匮乏的心脏

Metabolic changes also affect the diabetic heart as it relies on energy provided by a balanced burning of glucose and free fatty acids.⁷Insulin resistance leads to a decreased uptake of glucose in the myocyte, with a compensatory uptake of free fatty acids (a less efficient source of energy production) which are oxidized and used as a fuel in place of glucose. This oxidation can trigger an increased production of reactive oxygen species, leading to cellular damage or programmed cell death (apoptosis).

脂毒性的链接

Switching of the heart’s main energy source to fatty acids can also lead to increased lipid deposition in the myocardium resulting in “lipotoxicity” or direct toxic effects of lipids on cardiac function. Novel technologies like NMR proton spectroscopy have been used to noninvasively evaluate cardiac lipid deposition. A recent study found an association between spectroscopic measurement of myocardial lipid deposition or “steatosis” and Doppler echocardiographic evidence of ventricular diastolic dysfunction in a diabetic population.⁸

Destabilization of Small Vessels

Exploring another angle in the diabetic-CV linkage, Hinkel et al.,⁹观察到稳定的微血管解剖和糖尿病组织学染色的心肌减少毛细血管密度。无论这一效果是否是由于年龄或血管内皮生长因子（VEGF）的降低，最终结果是心肌血液灌注和氧气和养分给肌肉细胞的抑郁症。

Summary

In summary, there are many potential mechanisms in which diabetes can play a role in cardiomyopathy and eventual HF. This is an exciting time for research into mechanisms of the diabetic heart. Novel translational medical approaches can test pre-clinically-based mechanisms of action in the clinic. Advanced diagnostic imaging techniques have opened up new areas of inquiry that may result in a better understanding of diabetic mechanisms of myocyte injury and LV dysfunction. Hopefully a combination of these approaches will clarify the relationship between diabetes and heart failure and determine whether “diabetic cardiomyopathy” is a true entity. This new knowledge may result in targeted/tailored therapies for the diabetic heart and associated HFpEF and HFrEF.

虽然本文只划伤了影响糖尿病心脏的复杂代谢变化和机制的表面，但您可以通过收听按需网络研讨会来了解更多信息：The Diabetic Heart: A Focus On Heart Failure。

Read more in the next series of this blog:Antihyperglycemic Agents and Heart Failure: An Examination of Recent Studies。

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References

1. Zinman B et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med(2015) 373:2117-2128.
2. Lundbaek K. Diabetic Angiopathy: a specific vascular disease.兰蔻(1954) 266(6808):377-9.
3. Lundbaek K. Is there a diabetic cardiopathy? in: Schettler G. (ed.). Pathogenetische faktoren des myokardinfarkts. Schattauer, Stuttgart, 1969, p.63-71.
4. Rubler S等人。与糖尿病肾小球粥样硬化相关的新型心肌病。AM Cardiol.(1972) 30:595-602.
5. Regan TJ et al. Evidence for cardiomyopathy in familial diabetes mellitus.J Clin Invest。(1977) 60:885-899.
6. van Heerebeek L et al. Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension.Circulation。(2008) 117:43–51.
7. Ferrannini E等人。在EMPA-REG结果试验中的CV保护：“节俭的底物”假设。糖尿病护理2016. epub。
8. Rijzewijk LJ et al. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus.J Am Coll Cardiol。（2008）52（22）：1793-9。
9. Hinkel R et al. Diabetes mellitus-induced microvascular destabilization in the myocardium.J Am Coll Cardiol。（2017）69（2）：131-43。