Glycosylation , liver disease and 80% of nervous system disorder

Glycosylation and carbohydrate processing by the liver

Glycosylation is the process by which a carbohydrate is covalently attached to a target macromolecule, typically proteins and lipids. This modification serves various functions.[4]

For instance, some proteins do not fold correctly unless they are glycosylated.[1] In other cases, proteins are not stable unless they contain oligosaccharides linked at the amide nitrogen of certain asparagine. The influence of glycosylation on the folding and stability of glycoprotein is twofold. Firstly, the highly soluble glycans may have a direct physicochemical stabilisation effect. Secondly, N-linked glycan mediate a critical quality control check point in glycoprotein folding in the endoplasmic reticulum.[5]

Glycosylation also plays a role in cell-cell adhesion (a mechanism employed by cells of the immune system) via sugar-binding proteins called lectins, which recognize specific carbohydrate moieties.[1] Glycosylation is an important parameter in the optimization of many glycoprotein-based drugs such as monoclonal antibodies.[5] Glycosylation also underpins the ABO blood group system.

It is the presence or absence of glycosyltransferases which dictates which blood group antigens are presented and hence what antibody specificities are exhibited. This immunological role may well have driven the diversification of glycan heterogeneity and creates a barrier to zoonotic transmission of viruses.[6] In addition, glycosylation is often used by viruses to shield the underlying viral protein from immune recognition. A significant example is the dense glycan shield of the envelope spike of the human immunodeficiency virus.[7]

Overall, glycosylation needs to be understood by the likely evolutionary selection pressures that have shaped it. In one model, diversification can be considered purely as a result of endogenous functionality (such as cell trafficking). However, it is more likely that diversification is driven by evasion of pathogen infection mechanism (e.g. Helicobacter attachment to terminal saccharide residues) and that diversity within the multicellular organism is then exploited endogenously.

Glycoprotein Diversity

Glycosylation increases diversity in the proteome, because almost every aspect of glycosylation can be modified, including:

  • Glycosidic bond — the site of glycan linkage
  • Glycan composition — the types of sugars that are linked to a given protein
  • Glycan structure — can be unbranched or branched chains of sugars
  • Glycan length — can be short- or long-chain oligosaccharides

Mechanisms

There are various mechanisms for glycosylation, although most share several common features:[1]

Types of glycosylation

N-linked glycosylation

N-linked glycosylation is a very prevalent form of glycosylation and is important for the folding of many eukaryotic glycoproteins and for cell-cell and cell-extracellular matrix attachment. The N-linked glycosylation process occurs in eukaryotes in the lumen of the endoplasmic reticulum and widely in archaea, but very rarely in bacteria. In addition to their function in protein folding and cellular attachment, the N-linked glycans of a protein can modulate a protein’s function, in some cases acting as an on-off switch.[9]

O-linked glycosylation

O-linked glycosylation is a form of glycosylation that occurs in eukaryotes in the Golgi apparatus,[10] but also occurs in archaea and bacteria.

Phospho-serine glycosylation

Xylose, fucose, mannose, and GlcNAc phosphoserine glycans have been reported in the literature. Fucose and GlcNAc have been found only in Dictyostelium discoideum, mannose in Leishmania mexicana, and xylose in Trypanosoma cruzi. Mannose has recently been reported in a vertebrate, the mouse, Mus musculus, on the cell-surface laminin receptor alpha dystroglycan4. It has been suggested this rare finding may be linked to the fact that alpha dystroglycan is highly conserved from lower vertebrates to mammals.[11]

C-mannosylation

A mannose sugar is added to the first tryptophan residue in the sequence W-X-X-W (W indicates tryptophan; X is any amino acid). Thrombospondins are one of the most commonly C-modified proteins, although this form of glycosylation appears elsewhere as well. C-mannosylation is unusual because the sugar is linked to a carbon rather than a reactive atom such as nitrogen or oxygen. Recently, the first crystal structure of a protein containing this type of glycosylation has been determined – that of human complement component 8, PDB ID 3OJY.

Formation of GPI anchors (glypiation)

A special form of glycosylation is the formation of a GPI anchor. In this kind of glycosylation a protein is attached to a lipid anchor, via a glycan chain. (See also prenylation.)

Clinical

Over 40 disorders of glycosylation have been reported in humans.[12] These can be divided into four groups: disorders of protein N-glycosylation, disorders of protein O-glycosylation, disorders of lipid glycosylation and disorders of other glycosylation pathways and of multiple glycosylation pathways. No effective treatment is known for any of these disorders. 80% of these affect the nervous system.

Oligosaccharides food sources/Fiber

Oligosaccharides are one of the components of fibre, found in plants. FOS and inulin are found naturally in Jerusalem artichoke, burdock, chicory, leeks, onions, andasparagus. FOS products derived from chicory root contain significant quantities of inulin, a fiber widely distributed in fruits, vegetables and plants.

Save $5000 per year by taking care of your heart and liver

liver 3liver 2liver 1If you exercise, eat right, and follow other heart-friendly habits, you’re probably less likely to end up in the hospital with heart problems, which translates to far lower health care costs. A recent study on heart disease concluded that health care costs were about $5,000 less per year in people with the most heart-healthy factors compared with those with the least number of factors. The positive thing about heart disease is that there are lots of things you can do on your own to reduce your risk substantially.

  • Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease in the United States—and an increasingly recognized contributor to heart disease.
    When eating, know how the food (alcohol, smoking,moldy food, toxic food) or stress or lack of sleep can affect your liver.
  • The inflammatory compounds and other substances pumped out by a fat-afflicted liver might promote the atherosclerotic process that damages the insides of arteries and makes blood more likely to clot. This combination may lead to a heart attack or a stroke.
  • Drink water with a tsp of apple cider vinegar and warm water with cinnamon, lemon and honey during the day.
  • Sleep at regular hours and exercise at least 30 min a day.
  • Get some sunshine and ensure clean air and water.
  • Avoid all toxins. Limit saturated fats (found in meat, dairy, and eggs), refined carbohydrates (anything made with white flour), and added sugar, especially from sodas and other sweetened beverages.
  • Eat colored veggies and fruits. When eating lean and grass fed meat, add pineapple and papaya as your snack as digestive enzymes.
  • Take probiotics and fish oil.

Foods for liver detox

1. Garlic

Garlic

Just a small amount of this pungent white bulb has the ability to activate liver enzymes that help your body flush out toxins.[1] Garlic also holds high amounts of allicin and selenium, two natural compounds that aid in liver cleansing.

2. Grapefruit

High in both vitamin C and antioxidants, citrus fruits like grapefruit, oranges, limes, and lemons support the natural cleansing abilities of the liver.[2] Have a small glass of freshly-squeezed grapefruit juice to boost production of the liver detoxification enzymes that help flush out carcinogens and other toxins.

3. Beets and Carrots

Beets

Both are extremely high in plant-flavonoids and beta-carotene; eating beets and carrots can stimulate and support overall liver function.[3]

4. Green Tea

This liver-loving beverage is full of plant-based antioxidants known as catechins—compounds known to assist liver function.[4] Green tea is a delicious, healthy addition to any diet. Just remember that green tea offers the benefits, not green tea extract. Some research suggests green tea extract may actually have a negative effect on liver health.[5] Keep it simple and stick to the beverage to enjoy the benefits of green tea.

5. Leafy Green Vegetables

Leafy Greens

One of our most powerful allies in cleansing the liver, leafy greens can be eaten raw, cooked, or juiced. Extremely high in chlorophyll, greens soak up environmental toxins from the blood stream.[6] With their distinct ability to neutralize heavy metals, chemicals, and pesticides, these cleansing foods offer a powerful protective mechanism for the liver.

Incorporate leafy greens such as bitter gourd, arugula, dandelion greens, spinach, mustard greens, and chicory into your diet. This will increase creation and flow of bile—the substance that removes waste from the organs and blood.

6. Avocados

This nutrient-dense superfood helps the body produce glutathione, a compound that is necessary for the liver to cleanse harmful toxins.[7]

7. Apples

Apple

High in pectin, apples hold the chemical constituents necessary for the body to cleanse and release toxins from the digestive tract. This, in turn, makes it easier for the liver to handle the toxic load during the cleansing process.[2, 8]

8. Olive Oil

Cold-pressed organic oils such as olive, hemp, and flaxseed are great for the liver when used in moderation. They help the body by providing a lipid base that can absorb harmful toxins in the body.[9] In this way, they take some of the burden off the liver.

9. Alternative Grains

If your diet includes wheat, flour, or other standard grains, it’s time to make changes. And alternative grains like quinoa, millet, and buckwheat can help. Your liver is your body’s filter for toxins, and if you have certain sensitivities, grains that contain gluten only add to them. One study found that persons who experienced sensitivity to gluten also experienced abnormal liver enzyme test results.[10]

10. Cruciferous Vegetables

Broccoli and cauliflower are good sources of glucosinolate, which supports enzyme production in the liver. These natural enzymes flush carcinogens and other toxins from the body, and may significantly lower risks associated with cancer.[2]

11. Lemons and Limes

Lemons and Limes

These citrus fruits are high in vitamin C, which aids the body in synthesizing toxic materials into substances that can be absorbed by water. Drinking freshly-squeezed lemon or lime juice in the morning can stimulate the liver.[2]

12. Walnuts

High in the amino acid arginine, walnuts support the liver in detoxifying ammonia. [11]Walnuts are also high in glutathione and omega-3 fatty acids,[12] which support normal liver cleansing.[13, 14] Make sure you chew the nuts until they are liquefied before swallowing.

13. Cabbage

Much like broccoli and cauliflower, eating cabbage stimulates liver detoxifying enzymes that help flush out toxins. Kimchi, coleslaw, cabbage soup, and sauerkraut are great cabbage-foods to add to your diet.[2]

14. Turmeric

Turmeric is the liver’s favorite spice. Try adding some of this detoxifying goodness into your next lentil stew or veggie dish for an instant liver pick-me-up. Turmeric helps boost liver detoxification by assisting enzymes that actively flush out dietary toxins.[1]

This golden spice tastes great in all kinds of dishes, but you can further boost your intake with a turmeric supplement. A word of warning; turmeric supplements are somewhat notorious for low-quality ingredients and even outright dangerous contamination.[15] Only buy the highest quality turmeric from the most reputable sources. I encourage you to try Global Healing Center’s own Turmeric supplement. This premium liquid supplement contains potent antioxidants and is sourced only from organic Curcuma longa root.

Link between liver disease and heart problems


New study explains link between liver disease and heart problems

Physiologically, blood and bile intimately tie liver and heart health together:

· Blood – The liver receives 25 percent of the blood pumped by the heart and filters over two quarts of blood a minute. To ensure optimal circulation and filtration, the heart pumps blood while the liver cleans it.

· Bile – To dissolve fat in the blood vessels, the liver produces up to two cups of bile a day. Without bile, our arteries would be as hard as rocks without any hope of circulating blood throughout the heart, liver or remainder of the body.

Atherosclerosis
Atherosclerosis comes from the Greek words athero (meaning gruel or paste) and sclerosis (hardness). It describes the process in which deposits of fatty substances, cholesterol, cellular waste products, calcium and other substances build up in the inner lining of an artery. Called plaque, this buildup can grow large enough to significantly reduce the blood’s flow through an artery. In addition to the danger of breaking off and throwing a blood clot into circulation, this restriction of blood flow can cause high blood pressure, heart disease and can even contribute to some liver diseases.

Study Confirming the Link
Although the heart and liver share in the responsibility of keeping us healthy, scientists are now discovering similarities in these organs during illness. In the June 2007 Journal of Hepatology, Italian researchers reported on their trial indicating early signs of atherosclerosis are linked with several types of chronic liver disease. By studying the thickness of the carotid arteries in the necks of over 200 patients with one of three forms of chronic liver disease – chronic Hepatitis B, chronic Hepatitis C and non-alcoholic steatohepatitis (a kind of fatty liver disease) – a relationship between the two was discovered.

An increase in the thickness of carotid neck arteries is considered by experts to be an indicator of early atherosclerosis. Found to be independent of other factors contributing to atherosclerosis, the researchers realized the following about carotid artery thickness:

· It was lowest in healthy controls with an average value of 0.84.
· It was elevated in people with Hepatitis B with an average value of 0.97.
· It was elevated in people with Hepatitis C with an average of 1.09.
· It was highest in people with non-alcoholic steatohepatitis with an average value of 1.23.

The authors concluded that Hepatitis B, Hepatitis C and non-alcoholic steatohepatitis are strongly associated with early atherosclerosis. This study clearly demonstrates the interconnectivity between heart and liver health. Based on the Italian research results, we can predict that lowering the amount of plaque accumulation in the arteries may lower susceptibility to several liver diseases.

Minimizing Atherosclerosis
There are many approaches to keeping your body healthy and resistant to the increasingly common occurrences of heart and liver disease. By understanding that the health of our arteries impacts more than just blood pressure, we realize how important it is to keep our blood circulation system at an optimal level of operation.


 

Researchers have identified molecular changes that occur in the liver that may explain why people with liver disease have abnormal cholesterol levels. In conjunction with liver panel tests, these changes may predict the severity of a patient’s condition.

In the study, researchers from Virginia Commonwealth University showed that more seriously diseased livers produce more cholesterol than healthy organs, and also lack a receptor that instructs cells to remove cholesterol from the blood. These findings explain why people with liver disease frequently have unhealthy cholesterol levels.

This link to high cholesterol levels helps explain why people with liver disease often experience cardiovascular complications.

Additionally, the research showed that the presence of these abnormalities predicted the progression of patients’ conditions. Individuals were more likely to have severe cases when these abnormalities were present than when they weren’t.

This new understanding of factors that influence the development of serious liver problems could help doctors more effectively diagnose and treatment the condition.Given the skyrocketing rates of non-alcoholic fatty liver disease, which are largely a result of the obesity epidemic, this could come as a major benefit to the healthcare system. ADNFCR-2248-ID-800793965-ADNFCR


A new study adds to growing evidence of a link between a common liver disease associated with obesity and high risk for heart disease.

People with non-alcoholic fatty liver disease have an accumulation of fat in the liver that is not caused by drinking alcohol. The fat can cause inflammation and scarring in the liver and progress to life-threatening illness.

The new findings “suggest that patients with coronary artery disease should be screened for liver disease, and likewise [patients with non-alcoholic fatty liver disease] should be evaluated for coronary artery disease,” said Dr. Rajiv Chhabra, a gastroenterologist at Saint Luke’s Health System’s Liver Disease Management Center in Kansas City, Mo.

Researchers looked at upper-abdominal CT scans of nearly 400 patients and found that those with non-alcoholic fatty liver disease were more likely to have coronary artery disease. The effect of non-alcoholic fatty liver disease was stronger than other more traditional risk factors for heart disease, such as smoking, high blood pressure, diabetes, high cholesterol, metabolic syndrome and being male.

Chhabra conducted the study with a colleague, Dr. John Helzberg. Their findings were presented at the American Gastroenterological Association’s recent annual meeting.

Current treatments for non-alcoholic fatty liver disease include diet changes, exercise and increased monitoring.

Non-alcoholic fatty liver disease is the most common liver disorder in Western countries, and is of growing concern among doctors due to rising rates of obesity and diabetes.

“If current trends continue, the prevalence of [non-alcoholic fatty liver disease] is expected to increase to 40 percent of the population by 2020,” Helzberg said in a Saint Luke’s Health System news release.

Data and conclusions presented at meetings should be considered preliminary until published in a peer-reviewed medical journal.

— Robert Preidt

MedicalNews


Fatty liver disease and your heart

About one in three adults has nonalcoholic fatty liver disease, an often-silent condition closely linked to heart disease.

fatty liver disease and your heart
Image: decade3d/ iStock

Published: September, 2016

The largest organ inside your body, your liver performs hundreds of vital functions. It converts food into fuel, processes cholesterol, clears harmful toxins from the blood, and makes proteins that help your blood clot, to name a few. But an alarming number of Americans have a potentially dangerous accumulation of fat inside their livers. Known as nonalcoholic fatty liver disease (NAFLD), this condition is a leading cause of chronic liver disease in the United States—and an increasingly recognized contributor to heart disease.

“NAFLD increases the risk of heart disease independent of other traditional risk factors such as high blood pressure and cholesterol,” says Dr. Kathleen Corey, director of the Fatty Liver Disease Clinic at Massachusetts General Hospital. Among people with NAFLD, heart disease is the top killer, accounting for more than 25% of deaths.

The obesity connection

Prior to 1980, fatty liver disease was rarely diagnosed except in people who drank large amounts of alcohol. However, scientists discovered that excess body fat and diabetes can also cause fatty liver disease, even in people who drink very little. As Americans have gotten fatter, so have their livers. Up to one-third of American adults have NAFLD, and nearly all (90%) people with severe obesity who are candidates for weight-loss surgery have the disease. Half of people with diabetes have NAFLD.

Under the microscope, the fat buildup inside the liver looks just like alcohol-induced fatty liver disease. But NAFLD affects people who consume little or no alcohol. They also often have high cholesterol and triglyceride levels. But not everyone with obesity, diabetes, and abnormal lipids has the problem. And some people with fatty livers have none of these risk factors, suggesting that genes and other factors play a role.

Diagnosing the problem

The early stage of NAFLD is an accumulation of fat in liver cells called steatosis (steato means fat). It has no symptoms; it’s usually discovered when a blood test reveals slightly elevated liver enzymes or by chance during an imaging test done for another reason. A doctor may then order additional tests to rule out other possible liver problems, such as hepatitis C, which is caused by a virus. An ultrasound of the liver can reveal signs of steatosis and a change in the texture of the liver. But a definitive diagnosis requires a liver biopsy, which involves inserting a needle into the right side of the abdomen and extracting a small piece of liver tissue that can be examined under a microscope. Liver biopsies are an invasive procedure, so they aren’t entirely free of risk or complications. But they’re also fairly routine these days and can be done on an outpatient basis. Whether a doctor will order a biopsy to nail down a diagnosis depends on many factors, including whether the person is obese or has diabetes or shows other signs of liver trouble.

Over time, as many as 40% of people with NAFLD will develop a more serious form of the condition, called nonalcoholic steatohepatitis (NASH). In this condition, the fat within the liver causes the liver to become inflamed. Most patients with NASH have no symptoms, although some report fatigue and discomfort in the upper right of the abdomen. In a subset of those with NASH, fibrosis or scarring of the liver will develop. Severe scarring, known as cirrhosis, increases the risk of liver cancer and end-stage liver disease. Currently, along with hepatitis C and alcohol-related liver damage, cirrhosis due to NASH is one of the leading reasons for a liver transplant in the United States. With the sharp rise in NAFLD cases, experts expect that fatty liver complications will be the leading cause within a decade.

The heart disease link

Growing evidence suggests there’s a strong link between NAFLD and dangerous plaque inside the heart’s arteries. The inflammatory compounds and other substances pumped out by a fat-afflicted liver might promote the atherosclerotic process that damages the insides of arteries and makes blood more likely to clot. This combination may lead to a heart attack or a stroke.

Most people who’ve had a heart attack or face a high risk of one take cholesterol-lowering statins. Liver damage is a very uncommon side effect with statins. But these drugs are still safe for people with NASH and, according to some research, may even help improve the condition.

Weight loss and other treatments

Treating NAFLD focuses on reducing or preventing further fatty buildup in the liver, mainly by addressing the underlying causes: obesity, diabetes, and elevated blood lipids.

Even losing just a little weight can make a difference. A recent study in JAMA Internal Medicine found that people who participated in a moderate to vigorous exercise program and lost just 3% to 6% of their body weight reduced their relative liver fat levels by 35% to 40%. “Even if you don’t lose weight, exercise can reduce fat in the liver,” says Dr. Corey. “I advise my patients to do at least 90 minutes of aerobic exercise weekly.”

As for diet, the recommendation is similar to what doctors advise for preventing heart disease: Eat plenty of vegetables, fruits, and whole grains, and modest amounts of lean protein, like fish and chicken. Limit saturated fats (found in meat, dairy, and eggs), refined carbohydrates (anything made with white flour), and added sugar, especially from sodas and other sweetened beverages. People with NAFLD should limit the amount of alcohol they drink, and those with NASH should avoid it completely. Treating conditions such as diabetes and high blood pressure also helps.

Pain killers damage to the liver and the heart

What Parts of the Body May Be Severely Damaged by Painkiller Abuse?

Lungs

Lungs: Because opiates and similar drugs suppress the body’s ability to breathe, they interfere with the normal function of the lungs. Thus medical research has found that opiate abuse is associated with a greater risk of pneumonia.

The inhalation of painkillers, as when an opiate like oxycodone or hydrocodone is smoked, also results in a buildup of fluids in the lungs, according to a British Medical Journal article. The result can be shortness of breath for the drug abuser.

Stomach and intestines: Opiates are very well known for causing constipation, even at their normal dosage. Abuse of painkillers means that the abusers is taking far more of the drug than a doctor would ever recommend. Long-term abuse of painkillers means that many users will need to rely on laxatives to move the bowels or risk damage to the anus (painful tears called fissures) or the sphincter.

There is a further syndrome that is suffered by opiate abusers. According to the International Foundation for Functional Gastrointestinal Disorders, a narcotic abuser can suffer from “narcotic bowel syndrome” or NBS. This disorder is a result of the slowing down of the bowel function. The symptoms include nausea, bloating, vomiting, abdominal distention and of course, constipation.

When a person is given opiates for treatment of stomach or abdominal pain resulting from injury or cancer, these drugs may actually make the nerves more sensitive and make pain worse instead of better. The patient suffers a severe colicky pain. The same problem can occur when a person is abusing one of these drugs.

Lungs

Liver: Every drug is broken down and processed by the liver. The liver is therefore heavily stressed by prescription painkiller abuse and can store toxins from the breakdown process. But the most significant liver damage results from the acetaminophen that is included in many of the formulas. Common drugs like Vicodin, Lortab and Percocet have high dosages of acetaminophen. When these pills are abused, very high levels of acetaminophen can cause liver failure.

Some people who abuse these drugs process the pills through a washing technique that is supposed to remove most of the acetaminophen. Many people skip this step and abuse the pills in their original forms.

In 2011, the FDA limited the amount of acetaminophen in an opiate painkiller to 325 mg per pill in an effort to save the lives of some people who were abusing these drugs. One of the FDA staff commented: “Overdose from prescription combination products containing acetaminophen account for nearly half of all cases of acetaminophen-related liver failure in the U.S., many of which result in liver transplant or death.” Despite this limitation, many abusers take far more of this combination than is recommended. As many as 50,000 people are rushed to emergency rooms each year as a result, with more than 200 dying.

Muscles and kidneys: If a person abuses painkillers to the point of becoming comatose, he can suffer severe and life-threatening injury that has nothing directly to do with the respiratory suppression effect of the drugs. A condition called “rhabdomyolysis” can occur. This is a rapid breakdown of muscle tissue that results from a person lying completely immobilized for a number of hours. The compression experienced by the muscles causes the tissue to begin to disintegrate. The chemicals that are produced by this disintegration pour into the bloodstream and cause a chain reaction of damage in other organs. This is a leading cause of kidney failure. If dialysis is not started in time, a person can die. Damage to the heart can also occur, including heart attack.

Chronic use of painkillers for years can have a directly damaging effect on the kidneys, leading to the need for dialysis or transplant. It is not the opiate in the painkillers that disables the kidneys, but the secondary analgesics such as acetaminophen.

While these would be enough to scare most people away from abusing these drugs, there are even more threats from snorting, injecting or even swallowing these drugs. Continue reading to learn more.


Resources:

Sugar , transfat and poor lifestyle – causes of American death in last 35 years

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Smoking , alcohol, meds/drugs and poor lifestyle (absence of exercise, clean water, air and whole foods) contributed to poor health in the southern part of the United States.

https://projects.fivethirtyeight.com/mortality-rates-united-states/cardiovascular/#2014

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Mitochondrial function between the heart and skeletal muscles and biomarkers of Heart Failure

Heart failure (HF) is a chronic and devastating illness becoming an increasingly important burden on the health care system. Reduced exercise tolerance is an independent predictor of hospital readmission and mortality in patients with HF [1], and is thought to be a therapeutic target [2]. Although central factors such as ejection fraction (EF) or cardiac output do play a role, peripheral factors which include reduced skeletal muscle, an alteration in fiber type to one with less oxidative properties, and decreased ATP production, are mainly responsible for the reduction in exercise capacity [3]. From these findings, mitochondrial function is thought to be an important factor in the skeletal muscle in HF patients.

We recently reported that the retention of Technetium-99m sestamibi (99mTc-MIBI) correlated inversely with mitochondrial function in vivo and ex vivo in various organs [4]. 99mTc-MIBI is a lipophilic cation used for the clinical diagnosis of coronary artery disease. 99mTc-MIBI is transported to the myocardium via coronary blood flow, where it is rapidly incorporated into myocardial cells by diffusion, and binds to mitochondria [[4], [5]]. In clinical settings, the MIBI washout rate increased if mitochondrial dysfunction was present in HF patients [6]. Moreover, we and other groups demonstrated that mitochondrial functional assessment by 99mTc-MIBI was not organ-specific including the skeletal muscle [[4], [7], [8]].

To gain insight into the mechanisms underlying exercise intolerance in HF, we analyzed 99mTc-MIBI washout of the heart and leg muscles along with other clinical and cardiopulmonary exercise (CPX) parameters.

We studied 45 consecutive hospitalized patients with CHF treated for acute decompensation. CHF was defined by the Framingham criteria. Written informed consent was obtained from all patients, and the study conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Institutional Review Board of Kitano Hospital. The exclusion criteria consisted of Killip class IV HF at the time of the study, acute myocardial infarction, and no consent. Echocardiographic data, levels of brain natriuretic peptide (BNP), the estimated glomerular filtration rate, C-reactive protein levels, and medical history were analyzed. A dose of 740 MBq (20 mCi) of 99mTc-MIBI was administered intravenously under resting conditions after an overnight fast. Planar images followed by single photon emission computed tomography images were obtained 20 min and 3 h after the injection for the calculation of the washout rate (Supplementary materials) [6].

All data are expressed as the mean ± standard deviation (SD). Differences between groups were compared using the Mann–Whitney U-test. The correlation analysis was carried out using the Pearson’s product-moment. A multiple general linear model in Poisson distribution by the likelihood-ratio chi-square test was used when the determinants of parameters were analyzed. In all tests, a value of p < 0.05 was considered significant.

Patient characteristics were as follows: 62% were male; 37% had dilated cardiomyopathy; 55% had hypertension; 24% had diabetes; the mean age was 68 years; the mean EF was 41%; the mean BNP level was 370 pg/mL; and the mean washout rate of the heart and the leg muscles was 46% and 30%, respectively. See details in Supplementary Table 1.

Fig. 1A and B show multiple scatter plots and correlation coefficient, respectively, of the variables. The 99mTc-MIBI washout of the heart and BNP and the washout of the heart and leg muscles were focused in Fig. 1C and D, respectively. A higher washout rate represents mitochondrial dysfunction. The washout rate of the heart inversely correlated to BNP level increase (Fig. 1C). 99mTc-MIBI washout rate of the heart positively correlated with the washout rate of the leg muscles (Fig. 1D), but not with left ventricular EF (Fig. 1A, pink circle). In multivariate regression analyses (Supplementary Table 2), the 99mTc-MIBI washout rate of the leg muscle and BNP levels were the factors that determined the washout rate of the heart.

Thumbnail image of Fig. 1. Opens large image

Fig. 1

Association between the MIBI washout rate of the heart and leg muscles (A). Multiple scatter plots of the variables. A red circle focused in panel C. A purple circle focused in panel D. A pink circle indicated the relationship between 99mTc-MIBI washout rate of the heart and left ventricular ejection fraction. (B) Pearson’s correlation coefficient. (C) BNP levels and 99mTc-MIBI washout rate of the heart and (D) 99mTc-MIBI washout rate of the heart and leg muscles. Line, linear correlation with standard deviation.

We analyzed data obtained from 22 patients who underwent CPX. Patients who underwent CPX were younger, but the other parameters were not significantly different from those who did not undergo CPX (Supplementary Fig. 2 and Table 3). PeakVO2 was negatively correlated with the 99mTc-MIBI washout of the leg muscles and weakly positively correlated with the length of the circumflex of the thigh (Fig. 2A ). Fig. 2B shows the relationship between peak oxygen consumption and 99mTc-MIBI washout of the leg muscles. Determinants of peak oxygen consumption in the subgroup were the 99mTc-MIBI washout of the leg and EF. Multi-collinearity was observed between the 99mTc-MIBI washout of the heart and leg muscles and the length of the circumflex of the thigh (Supplementary Table 4).

Thumbnail image of Fig. 2. Opens large image

Fig. 2

Association between the CPX parameters and the MIBI washout rate of the heart and leg muscles (A). Multiple scatter plots of the variables. (B) Peak oxygen consumption and 99mTc-MIBI washout rate of the leg muscles. Line, linear correlation with standard deviation.

The factors linking the heart and the leg muscle are currently unknown. Mechanisms involving sympathetic neural activation; cellular metabolism in the cardiac and skeletal muscles; inter-organ relationships such as anemia, chronic kidney disease, liver congestion, and depression; and inflammatory cytokines may contribute to the linkage between mitochondrial function of the heart and peripheral muscles in HF patients [9]. Brain-derived neurotrophic factor is involved in depression and is decreased in HF patients. It regulates skeletal muscle energy metabolism and is one of the linking factor candidates [10].

Muscle mass (i.e., circumflex of the thigh), in addition to the mitochondrial function of the legs, is the deciding factor for exercise capacity. In fact, a reduction in mitochondrial function and the inability to utilize oxygen delivered, i.e. low peripheral O2 extraction may contribute to the reduction in oxidative capacity. Thus, possible targets for exercise interventions to improve exercise intolerance in HF are not only the muscle’s mass but also the quality of the skeletal muscle [3].

There are several limitations. First, CPX was not done in all patients, and there were no CPX values in healthy controls. Second, we could not assess other markers of mitochondrial function or morphology of the heart and skeletal muscles as such analysis requires biopsy samples, which is beyond the scope of the study.

In summary, we demonstrated a clear correlation of mitochondrial function between the heart and skeletal muscles and biomarkers of HF.

Our results indicate that mitochondrial function of the leg muscle, along with the muscle volume, may limit exercise capacity in patients with CHF.