Diabetic cardiomyopathy

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Diabetic cardiomyopathy
Blue circle for diabetes.svg
Universal blue circle symbol for diabetes. [1]
Specialty Cardiology

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(HF), [2] 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. [3]

Contents

Signs and symptoms

One particularity of diabetic cardiomyopathy is the long latent phase, during which the disease progresses but is completely asymptomatic. In most cases, diabetic cardiomyopathy 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 diabetic cardiomyopathy 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 diabetic cardiomyopathy 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 diabetic cardiomyopathy'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, [4] when the hypertrophy and fibrosis become very pronounced.

Pathophysiology

Defects in cellular processes such as autophagy and mitophagy are thought to contribute to the development of diabetic cardiomyopathy. [2] Diabetic cardiomyopathy is characterized functionally by ventricular dilation, enlargement of heart cells, prominent interstitial fibrosis and decreased or preserved systolic function [5] in the presence of a diastolic dysfunction. [6] [7] [8]

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 diabetic cardiomyopathy: 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.[ citation needed ] Additional effects include inflammation and upregulation of local angiotensin systems.

Diabetic cardiomyopathy may be associated with restrictive (HFPEF) and dilated phenotypes (HFREF). HFPEF results predominantly from hyperinsulinemia, hyperglycemia, lipotoxicity, AGEs and microvascular rarefication. HFREF is associated with autoimmunity, hyperglycemia, lipotoxicity, microvascular rarefication and AGE formation. [9]

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 echocardiography. [10] About 50% of diabetics with diabetic cardiomyopathy show pathologic evidence for microangiopathy such as sub-endothelial and endothelial fibrosis, compared to only 21% of non-diabetic heart failure patients. [11] 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. [12] 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. [13] 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. [12] 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. [14] 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. [15] 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. [16] Finally, exported glycation products bind extracellular proteins and alter the matrix, cell-matrix interactions and promote fibrosis. [17] 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. [18]

Autonomic neuropathy

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 diabetic cardiomyopathy 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.[ citation needed ]

Inflammation

Diabetes is associated with increased inflammation, which is mediated by generation of abnormal fatty acids, AGEs and other mechanisms. [19] The resulting cytokine profile promotes hypertrophy and apoptosis of cardiomyocytes, abnormal calcium signaling, impaired myocardial contractility and myocardial fibrosis. [20] Additionally, it may lead to microvascular dysfunction, either directly or via endothelial damage, thereby promoting myocardial ischemia. [21]

Diagnosis

Diagnostic approaches for diabetic cardiomyopathy include echocardiography, cardiac MRI investigations, Multi‐slice computed tomography (MsCT), and nuclear imaging. [22] Potential risks of the investigation (e.g. exposure to radiation) and diagnostic utility should be weighed for an optimised personalised procedure. [22]

Treatment

At present, there is no effective specific treatment available for diabetic cardiomyopathy. [23] Treatment rationale centers around intense glycemic control through diet and preferential use of certain medications in diabetic patients at high risk for developing cardiovascular disease or heart failure. A rationale for therapeutic decision making in individuals with coexistent diabetes mellitus and HF is less clear because there is a possibility that additional factors beyond glycemia might contribute to the increased HF risk in diabetes mellitus. [24] Thiazolidinediones are not recommended in patients with NYHA Class III or IV heart failure secondary to fluid retention. [25]

As with most other heart diseases, 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. [26] Similarly, beta blockers are also common in the treatment of heart failure concurrently with ACE inhibitors. [24]

Related Research Articles

<span class="mw-page-title-main">Beta cell</span> Type of cell found in pancreatic islets

Beta cells (β-cells), are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vital role in maintaining blood glucose levels. Problems with beta cells can lead to disorders such as diabetes.

<span class="mw-page-title-main">Hyperglycemia</span> Too much blood sugar, usually because of diabetes

Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200 mg/dL), but symptoms may not start to become noticeable until even higher values such as 13.9–16.7 mmol/L (~250–300 mg/dL). A subject with a consistent fasting blood glucose range between ~5.6 and ~7 mmol/L is considered slightly hyperglycemic, and above 7 mmol/L is generally held to have diabetes. For diabetics, glucose levels that are considered to be too hyperglycemic can vary from person to person, mainly due to the person's renal threshold of glucose and overall glucose tolerance. On average, however, chronic levels above 10–12 mmol/L (180–216 mg/dL) can produce noticeable organ damage over time.

<span class="mw-page-title-main">Premature ventricular contraction</span> Skipped beat with ventricular origin

A premature ventricular contraction (PVC) is a common event where the heartbeat is initiated by Purkinje fibers in the ventricles rather than by the sinoatrial node. PVCs may cause no symptoms or may be perceived as a "skipped beat" or felt as palpitations in the chest. PVCs do not usually pose any danger.

<span class="mw-page-title-main">Microangiopathy</span> Medical condition

Microangiopathy is a disease of the microvessels, small blood vessels in the microcirculation. It can be contrasted to macroangiopathies such as atherosclerosis, where large and medium-sized arteries are primarily affected.

Glycated hemoglobin is a form of hemoglobin (Hb) that is chemically linked to a sugar. Most monosaccharides, including glucose, galactose and fructose, spontaneously bond with hemoglobin when present in the bloodstream. However, glucose is only 21% as likely to do so as galactose and 13% as likely to do so as fructose, which may explain why glucose is used as the primary metabolic fuel in humans.

Advanced glycation end products (AGEs) are proteins or lipids that become glycated as a result of exposure to sugars. They are a bio-marker implicated in aging and the development, or worsening, of many degenerative diseases, such as diabetes, atherosclerosis, chronic kidney disease, and Alzheimer's disease.

<span class="mw-page-title-main">Diabetic nephropathy</span> Chronic loss of kidney function

Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally. The triad of protein leaking into the urine, rising blood pressure with hypertension and then falling renal function is common to many forms of CKD. Protein loss in the urine due to damage of the glomeruli may become massive, and cause a low serum albumin with resulting generalized body swelling (edema) so called nephrotic syndrome. Likewise, the estimated glomerular filtration rate (eGFR) may progressively fall from a normal of over 90 ml/min/1.73m2 to less than 15, at which point the patient is said to have end-stage renal disease. It usually is slowly progressive over years.

<span class="mw-page-title-main">Type 1 diabetes</span> Form of diabetes mellitus

Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for energy and it helps regulate glucose levels in the bloodstream. Before treatment this results in high blood sugar levels in the body. The common symptoms of this elevated blood sugar are frequent urination, increased thirst, increased hunger, weight loss, and other serious complications. Additional symptoms may include blurry vision, tiredness, and slow wound healing. Symptoms typically develop over a short period of time, often a matter of weeks if not months.

The term diabetes includes several different metabolic disorders that all, if left untreated, result in abnormally high concentrations of a sugar called glucose in the blood. Diabetes mellitus type 1 results when the pancreas no longer produces significant amounts of the hormone insulin, usually owing to the autoimmune destruction of the insulin-producing beta cells of the pancreas. Diabetes mellitus type 2, in contrast, is now thought to result from autoimmune attacks on the pancreas and/or insulin resistance. The pancreas of a person with type 2 diabetes may be producing normal or even abnormally large amounts of insulin. Other forms of diabetes mellitus, such as the various forms of maturity-onset diabetes of the young, may represent some combination of insufficient insulin production and insulin resistance. Some degree of insulin resistance may also be present in a person with type 1 diabetes.

Diabetic angiopathy is a form of angiopathy associated with diabetic complications. While not exclusive, the two most common forms are diabetic retinopathy and diabetic nephropathy, whose pathophysiologies are largely identical. Other forms of diabetic angiopathy include diabetic neuropathy and diabetic cardiomyopathy.

Tachycardia-induced cardiomyopathy (TIC) is a disease where prolonged tachycardia or arrhythmia causes an impairment of the myocardium, which can result in heart failure. People with TIC may have symptoms associated with heart failure and/or symptoms related to the tachycardia or arrhythmia. Though atrial fibrillation is the most common cause of TIC, several tachycardias and arrhythmias have been associated with the disease.

<span class="mw-page-title-main">Takotsubo cardiomyopathy</span> Sudden temporary weakening of the heart muscle

Takotsubo cardiomyopathy or takotsubo syndrome (TTS), also known as stress cardiomyopathy, is a type of non-ischemic cardiomyopathy in which there is a sudden temporary weakening of the muscular portion of the heart. It usually appears after a significant stressor, either physical or emotional; when caused by the latter, the condition is sometimes called broken heart syndrome. Examples of physical stressors that can cause TTS are sepsis, shock, subarachnoid hemorrhage, and pheochromocytoma. Emotional stressors include bereavement, divorce, or the loss of a job. Reviews suggest that of patients diagnosed with the condition, about 70–80% recently experienced a major stressor, including 41–50% with a physical stressor and 26–30% with an emotional stressor. TTS can also appear in patients who have not experienced major stressors.

<span class="mw-page-title-main">AOC3</span> Enzyme

Amine oxidase, copper containing 3 (AOC3), also known as vascular adhesion protein (VAP-1) and HPAO is an enzyme that in humans is encoded by the AOC3 gene on chromosome 17. This protein is a member of the semicarbazide-sensitive amine oxidase family of enzymes and is associated with many vascular diseases.

The dawn phenomenon, sometimes called the dawn effect, is an observed increase in blood sugar (glucose) levels that takes place in the early-morning, often between 2 a.m. and 8 a.m. First described by Schmidt in 1981 as an increase of blood glucose or insulin demand occurring at dawn, this naturally occurring phenomenon is frequently seen among the general population and is clinically relevant for patients with diabetes as it can affect their medical management. In contrast to Chronic Somogyi rebound, the dawn phenomenon is not associated with nocturnal hypoglycemia.

Complications of diabetes are secondary diseases that are a result of elevated blood glucose levels that occur in diabetic patients. These complications can be divided into two types: acute and chronic. Acute complications are complications that develop rapidly and can be exemplified as diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar state (HHS), lactic acidosis (LA), and hypoglycemia. Chronic complications develop over time and are generally classified in two categories: microvascular and macrovascular. Microvascular complications include neuropathy, nephropathy, and retinopathy; while cardiovascular disease, stroke, and peripheral vascular disease are included in the macrovascular complications.

<span class="mw-page-title-main">Heart failure with preserved ejection fraction</span> Medical condition

Heart failure with preserved ejection fraction (HFpEF) is a form of heart failure in which the ejection fraction – the percentage of the volume of blood ejected from the left ventricle with each heartbeat divided by the volume of blood when the left ventricle is maximally filled – is normal, defined as greater than 50%; this may be measured by echocardiography or cardiac catheterization. Approximately half of people with heart failure have preserved ejection fraction, while the other half have a reduction in ejection fraction, called heart failure with reduced ejection fraction (HFrEF).

In recent years it has become apparent that the environment and underlying mechanisms affect gene expression and the genome outside of the central dogma of biology. It has been found that many epigenetic mechanisms are involved in the regulation and expression of genes such as DNA methylation and chromatin remodeling. These epigenetic mechanisms are believed to be a contributing factor to pathological diseases such as type 2 diabetes. An understanding of the epigenome of Diabetes patients may help to elucidate otherwise hidden causes of this disease.

<span class="mw-page-title-main">Diabetes</span> Group of endocrine diseases characterized by high blood sugar levels

Diabetes mellitus, often known simply as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough insulin, or the cells of the body becoming unresponsive to the hormone's effects. Classic symptoms include thirst, polyuria, weight loss, and blurred vision. If left untreated, the disease can lead to various health complications, including disorders of the cardiovascular system, eye, kidney, and nerves. Untreated or poorly treated diabetes accounts for approximately 1.5 million deaths every year.

<span class="mw-page-title-main">Argpyrimidine</span> Chemical compound

Argpyrimidine is an organic compound with the chemical formula C11H18N4O3. It is an advanced glycation end-product formed from arginine and methylglyoxal through the Maillard reaction. Argpyrimidine has been studied for its food chemistry purposes and its potential involvement in aging diseases and Diabetes Mellius.

<span class="mw-page-title-main">Ischemic cardiomyopathy</span> Medical condition

Ischemic cardiomyopathy is a type of cardiomyopathy caused by a narrowing of the coronary arteries which supply blood to the heart. Typically, patients with ischemic cardiomyopathy have a history of acute myocardial infarction, however, it may occur in patients with coronary artery disease, but without a past history of acute myocardial infarction. This cardiomyopathy is one of the leading causes of sudden cardiac death. The adjective ischemic means characteristic of, or accompanied by, ischemia — local anemia due to mechanical obstruction of the blood supply.

References

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  3. ↑ Avogaro A, Vigili de Kreutzenberg S, Negut C, Tiengo A, Scognamiglio R (April 2004). "Diabetic cardiomyopathy: a metabolic perspective". Am J Cardiol. 93 (8A): 13A–16A. doi:10.1016/j.amjcard.2003.11.003. PMID   15094099.
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  19. ↑ Marfella R, Sardu C, Mansueto G, Napoli C, Paolisso G (August 2021). "Evidence for human diabetic cardiomyopathy". Acta Diabetol. 58 (8): 983–988. doi:10.1007/s00592-021-01705-x. PMC   8272696 . PMID   33791873.
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