Diabetic cardiomyopathy
Encyclopedia
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 lung
s (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.
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.
, 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.
. 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 endproduct
s (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.
, 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.
, 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.
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 -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 through - exchange and -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 []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 - pump activity due to hyperglycemia. Furthermore, there is a decrease in a - ATPase
subunit expression, correlating with a decrease in expression of the - 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 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 transmembrane permeability
.
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 blocker
s are also common in the treatment of heart failure concurrently with ACE inhibitors.
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
. 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 lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s (pulmonary edema
Pulmonary edema
Pulmonary edema , or oedema , is fluid accumulation in the air spaces and parenchyma of the lungs. It leads to impaired gas exchange and may cause respiratory failure...
) or legs
Human leg
The human leg is the entire lower extremity or limb of the human body, including the foot, thigh and even the hip or gluteal region; however, the precise definition in human anatomy refers only to the section of the lower limb extending from the knee to the ankle.Legs are used for standing,...
(peripheral edema
Peripheral edema
Peripheral edema is the swelling of tissues, usually in the lower limbs, due to the accumulation of fluids.The condition is commonly associated with aging, but can be caused by many other conditions, including congestive heart failure, trauma, alcoholism, altitude sickness, pregnancy,...
). 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 hypertensionHypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
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
Systole (medicine)
Systole is the contraction of the heart. Used alone, it usually means the contraction of the left ventricle.In all mammals, the heart has 4 chambers. The left and right ventricles pump together. The atria and ventricles pump in sequence...
. 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
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
may be indicative of fibrosis. Given that DCM’s definition excludes concomitant atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
or hypertension, there are no changes in perfusion or in atrial natriuretic peptide
Atrial natriuretic peptide
Atrial natriuretic peptide , atrial natriuretic factor , atrial natriuretic hormone , or atriopeptin, is a powerful vasodilator, and a protein hormone secreted by heart muscle cells. It is involved in the homeostatic control of body water, sodium, potassium and fat...
levels up until the very late stages of the disease, when the hypertrophy and fibrosis become very pronounced.
Pathophysiology
Diabetic cardiomyopathy is characterized functionally by ventricular dilation, myocyte hypertrophyHypertrophy
Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It should be distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number...
, prominent interstitial fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
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
Hyperglycemia
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
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
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 echocardiographyEchocardiography
An echocardiogram, often referred to in the medical community as a cardiac ECHO or simply an ECHO, is a sonogram of the heart . Also known as a cardiac ultrasound, it uses standard ultrasound techniques to image two-dimensional slices of the heart...
. 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
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
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
Aldose reductase
Aldose reductase is an NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monosaccharides...
and the polyol pathway. Increased activity of the detoxifying aldose reductase enzyme leads to a depletion of the essential cofactor
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
NADH, thereby disrupting crucial cell processes. Second, increasing fructose 6-phosphate
Fructose 6-phosphate
Fructose 6-phosphate is fructose sugar phosphorylated on carbon 6 . The β-D-form of this compound is very common in cells. The vast majority of glucose and fructose entering a cell will become converted to this at some point...
, a glycolysis intermediate, will lead to increased flux through the hexosamine pathway. This produces N-acetyl glucosamine that can add on serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
and threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
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
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
(PKC) signaling pathway. Induction of PKC causes multiple deleterious effects, including but not limited to blood flow abnormalities, capillary
Capillary
Capillaries are the smallest of a body's blood vessels and are parts of the microcirculation. They are only 1 cell thick. These microvessels, measuring 5-10 μm in diameter, connect arterioles and venules, and enable the exchange of water, oxygen, carbon dioxide, and many other nutrient and waste...
occlusion and pro-inflammatory gene expression. Finally, glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
, as well as other intermediates such as fructose and glyceraldehyde-3-phosphate, when present in high concentrations, promote the formation of advanced glycation endproduct
Advanced glycation endproduct
An advanced glycation end-product is the result of a chain of chemical reactions after an initial glycation reaction. The intermediate products are known, variously, as Amadori, Schiff base and Maillard products, named after the researchers who first described them. An advanced glycation...
s (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
Oxidase
An oxidase is any enzyme that catalyzes an oxidation-reduction reaction involving molecular oxygen as the electron acceptor. In these reactions, oxygen is reduced to water or hydrogen peroxide ....
production of free radicals further damaging the surrounding cells. Finally, exported glycation
Glycation
Glycation is the result of the bonding of a protein or lipid molecule with a sugar molecule, such as fructose or glucose, without the controlling action of an enzyme. All blood sugars are reducing molecules. Glycation may occur either inside the body or outside the body...
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 ischemiaIschemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
, 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
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
.
Under normal conditions, fatty acids are the preferred substrate in the adult myocardium, supplying up to 70% of total ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
. They are oxidized in the mitochondrial matrix
Mitochondrial matrix
In the mitochondrion, the matrix contains soluble enzymes that catalyze the oxidation of pyruvate and other small organic molecules.The mitochondrial matrix also contains the mitochondria's DNA and ribosomes. The word "matrix" stems from the fact that this space is viscous, compared to the...
by the process of fatty acid β-oxidation, whereas pyruvate derived from glucose, glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
, lactate
Lactate
Lactate may refer to:*The act of lactation*The conjugate base of lactic acid...
and exogenous pyruvate is oxidized by the pyruvate dehydrogenase complex, localized within the inner mitochondrial membrane
Inner mitochondrial membrane
The mitochondrial inner membrane forms internal compartments known as cristae, which allow greater space for the proteins such as cytochromes to function properly and efficiently. The electron transport chain is located on the inner membrane of the mitochondria...
. Substrate choice in the adult heart is mainly regulated by availability, energy demand and oxygen supply (Randle cycle
Randle cycle
The Randle cycle is a metabolic process involving the competition of glucose and fatty acids for substrates. It is theorized to play a role in explaining type 2 diabetes and insulin resistance....
/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
GLUT4
Glucose transporter type 4, also known as GLUT4, is a protein that in humans is encoded by the GLUT4 gene. GLUT4 is the insulin-regulated glucose transporter found in adipose tissues and striated muscle that is responsible for insulin-regulated glucose translocation into the cell...
. When looking at the carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
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
Lactate dehydrogenase
Lactate dehydrogenase is an enzyme present in a wide variety of organisms, including plants and animals.Lactate dehydrogenases exist in four distinct enzyme classes. Two of them are cytochrome c-dependent enzymes, each acting on either D-lactate or L-lactate...
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
CD36
CD36 is an integral membrane protein found on the surface of many cell types in vertebrate animals and is also known as FAT, SCARB3, GP88, glycoprotein IV and glycoprotein IIIb . CD36 is a member of the class B scavenger receptor family of cell surface proteins...
that is postulated to have an important role in the etiology
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
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
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
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
Citrate
A citrate can refer either to the conjugate base of citric acid, , or to the esters of citric acid. An example of the former, a salt is trisodium citrate; an ester is triethyl citrate.-Other citric acid ions:...
in the cell, a very potent inhibitor of phosphofructokinase
Phosphofructokinase
Phosphofructokinase-1 is the most important regulatory enzyme of glycolysis. It is an allosteric enzyme made of 4 subunits and controlled by many activators and inhibitors...
, 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
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
synthesis pathway. Increasing triglyceride stores prevent lipotoxicity
Lipotoxicity
Lipotoxicity refers to cell damage or cell death following the accumulation of fatty acids in tissues other than adipose tissue. The term was originally coined to describe beta-cell insulin resistance caused by high levels of plasma free fatty acids....
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.
Autonomic neuropathy
While the heart can function without help from the nervous systemNervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
, it is highly innervated with autonomic nerves
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
, 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
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, 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, calciumCalcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
is a major player of cardiac electromechanical events, energy metabolism and contractile function. It moves across the sarcolemma
Sarcolemma
The sarcolemma is the cell membrane of a muscle cell . It consists of a true cell membrane, called the plasma membrane, and an outer coat made up of a thin layer of polysaccharide material that contains numerous thin collagen fibrils...
, sarcoplasmic reticulum and mitochondrial membranes through various organelle
Organelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
specific channels by active transport
Active transport
Active transport is the movement of a substance against its concentration gradient . In all cells, this is usually concerned with accumulating high concentrations of molecules that the cell needs, such as ions, glucose, and amino acids. If the process uses chemical energy, such as from adenosine...
as well as passive diffusion. Around 30-40% of the ATP production of a cardiomyocyte is primarily used by the sarcoplasmic reticulum -ATPase (SERCA
SERCA
SERCA, or sarco/endoplasmic reticulum Ca2+-ATPase, or SR Ca2+-ATPase, is a calcium ATPase-type P-ATPase.-Function:SERCA resides in the sarcoplasmic reticulum within muscle cells...
) 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 through - exchange and -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 []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 - pump activity due to hyperglycemia. Furthermore, there is a decrease in a - ATPase
ATPase
ATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate into adenosine diphosphate and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme harnesses to drive other chemical reactions that would not otherwise occur...
subunit expression, correlating with a decrease in expression of the - exchanger. More importantly, several potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
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 can be restored in vitro following incubation with insulin. Further, altered duration of the action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
, known
to be increased in DCM, was shown to result mainly from a decreased transmembrane permeability
Semipermeable membrane
A semipermeable membrane, also termed a selectively permeable membrane, a partially permeable membrane or a differentially permeable membrane, is a membrane that will allow certain molecules or ions to pass through it by diffusion and occasionally specialized "facilitated diffusion".The rate of...
.
Treatment
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
Angiotensin-converting enzyme
Angiotensin I-converting enzyme , an exopeptidase, is a circulating enzyme that participates in the body's renin-angiotensin system , which mediates extracellular volume , and arterial vasoconstriction...
(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 blocker
Beta blocker
Beta blockers or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction ,...
s are also common in the treatment of heart failure concurrently with ACE inhibitors.