|This article or section possibly contains previously unpublished synthesis of published material that conveys ideas not attributable to the original sources. (March 2011)|
Diabetic cardiomyopathy is a disorder of the heart muscle in people with diabetes. It can lead to inability of the heart to circulate blood through the body effectively, a state known as heart failure, with accumulation of fluid in the lungs (pulmonary edema) or legs (peripheral edema). Most heart failure in people with diabetes results from coronary artery disease, and diabetic cardiomyopathy is only said to exist if there is no coronary artery disease to explain the heart muscle disorder.
Signs and symptoms
One particularity of DCM is the long latent phase, during which the disease progresses but is completely asymptomatic. In most cases, DCM is detected with concomitant hypertension or coronary artery disease. One of the earliest signs is mild left ventricular diastolic dysfunction with little effect on ventricular filling. Also, the diabetic patient may show subtle signs of DCM related to decreased left ventricular compliance or left ventricular hypertrophy or a combination of both. A prominent “a” wave can also be noted in the jugular venous pulse, and the cardiac apical impulse may be overactive or sustained throughout systole. After the development of systolic dysfunction, left ventricular dilation and symptomatic heart failure, the jugular venous pressure may become elevated, the apical impulse would be displaced downward and to the left. Systolic mitral murmur is not uncommon in these cases. These changes are accompanied by a variety of electrocardiographic changes that may be associated with DCM in 60% of patients without structural heart disease, although usually not in the early asymptomatic phase. Later in the progression, a prolonged QT interval may be indicative of fibrosis. Given that DCM’s definition excludes concomitant atherosclerosis or hypertension, there are no changes in perfusion or in atrial natriuretic peptide levels up until the very late stages of the disease, when the hypertrophy and fibrosis become very pronounced.
Diabetic cardiomyopathy is characterized functionally by ventricular dilation, myocyte hypertrophy, prominent interstitial fibrosis and decreased or preserved systolic function in the presence of a diastolic dysfunction.
While it has been evident for a long time that the complications seen in diabetes are related to the hyperglycemia associated to it, several factors have been implicated in the pathogenesis of the disease. Etiologically, four main causes are responsible for the development of heart failure in DCM: microangiopathy and related endothelial dysfunction, autonomic neuropathy, metabolic alterations that include abnormal glucose use and increased fatty acid oxidation, generation and accumulation of free radicals, and alterations in ion homeostasis, especially calcium transients.
Microangiopathy can be characterized as subendothelial and endothelial fibrosis in the coronary microvasculature of the heart. This endothelial dysfunction leads to impaired myocardial blood flow reserve as evidence by echocardiography. About 50% of diabetics with DCM show pathologic evidence for microangiopathy such as sub-endothelial and endothelial fibrosis, compared to only 21% of non-diabetic heart failure patients. Over the years, several hypotheses were postulated to explain the endothelial dysfunction observed in diabetes. It was hypothesized that the extracellular hyperglycemia leads to an intracellular hyperglycemia in cells unable to regulate their glucose uptake, most predominantly, endothelial cells. Indeed, while hepatocytes and myocytes have mechanisms allowing them to internalize their glucose transporter, endothelial cells do not possess this ability. The consequences of increased intracellular glucose concentration are fourfold, all resulting from increasing concentration of glycolytic intermediates upstream of the rate-limiting glyceraldehyde-3-phosphate reaction which is inhibited by mechanisms activated by increased free radical formation, common in diabetes. Four pathways, enumerated below all explain part of the diabetic complications. First, it has been widely reported since the 1960s that hyperglycemia causes an increase in the flux through aldose reductase and the polyol pathway. Increased activity of the detoxifying aldose reductase enzyme leads to a depletion of the essential cofactor NADH, thereby disrupting crucial cell processes. Second, increasing fructose 6-phosphate, a glycolysis intermediate, will lead to increased flux through the hexosamine pathway. This produces N-acetyl glucosamine that can add on serine and threonine residues and alter signaling pathways as well as cause pathological induction of certain transcription factors. Third, hyperglycemia causes an increase in diacylglycerol, which is also an activator of the Protein Kinase C (PKC) signaling pathway. Induction of PKC causes multiple deleterious effects, including but not limited to blood flow abnormalities, capillary occlusion and pro-inflammatory gene expression. Finally, glucose, as well as other intermediates such as fructose and glyceraldehyde-3-phosphate, when present in high concentrations, promote the formation of advanced glycation endproducts (AGEs). These, in turn, can irreversibly cross link to proteins and cause intracellular aggregates that cannot be degraded by proteases and thereby, alter intracellular signalling. Also, AGEs can be exported to the intercellular space where they can bind AGE receptors (RAGE). This AGE/RAGE interaction activates inflammatory pathways such as NF-κB, in the host cells in an autocrine fashion, or in macrophages in a paracrine fashion. Neutrophil activation can also lead to NAD(P)H oxidase production of free radicals further damaging the surrounding cells. Finally, exported glycation products bind extracellular proteins and alter the matrix, cell-matrix interactions and promote fibrosis. A major source of increased myocardial stiffness is crosslinking between AGEs and collagen. In fact, a hallmark of uncontrolled diabetes is glycated products in the serum and can be used as a marker for diabetic microangiopathy.
Myocardial metabolic abnormalities
Possibly one of the first difference alteration noticed in diabetic hearts were metabolic derangements. Indeed, even in the 1950s, it was recognized that cardiac myocyte from a diabetic patient had an abnormal, energy-inefficient metabolic function, with almost no carbohydrate oxidation. The changes seen in DCM are not dissimilar to those of ischemia, and might explain why diabetics are more susceptible to ischemic damage, and are not easily preconditioned. Further, diabetes leads to a persistent hyperglycemia very often accompanied by a hyperlipidemia. This alters substrate availability to the heart and surely affects its metabolism.
Under normal conditions, fatty acids are the preferred substrate in the adult myocardium, supplying up to 70% of total ATP. They are oxidized in the mitochondrial matrix by the process of fatty acid β-oxidation, whereas pyruvate derived from glucose, glycogen, lactate and exogenous pyruvate is oxidized by the pyruvate dehydrogenase complex, localized within the inner mitochondrial membrane. Substrate choice in the adult heart is mainly regulated by availability, energy demand and oxygen supply (Randle cycle/Glucose fatty-acid cycle). Therefore, it is not surprising that alterations are present in diabetes and contribute greatly to its pathogenesis. Cardiomyocytes, unlike endothelial cells, have the ability to regulate their glucose uptake. Thus, they are mostly spared from the complications associated with hyperglycemia that plague endothelial cells. In order to protect themselves from the extracellular hyperglycemia, cardiac cells can internalize their insulin-dependent glucose transporter, GLUT4. When looking at the carbohydrate utilization of the myocardium, diabetic hearts not only show a decrease in glucose utilization but also a very pronounced decrease in lactate utilization, to a greater extent than glucose utilization. The mechanisms are unclear but are not related to lactate transport or lactate dehydrogenase expression. Further, due to a deficient carbohydrate uptake, the diabetic myocardium shows increases in intracellular glycogen pool, possibly through augmented synthesis or decreased glycogenolysis.
However, as a downside to this decrease glucose uptake, cardiomyocytes are faced with a reduced glucose oxidation rate and a dramatically increased fatty acid β-oxidation to almost 100% of ATP production. This is translated into a dramatic increase of fatty acid transporter, especially CD36 that is postulated to have an important role in the etiology of cardiac disease. Interestingly, it seems that the decrease in carbohydrate oxidation precedes the appearance of hyperglycemia in type II diabetes. It is likely due to the increased β-oxidation due to the hyperlipidemia and altered insulin signaling. The rate of uptake of lipids, unlike that of glucose, is not regulated by a hormone. Therefore, increased circulating lipids will increase uptake and thereby fatty acid oxidation. This, in turn, increases the concentration of citrate in the cell, a very potent inhibitor of phosphofructokinase, the first rate-limiting step of glycolysis. When the rate of uptake is greater than the rate of oxidation, fatty acids are shuttled to the triglyceride synthesis pathway. Increasing triglyceride stores prevent lipotoxicity but decrease heart function.
Why are all those alterations detrimental to the heart? Emerging evidence supports the concept that alterations in metabolism contribute to cardiac contractile dysfunction. In animal models, contractile failure begins as a diastolic dysfunction, and progresses occasionally to systolic dysfunction ultimately leading to heart failure. Normalizing energy metabolism in these hearts reversed the impaired contractility. During diabetes, metabolic remodeling precedes the cardiomyopathy and it is valid to hypothesize that these changes may contribute to cardiac dysfunction. Indeed, when treating animal models with metabolic modulators at an early age, prior to any sign of cardiomyopathy, improvements of heart function can be noted. Thus, it is evident that metabolic derangements seen in DCM not only precede the pathology, but also contribute greatly to its development.
While the heart can function without help from the nervous system, it is highly innervated with autonomic nerves, regulating the heart beat according to demand in a fast manner, prior to hormonal release. The autonomic innervations of the myocardium in DCM are altered and contribute to myocardial dysfunction. Unlike the brain, the peripheral nervous system does not benefit from a barrier protecting it from the circulating levels of glucose. Just like endothelial cells, nerve cells cannot regulate their glucose uptake and suffer the same type of damages listed above. Therefore, the diabetic heart shows clear denervation as the pathology progresses. This denervation correlates with echocardiographic evidence of diastolic dysfunction and results in a decline of survival in patients with diabetes from 85% to 44%. Other causes of denervation are ischemia from microvascular disease and thus appear following the development of microangiopathy.
Altered ion homeostasis
Unlike most other cell types, the heart has constantly and rapidly changing ionic status, with various ion currents going in out of the cell during each beat cycle. More importantly, calcium is a major player of cardiac electromechanical events, energy metabolism and contractile function. It moves across the sarcolemma, sarcoplasmic reticulum and mitochondrial membranes through various organelle specific channels by active transport as well as passive diffusion. Around 30-40% of the ATP production of a cardiomyocyte is primarily used by the sarcoplasmic reticulum Ca2+
-ATPase (SERCA) and other ion pumps. Thus, it is evident that any alteration in homeostasis will have serious consequences on the heart’s function and possibly its integrity and structure.
In DCM, such alterations have been noted since the late 80s. Indeed, studies indicate a decrease in the ability of the cell to remove Ca2+
exchange and Ca2+
-pump systems in the sarcolemma of diabetic rat hearts. More recently, decreased SERCA activity was shown to be a major contributor to the development of cardiac dysfunction in diabetes and decreased expression of the channel was also reported. These differences are partly explained by altered calcium signaling at the level of the ryanodine receptor, a key regulator of SERCA as well as increases in phospholamban observed in diabetic hearts. Originally, these abnormalities were thought to be associated with intracellular calcium overload; however, subsequent evidence blames altered [Ca2+
]i transients with unchanged basal concentrations.
These alterations are not limited to calcium currents. Increases in intracellular sodium concentrations also play a causative role of ischemic damage sensitivity in diabetes and are related to a decrease in the Na+
pump activity due to hyperglycemia. Furthermore, there is a decrease in a Na+
ATPase subunit expression, correlating with a decrease in expression of the Na+
exchanger. More importantly, several potassium current abnormalities are observed. DCM causes alterations in transcription and surface expression of potassium channel proteins, which are theorized to be under the control of insulin-signaling cascade. Indeed, abnormalities in K+
can be restored in vitro following incubation with insulin. Further, altered duration of the action potential, known to be increased in DCM, was shown to result mainly from a decreased K+
At present, there is not a single clinically effective treatment for diabetic cardiomyopathy. Treatment centers around intense glycemic control through diet, oral hypoglycemics and frequently insulin and management of heart failure symptoms. There is a clear correlation between increased glycemia and risk of developing diabetic cardiomyopathy, therefore, keeping glucose concentrations as controlled as possible is paramount. Thiazolidinediones are not recommended in patients with NYHA Class III or IV heart failure secondary to fluid retention.
As with most other heart diseases, angiotensin-converting enzyme (ACE) inhibitors can also be administered. An analysis of major clinical trials shows that diabetic patients with heart failure benefit from such a therapy to a similar degree as non-diabetics. Similarly, beta blockers are also common in the treatment of heart failure concurrently with ACE inhibitors.
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