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Pathophysiological Fundamentals of Diabetic Cardiomyopathy

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Diabetic cardiomyopathy (DCM) was first recognized more than four decades ago and occurred independent of cardiovascular diseases or hypertension in both type 1 and type 2 diabetic patients. The exact mechanisms underlying this disease remain incompletely understood. Several pathophysiological bases responsible for DCM have been proposed, including the presence of hyperglycemia, nonenzymatic glycosylation of large molecules (e.g., proteins), energy metabolic disturbance, mitochondrial damage and dysfunction, impaired calcium handling, reactive oxygen species formation, inflammation, cardiac cell death, and cardiac hypertrophy and fibrosis, leading to impairment of cardiac contractile functions. Increasing evidence also indicates the phenomenon called “metabolic memory” for diabetes‐induced cardiovascular complications, for which epigenetic modulation seemed to play an important role, suggesting that the aforementioned pathogenic bases may be regulated by epigenetic modification. Therefore, this review aims at briefly summarizing the current understanding of the pathophysiological bases for DCM. Although how epigenetic mechanisms play a role remains incompletely understood now, extensive clinical and experimental studies have implicated its importance in regulating the cardiac responses to diabetes, which are believed to shed insight into understanding of the pathophysiological and epigenetic mechanisms for the development of DCM and its possible prevention and/or therapy. © 2017 American Physiological Society. Compr Physiol 7:693‐711, 2017.

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Figure 1. Figure 1. Cardiac dysfunction can be derived from structural abnormality (cardiac hypertrophy and fibrosis) and also from the Ca2+ signaling dyshomeostasis.
Figure 2. Figure 2. Pathophysiological mechanisms responsible for DCM. The persistent presence of hyperglycemia, induce AGEs, and both hyperglycemia and hyperlipidemia cause energy metabolic disturbance along with mitochondrial damage and dysfunction. Mitochondrial dysfunction results in excessive ROS formation and calcium signaling abnormality, leading to cardiomyocyte death. The oxidative stress and cell death would cause inflammation, which feedback to further increase oxidative stress and cell death. Compensative cardiac hypertrophy occurs and meanwhile also evocates certain cytokines and inflammation that stimulates fibroblasts in the interstitium to differentiate into myofibroblasts that generate excess ECM accumulation, leading to fibrosis. These abnormal calcium signaling and cardiac structural remodeling result in the dysfunction of cardiac contractility, that is, cardiomyopathy.
Figure 3. Figure 3. Secreted matrix protein (including various collagens) can be accumulated in the interstitium, ECM, leading to the pathological level of fibrosis. In fact, the balance of MMPs and TIMPs also determines the pathogenic fibrosis in ECM.

Figure 1. Cardiac dysfunction can be derived from structural abnormality (cardiac hypertrophy and fibrosis) and also from the Ca2+ signaling dyshomeostasis.

Figure 2. Pathophysiological mechanisms responsible for DCM. The persistent presence of hyperglycemia, induce AGEs, and both hyperglycemia and hyperlipidemia cause energy metabolic disturbance along with mitochondrial damage and dysfunction. Mitochondrial dysfunction results in excessive ROS formation and calcium signaling abnormality, leading to cardiomyocyte death. The oxidative stress and cell death would cause inflammation, which feedback to further increase oxidative stress and cell death. Compensative cardiac hypertrophy occurs and meanwhile also evocates certain cytokines and inflammation that stimulates fibroblasts in the interstitium to differentiate into myofibroblasts that generate excess ECM accumulation, leading to fibrosis. These abnormal calcium signaling and cardiac structural remodeling result in the dysfunction of cardiac contractility, that is, cardiomyopathy.

Figure 3. Secreted matrix protein (including various collagens) can be accumulated in the interstitium, ECM, leading to the pathological level of fibrosis. In fact, the balance of MMPs and TIMPs also determines the pathogenic fibrosis in ECM.
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Teaching Material

Hu X, Bai T, Xu Z, Liu Q, Zheng Y, Cai L. Pathophysiological Fundamentals of Diabetic Cardiomyopathy. Compr Physiol 2017, 7: 693-711. doi: 10.1002/cphy.c160021


Didactic Synopsis

Major Teaching Points: 

              Understand how diabetes mellitus lead to cardiovascular complications and what is diabetic cardiomyopathy:

              Structural and functional changes of the heart under diabetic conditions:

o             Diabetes can induce cardiac arrhythmia and left ventricular dysfunction (both diastolic and systolic dysfunction)

o             The aforementioned diastolic and systolic dysfunction of the heart is associated with impaired calcium signaling.

o            Cardiac fibrosis and cardiac hypertrophy are two common structural alterations found in the diabetic heart.

              Cellular and molecular mechanisms by which diabetes induces the development of diabetic cardiomyopathy:

o             Classical mechanisms: Glucose and fatty acids metabolic disorders, Advanced glycated end-products (AGEs) and matrix remodeling, mitochondria dysfunction and mitophagy, oxidative stress and inflammation, and cell death.

o             New-discovered mechanisms: Metabolic memory is a phenomenon of the epigenetic mechanism, and the main theories include histone acetylation, DNA methylation, and dysregulation of microRNAs.

The importance to understand and clarify of mechanisms is its potential for developing target-specific treatments for diabetic patients.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: Understanding that cardiac dysfunctions (left ventricular dysfunction and arrhythmia) are results of both macro and micro pathological changes.

Figure 2. Teaching points: Interacting pathophysiological mechanisms of diabetic cardiomyopathy. Metabolic disorders (such as hyperglycemia and elevated free fatty acids), and mitochondria dysfunction (mainly causing intracellular energy disruption, also involve abnormal calcium signaling) promote the accumulation of free radicals [reactive oxygen species and reactive nitrogen species are the main participants] that lead to an oxidative stress condition. From this, inflammation, cell death, and other pathological events occur and go into a vicious circle that ultimately results in cardiac morphology and functional alterations that eventually cause diabetic cardiomyopathy.

Figure 3. Teaching points: Normally between cardiomyocytes, there are some space called extracellular matrix (ECM), composed of fibroblasts and proteins. Under diabetic conditions, inflammatory cytokines secreted by inflammatory cells stimulate the collagen accumulation in ECM. The collagen accumulated in ECM can also be removed by matrix metalloproteinases (MMP); however, the activity of MMPs would affect its tissue inhibitors (TIMPs). Therefore, the balance of MMP/TIMP is also important factor for the formation of ECM fibrosis.


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How to Cite

Xinyue Hu, Tao Bai, Zheng Xu, Qiuju Liu, Yang Zheng, Lu Cai. Pathophysiological Fundamentals of Diabetic Cardiomyopathy. Compr Physiol 2017, 7: 693-711. doi: 10.1002/cphy.c160021