Typically in America, if a person fails a stress test or suffers from a heart attack and then is found to have a blocked coronary artery, a stent will be introduced to correct the problem and high-dose statin therapy will be initiated, with the expectation that the drug will be needed for the rest of their life. The accepted belief today is that, no matter whether their cholesterol is already low, high-dose statin therapy will yield sufficient benefit to offset any side effects it might cause. At the same time, these patients are encouraged to spend up to an hour a day exercising on a treadmill, since exercise has been shown to be highly beneficial to heart disease prognosis. The exercise, in conjunction with the metabolic deficiencies induced by the statin drug, are a potentially lethal combination.
Typically, also, the patient is not alerted that a common side effect of statin drugs is muscle pain and muscle weakness. It is often the case that such symptoms don't appear immediately. In fact, it can sometimes be years before statin therapy leads to enough damage to cause obvious symptoms. By that time, the person may well believe that the pain and weakness are simply a consequence of getting older.
It has been widely claimed, and statin users seem to have embraced this concept, that, as long as you monitor your enzyme levels, you can simply terminate statin therapy if the enzymes get too high, and all will be well. However, judging from some of the sad stories that are showing up in comment pages all over the web, this has turned out not to be the case for some people.
An article published in July, 2009 [27] investigated the association between physical muscle damage and patients' complaints of muscle weakness or pain. Patients who reported weakness said, for example, that it was difficult to get up from a seated position without arm support. Those who reported pain generally said that it was worse after physical exercise. Only one out of 44 patients examined developed overt rhabdomyolysis, with the serum level of the muscle enzyme creatine kinase measured at 57,657 U/L. This patient required hospital treatment for management of his pain.
The authors were interested in investigating the extent to which muscle damage could be seen through muscle biopsy for these patients. They compared them with 20 patients who had never taken a statin drug. Twenty five of the 44 patients taking statins had clear muscle damage. None of the 20 controls had any evidence of damage. Other than the one patient with overt rhabdomyolysis, none of the others had muscle enzyme levels above the cut-off considered the upper level of "normal." For those patients with injuries, on average 10% of their fibers were injured. The authors concluded that the lack of elevated levels of creatine kinase does not rule out structural muscle injury.
Thursday, February 25, 2010
10. Statins and Heart Failure
A paper titled simply "Lovastatin decreases coenzyme Q levels in humans" [16] states unequivocally in the abstract: "It is established that Coenzyme Q10 is indispensable for cardiac function." The heart is a muscle, and hence it is subject to all the same laws of physics as the skeletal muscles. It faces the same problem of fuel deficiency due to the various effects statins have on metabolism discussed above. Heart muscle cells would also have to cannibalize themselves to get enough fuel, and would also suffer damage to their cell membranes due to exposure to Ferryl myoglobin.
An article published in 2004 [42] provides a plausible theory for the process by which muscle cells in the heart become dysfunctional with old age, leading ultimately to heart failure. The argument blends perfectly with the logical deductions associated with the mechanism by which statins damage cells, and leads to the unavoidable conclusion that statins make you age at an accelerated pace. The process involves a downward spiral caused by deficiencies in both the mitochondria and the lysosomes. Recall that the mitochondria are responsible for providing fuel to the cell, and the lysosomes are responsible for digesting and decomposing residues of waste products. The article claims that the downward spiral is caused by "continuous physiological oxidative stress." Oxidative stress is greatly enhanced by statins, because they deplete the supply of both antioxidants like coenzyme Q10 and fresh phospholipids and cholesterol to rebuild damaged cell walls. Debris from damaged phospholipids in the cell wall, the mitochondrial walls, and the lysosome walls must be taken up by the lysosomes, digested, and disposed of. Under normal circumstances the lysosomes would easily break them down in their highly acidic environment, using their powerful digestive enzymes.
When the lysosomes are unable to digest the debris that accumulates from damaged cell walls, the residue that remains is called "lipofuscin." Lipofuscin is considered to be a signature of old age, accumulating in the liver, kidney, heart muscle, and nerve cells as we get older. Lipofuscin is believed to be the product of oxidation of unsaturated fatty acids, and is indicative of membrane damage, whether to the cell's outer wall or to the walls of the lysosomes and mitochondria [17].
For long-term statin users, lipofuscin almost certainly accumulates, because their lysosomes are dysfunctional. This condition would arise not just in the heart, but in all the cells of the body. As I mentioned earlier, statins cripple the production of the dolichols, antioxidants that play a crucial role in protecting the lysosomes from hydrogen ion leakage. Lysosomes also depend upon cholesterol in their membranes to provide additional insulation against charge dissipation. With a constant leakage outward of H+ ions, lysosomes can not maintain their pH at a sufficiently acidic level to allow their enzymes to work. As a consequence, undegradable debris, i.e., lipofuscin, accumulates within the lysosomes, and the cell has no backup repair system to salvage the disaster. The last sentence in the abstract of [42] says: "This interrelated mitochondrial and lysosomal damage eventually results in functional failure and death of cardiac myocytes {heart muscle cells]."
Doctor Peter Langsjoehn believes that statins are inducing an epidemic rise in the incidence of heart failure. He wrote: "In my practice of 17 years in Tyler, Texas, I have seen a frightening increase in heart failure secondary to statin usage, 'statin cardiomyopathy.' Over the past five years, statins have become more potent, are being prescribed in higher doses, and are being used with reckless abandon in the elderly and in patients with 'normal' cholesterol levels. We are in the midst of a CHF epidemic in the US with a dramatic increase over the past decade. Are we causing this epidemic through our zealous use of statins? In large part I think the answer is yes. " (Statins and Heart Failure) .
Dr. Duane Graveline, a long-time advocate of the dangers of statin therapy, has provided a very clear description ( Duane Graveline on Statins and Heart Failure) of the role of coenzyme Q10 in the heart and the reason why its inhibition by statins would lead to heart failure. You can find several references to relevant articles by Dr. Langsjoehn on that page.
A very recent study (November, 2009) [8] found that patients with diastolic heart failure who were taking statins had a significantly poorer outcome than patients who were not on statin therapy. Diastolic heart failure is distinguished from systolic heart failure in that it is associated with dysfunction of the heart during the resting phase rather than the contracting phase. However, it is the cause of nearly half of the cases of heart failure, and it is equally as fatal as the systolic form. In the study, it was confirmed that people with diastolic heart failure who were on statin therapy were more likely to have problems with their lungs and were less able to exert themselves (weaker muscles, poorer exercise tolerance) than those not on statins.
An article published in 2004 [42] provides a plausible theory for the process by which muscle cells in the heart become dysfunctional with old age, leading ultimately to heart failure. The argument blends perfectly with the logical deductions associated with the mechanism by which statins damage cells, and leads to the unavoidable conclusion that statins make you age at an accelerated pace. The process involves a downward spiral caused by deficiencies in both the mitochondria and the lysosomes. Recall that the mitochondria are responsible for providing fuel to the cell, and the lysosomes are responsible for digesting and decomposing residues of waste products. The article claims that the downward spiral is caused by "continuous physiological oxidative stress." Oxidative stress is greatly enhanced by statins, because they deplete the supply of both antioxidants like coenzyme Q10 and fresh phospholipids and cholesterol to rebuild damaged cell walls. Debris from damaged phospholipids in the cell wall, the mitochondrial walls, and the lysosome walls must be taken up by the lysosomes, digested, and disposed of. Under normal circumstances the lysosomes would easily break them down in their highly acidic environment, using their powerful digestive enzymes.
When the lysosomes are unable to digest the debris that accumulates from damaged cell walls, the residue that remains is called "lipofuscin." Lipofuscin is considered to be a signature of old age, accumulating in the liver, kidney, heart muscle, and nerve cells as we get older. Lipofuscin is believed to be the product of oxidation of unsaturated fatty acids, and is indicative of membrane damage, whether to the cell's outer wall or to the walls of the lysosomes and mitochondria [17].
For long-term statin users, lipofuscin almost certainly accumulates, because their lysosomes are dysfunctional. This condition would arise not just in the heart, but in all the cells of the body. As I mentioned earlier, statins cripple the production of the dolichols, antioxidants that play a crucial role in protecting the lysosomes from hydrogen ion leakage. Lysosomes also depend upon cholesterol in their membranes to provide additional insulation against charge dissipation. With a constant leakage outward of H+ ions, lysosomes can not maintain their pH at a sufficiently acidic level to allow their enzymes to work. As a consequence, undegradable debris, i.e., lipofuscin, accumulates within the lysosomes, and the cell has no backup repair system to salvage the disaster. The last sentence in the abstract of [42] says: "This interrelated mitochondrial and lysosomal damage eventually results in functional failure and death of cardiac myocytes {heart muscle cells]."
Doctor Peter Langsjoehn believes that statins are inducing an epidemic rise in the incidence of heart failure. He wrote: "In my practice of 17 years in Tyler, Texas, I have seen a frightening increase in heart failure secondary to statin usage, 'statin cardiomyopathy.' Over the past five years, statins have become more potent, are being prescribed in higher doses, and are being used with reckless abandon in the elderly and in patients with 'normal' cholesterol levels. We are in the midst of a CHF epidemic in the US with a dramatic increase over the past decade. Are we causing this epidemic through our zealous use of statins? In large part I think the answer is yes. " (Statins and Heart Failure) .
Dr. Duane Graveline, a long-time advocate of the dangers of statin therapy, has provided a very clear description ( Duane Graveline on Statins and Heart Failure) of the role of coenzyme Q10 in the heart and the reason why its inhibition by statins would lead to heart failure. You can find several references to relevant articles by Dr. Langsjoehn on that page.
A very recent study (November, 2009) [8] found that patients with diastolic heart failure who were taking statins had a significantly poorer outcome than patients who were not on statin therapy. Diastolic heart failure is distinguished from systolic heart failure in that it is associated with dysfunction of the heart during the resting phase rather than the contracting phase. However, it is the cause of nearly half of the cases of heart failure, and it is equally as fatal as the systolic form. In the study, it was confirmed that people with diastolic heart failure who were on statin therapy were more likely to have problems with their lungs and were less able to exert themselves (weaker muscles, poorer exercise tolerance) than those not on statins.
11. Statins and Lung Disease
The statin industry has tried to promote the idea that statins might be beneficial in treating pneumonia. They came to this erroneous conclusion through retrospective studies, where the observed benefits come, I suspect, from the fact that those who took statins had benefited from high cholesterol for probably many years before introducing statin therapy. The industry was sufficiently encouraged by preliminary positive indications to then conduct placebo-controlled studies to try to legitimize their claim. However, the studies backfired, because they clearly showed that statin therapy not only wasn't helpful, but actually led to a significantly worse prognosis [26][12] (see ( Statins Increase Pneumonia Risk) . For pneumonia severe enough to require hospitalization, the increased risk incurred by taking a statin was an alarming 61% [12].
Statins' effects on muscles apply to the respiratory muscles as well, leading to difficulty in breathing and subsequent oxygen deprivation, which, of course, further aggravates both pneumonia and heart failure. Furthermore, it is now well known that, in rare cases, statin drugs cause severe lung disease, so-called "interstitial lung disease" (ILD) [24][44][15]. ILD is now listed as a rare side effect for all statin drugs.
In an excellent review article published in 2008, Fernandez et al. [15] identify several possibilities for how statins might cause interstitial pneumonia. They begin their discussion by drawing an analogy with amiodarone, a drug which is known to cause a very similar kind of pathology, which includes the accumulation of lysosomal inclusion bodies, i.e., lipofuscin, the cell-membrane debris that was described previously in the section under heart disease.
Amiodarone belongs to a very common class of drugs known as "amphiphilic" drugs: they have both a hydrophilic (water soluble) and a lipophilic (fat soluble) component in their chemical structure. This property allows them to cross through the membranes of cells in order to achieve their desired biochemical influence. However, the process by which they enter the cell involves degrading the lipids in the cell membrane [2] . Membrane fragments break away from the cell wall and carry the drug along with them into the cell. As a consequence of cell wall deterioration, sodium leaks will cause the cell to lose energy, with all the negative consequences that have been described before.
Fernandez et al. argue that, like amiodarone, statins have an amphiphilic structure, since they contain an apolar (lipophilic) ring and a hydrophilic side chain. A really disturbing observation they make is that, over time, amphiphilic drugs are known to become more efficient at entering cells. It seems logical that a deteriorating cell wall would allow better permeability to the drug molecule. But this then means that whatever effect the drug has on the cell will be increased, leading to accelerated damage and a destructive cascade.
Amiodarone is a potent antidysrhythmic agent, i.e., a drug used to try to correct an irregular heart beat during heart failure or post-operative. It has numerous side effects, but probably the most serious side effect is interstitial lung disease. An article written in 2001 [3] explored the likely mechanism of pulmonary damage. The authors conducted in vitro experiments on cells in lung tissue extracted from hamsters. They noted that exposure to the drug decreased the mitochondrial membrane potential (H+ ions leaked out of the mitochondria) and subsequently the amount of ATP in the cell dropped by 32 to 77%. Even with the addition of glucose, the mitochondria were not able to regenerate the depleted ATP; i.e., the mitochondria were not functioning properly to generate energy from glucose. Ultimately, the cells died. They concluded that mitochondrial dysfunction was the path by which the drug induced cell death.
What they describe is essentially the exact same process by which statins lead to problems in muscle cells. Fernandez et al. agree with my argument that, like amiodarone, statins may cause interstitial lung disease through their disruption of the mitochondrial electron transport chain and subsequent depletion of ATP. Lung cells are particularly vulnerable to oxidative damage, because they are tasked with capturing oxygen from the air and transporting it to the blood. I also suspect that, although the number of cases of reported interstial disease is small, there is a much larger number of people whose lungs have been compromised by statins, but whose pulmonary function has not yet deteriorated to a catastrophic point. Instead, they experience some difficulty breathing and a perceived inability to get enough oxygen. As with muscle weakness, such symptoms may go unreported, as the patient has no way of knowing that what he is experiencing is not a normal aspect of growing old. Certainly an increased susceptibility to viral pneumonia would be anticipated when the lung's cells are suffering from insufficient energy and a degraded cell wall.
Statins' effects on muscles apply to the respiratory muscles as well, leading to difficulty in breathing and subsequent oxygen deprivation, which, of course, further aggravates both pneumonia and heart failure. Furthermore, it is now well known that, in rare cases, statin drugs cause severe lung disease, so-called "interstitial lung disease" (ILD) [24][44][15]. ILD is now listed as a rare side effect for all statin drugs.
In an excellent review article published in 2008, Fernandez et al. [15] identify several possibilities for how statins might cause interstitial pneumonia. They begin their discussion by drawing an analogy with amiodarone, a drug which is known to cause a very similar kind of pathology, which includes the accumulation of lysosomal inclusion bodies, i.e., lipofuscin, the cell-membrane debris that was described previously in the section under heart disease.
Amiodarone belongs to a very common class of drugs known as "amphiphilic" drugs: they have both a hydrophilic (water soluble) and a lipophilic (fat soluble) component in their chemical structure. This property allows them to cross through the membranes of cells in order to achieve their desired biochemical influence. However, the process by which they enter the cell involves degrading the lipids in the cell membrane [2] . Membrane fragments break away from the cell wall and carry the drug along with them into the cell. As a consequence of cell wall deterioration, sodium leaks will cause the cell to lose energy, with all the negative consequences that have been described before.
Fernandez et al. argue that, like amiodarone, statins have an amphiphilic structure, since they contain an apolar (lipophilic) ring and a hydrophilic side chain. A really disturbing observation they make is that, over time, amphiphilic drugs are known to become more efficient at entering cells. It seems logical that a deteriorating cell wall would allow better permeability to the drug molecule. But this then means that whatever effect the drug has on the cell will be increased, leading to accelerated damage and a destructive cascade.
Amiodarone is a potent antidysrhythmic agent, i.e., a drug used to try to correct an irregular heart beat during heart failure or post-operative. It has numerous side effects, but probably the most serious side effect is interstitial lung disease. An article written in 2001 [3] explored the likely mechanism of pulmonary damage. The authors conducted in vitro experiments on cells in lung tissue extracted from hamsters. They noted that exposure to the drug decreased the mitochondrial membrane potential (H+ ions leaked out of the mitochondria) and subsequently the amount of ATP in the cell dropped by 32 to 77%. Even with the addition of glucose, the mitochondria were not able to regenerate the depleted ATP; i.e., the mitochondria were not functioning properly to generate energy from glucose. Ultimately, the cells died. They concluded that mitochondrial dysfunction was the path by which the drug induced cell death.
What they describe is essentially the exact same process by which statins lead to problems in muscle cells. Fernandez et al. agree with my argument that, like amiodarone, statins may cause interstitial lung disease through their disruption of the mitochondrial electron transport chain and subsequent depletion of ATP. Lung cells are particularly vulnerable to oxidative damage, because they are tasked with capturing oxygen from the air and transporting it to the blood. I also suspect that, although the number of cases of reported interstial disease is small, there is a much larger number of people whose lungs have been compromised by statins, but whose pulmonary function has not yet deteriorated to a catastrophic point. Instead, they experience some difficulty breathing and a perceived inability to get enough oxygen. As with muscle weakness, such symptoms may go unreported, as the patient has no way of knowing that what he is experiencing is not a normal aspect of growing old. Certainly an increased susceptibility to viral pneumonia would be anticipated when the lung's cells are suffering from insufficient energy and a degraded cell wall.
12. Statins and Diabetes
The JUPITER trial of the statin drug Crestor was widely heralded as evidence that statin drugs can delay heart attacks for people who have high levels of an indicator of inflammation called C-reactive protein. However, what is less known about this trial is that it uncovered a clear link between statin drugs (or, at least, Crestor) and increased risk of diabetes (JUPITER Trial and Diabetes) [36]. According to Dr. Jay Cohen, the people who took Crestor in the trial had a 25% increased risk of developing diabetes, compared to the control group. This is alarming, because diabetes itself is an extremely strong risk factor for heart disease.
The pancreas synthesizes insulin in its beta cells, and defects in insulin production (either too little of it, or a lack of response to it) is the cause of diabetes. Insulin is used by the body's cells to catalyze the transport of glucose into the cell. Without insulin, or with poorly functioning insulin, sugar piles up in the blood and the cells become energy starved.
There have been a large number of studies on the biochemistry of the beta cells and their insulin-producing machinery, and it has been determined that beta cells require both cholesterol [46] and fats [11] to be present before they will release insulin. Inadequate cholesterol and poor quality phospholipids in the beta cell's outer membrane likely impair its ability to transport insulin across the membrane. Statin drugs, of course, reduce the bioavailability of cholesterol, but also of fatty acids, because these are transported in the blood stream via the same LDL particles that statins suppress. Thus, it is easy to see why statins would cause an increased risk to diabetes.
In addition to the above defects in the cell membrane, impaired function of the mitochondria in the beta cells has also been clearly implicated in diabetes, in studies involving diabetic mice with defective mitochondrial genes [39]. These mice exhibited reduced insulin secretion when they were only five weeks old, and their mitochondria were abnormal in appearance and were unable to maintain an adequate charge gradient across their membranes. In other words, they exhibited defects that are similar to what would be expected with reduced coenzyme Q10 as a consequence of statin exposure. Older mice with the same defect were severely deficient in insulin production, as many of their pancreatic beta cells had died off.
Insulin suppresses the release of fats from both the fat cells and the liver, and therefore there will be a fat shortage in the blood supply subsequent to insulin release, unless abundant fats are already present. Thus, it is a good strategy, biologically, for the beta cells to be sure fats and cholesterol are well supplied before injecting insulin into the blood stream. I have previously written extensively on this subject (Essay on Metabolic Syndrome).
A study published in March, 2009 [41] looked at the relationship between statin drug usage and fasting blood glucose levels, the test typically conducted to assess diabetes risk. They grouped 345,417 patients into two categories: with or without a previous diabetes diagnosis. They compared fasting glucose levels before they began taking statins and then after they had been on statins for an average of two years. In both groups, they obtained a highly significant (P < 0.0001) result of increased fasting glucose levels for those on statin therapy.
A reduction in the ability of glucose to enter muscle cells, consequential to a reduction in insulin supply, would add insult onto injury for the muscle cells trying to survive with a defective aerobic metabolism factory. Because the muscles are forced to switch to the much less efficient anaerobic metabolism of glucose in order to avoid oxidative damage, they require enormously more glucose to meet their energy supply than they would require if their mitochondrial energy-generating factory were functioning properly. Yet the reduced insulin is making it harder to get enough glucose in. This will force the cell into the starvation mode that leads to cannibalization of its internal muscle protein. The perceived result over time will be extreme muscle weakness.
The pancreas synthesizes insulin in its beta cells, and defects in insulin production (either too little of it, or a lack of response to it) is the cause of diabetes. Insulin is used by the body's cells to catalyze the transport of glucose into the cell. Without insulin, or with poorly functioning insulin, sugar piles up in the blood and the cells become energy starved.
There have been a large number of studies on the biochemistry of the beta cells and their insulin-producing machinery, and it has been determined that beta cells require both cholesterol [46] and fats [11] to be present before they will release insulin. Inadequate cholesterol and poor quality phospholipids in the beta cell's outer membrane likely impair its ability to transport insulin across the membrane. Statin drugs, of course, reduce the bioavailability of cholesterol, but also of fatty acids, because these are transported in the blood stream via the same LDL particles that statins suppress. Thus, it is easy to see why statins would cause an increased risk to diabetes.
In addition to the above defects in the cell membrane, impaired function of the mitochondria in the beta cells has also been clearly implicated in diabetes, in studies involving diabetic mice with defective mitochondrial genes [39]. These mice exhibited reduced insulin secretion when they were only five weeks old, and their mitochondria were abnormal in appearance and were unable to maintain an adequate charge gradient across their membranes. In other words, they exhibited defects that are similar to what would be expected with reduced coenzyme Q10 as a consequence of statin exposure. Older mice with the same defect were severely deficient in insulin production, as many of their pancreatic beta cells had died off.
Insulin suppresses the release of fats from both the fat cells and the liver, and therefore there will be a fat shortage in the blood supply subsequent to insulin release, unless abundant fats are already present. Thus, it is a good strategy, biologically, for the beta cells to be sure fats and cholesterol are well supplied before injecting insulin into the blood stream. I have previously written extensively on this subject (Essay on Metabolic Syndrome).
A study published in March, 2009 [41] looked at the relationship between statin drug usage and fasting blood glucose levels, the test typically conducted to assess diabetes risk. They grouped 345,417 patients into two categories: with or without a previous diabetes diagnosis. They compared fasting glucose levels before they began taking statins and then after they had been on statins for an average of two years. In both groups, they obtained a highly significant (P < 0.0001) result of increased fasting glucose levels for those on statin therapy.
A reduction in the ability of glucose to enter muscle cells, consequential to a reduction in insulin supply, would add insult onto injury for the muscle cells trying to survive with a defective aerobic metabolism factory. Because the muscles are forced to switch to the much less efficient anaerobic metabolism of glucose in order to avoid oxidative damage, they require enormously more glucose to meet their energy supply than they would require if their mitochondrial energy-generating factory were functioning properly. Yet the reduced insulin is making it harder to get enough glucose in. This will force the cell into the starvation mode that leads to cannibalization of its internal muscle protein. The perceived result over time will be extreme muscle weakness.
13. Statins and Muscle Damage: Conclusions
If you live in the United States, and your doctor has identified that you are at high risk to heart attacks, he has likely prescribed a high dose statin even if your cholesterol levels are not high. You have likely also been put on a low-fat, low saturated fat diet, and you have been encouraged to work out on a treadmill every day.
My research indicates that, if you rigorously follow all of your doctor's advice, you will be facing severe muscle damage sooner or later. The statin drug's impact on the mitochondria and on the cell walls of the muscle cells is such that even modest exercise can lead to rhabdomyolysis. For some it will be obvious right away that the side effects are too damaging and the statin therapy must be terminated. For others, the damage will happen more insidiously, and will not become apparent until years after statin therapy was initiated. But often patients will find that the symptoms remain after the drug is stopped -- it will be too late to repair the muscle damage. Or, worse, they will develop kidney failure or heart failure as a consequence.
Statin drugs have many adverse side effects, but probably the most frequent complaints concern muscle pain and muscle weakness. In this essay, I have developed a physiological explanation for the mechanism responsible for this side effect. It is due to the fact that statins interfere with the synthesis of not only cholesterol, but also coenzyme Q10 and the dolichols. Statins also reduce the bioavailability to the cells of both fatty acids and all dietary antioxidants, due to the sharp reduction in serum levels of LDL, which delivers these essential nutrients to the cells.
Without sufficient coenzyme Q10, muscle cells suffer from an impaired ability to generate energy to fuel their contractions. They are forced to cannibalize their own proteins to survive. At the same time, powerful oxidative agents are generated which damage the myoglobin in the cell, rendering it both ineffective to transport oxygen and toxic to the cell wall. The oxidized myoglobin, known as "Ferryl myoglobin" is toxic to the fatty acids that are the main component of the cell wall. With insufficient cholesterol in the cell wall, the cell can't hold a charge, and this also causes it to waste energy. The lysosomes are unable to digest debris because they can't maintain a sufficiently acidic environment. The problem is further compounded by profound shortages of cholesterol, which would have offered further protection against oxidative damage to the fatty acids and ion leakage in the cell wall, the mitochondrial wall, and the lysosome wall. Eventually the cell disintegrates and the myoglobin is released into the blood stream. It makes its way to the kidneys, which try to dispose of it. But the Ferryl myoglobin is also toxic to the kidneys, which leads to severe kidney disease.
The low-fat diet and the exercise regime will both increase the likelihood that the statin drug will cause problems. Vigorous exercise increases the energy needs of the muscles, while the low-fat diet reduces even further the bioavailability of fatty acids to replace damaged cell walls. Furthermore, cell walls composed of unsaturated fats are more vulnerable to attack by the Ferryl myoglobin than those composed of saturated fats.
Because the heart is also a muscle, it also suffers from damage due to exposure to statins. This leads to a reduced likelihood of recovering from a diastolic heart attack, and an increased chance of developing heart failure. Damaged cells of the respiratory system lead to an increased risk of both pneumonia and interstitial lung disease, both of which are very dangerous for someone with a weak heart.
The JUPITER trial revealed that the treatment group had a 25% increased risk for diabetes, and I have explained above why this would be true. Diabetes is a significant risk factor for heart disease, so this outcome is disturbing, and one wonders whether the trial was terminated early to avoid making this number even worse. Dr. William Davis, a cardiologist who believes that statins should be a last resort in treating heart disease, has this to say about the JUPITER trial: "I view the foisting of Crestor via the JUPITER argument on the public as taking full advantage of the helpless situation many Americans find themselves in: Reduce fat intake, eat more healthy whole grains and . . . cholesterol and CRP skyrocket! 'You need Crestor! See, I told you it was genetic,' says the doctor after attending the nice AstraZeneca-sponsored drug dinner." ( Dr. Davis' Blog Post on JUPITER)
The news has just come out that even children are now being tested for high cholesterol, and it is being suggested that they should be put on a statin drug if they can not control their cholesterol levels (Children Taking Statins??). I find this news to be extremely disturbing, especially since none of the controlled statin trials have been conducted on children. We have no idea what negative consequences statin drugs might have on the developing nervous system of a child. However, it has been shown that statins can completely destroy the nervous system of an embryo [13].
A remarkable recent publication by Jeff Cable (December, 2009) [7] analyzes a set of 885 self-reported adverse effects of statin therapy by patients. Although the reports covered a wide range of known side effects of statins, including cognitive impairment, muscle pain and weakness, skin problems and sexual dysfunction, what was most disturbing was the large number of reports of severe neurological damage. Most distressing was the fact that there were a total of 17 reports of ALS with 2 additional reports related to motor neuron deterioration, which he counts together as 1 to give a total of 18. In ALS, nerve cells waste away or die, and can no longer send messages to muscles. This eventually leads to muscle weakening, twitching, and ultimately paralysis. As the disease progresses, swallowing and breathing become difficult. Most victims die within five years of diagnosis.
The author's comments related to neurological disorders and ALS are quoted here: "One fragment of information that was gained from the patient accounts is the apparent incidence of major neurodegenerative diseases which may well have been precipitated by statin therapy. ... The rarest of these conditions is ALS and yet in just 351 reports there were enough cases to have made the prediction (based upon incidence statistics) that an expected three million six hundred thousand accounts would have to be written before eighteen ALS/MND cases would have been revealed. This is such an astonishingly high number of cases to report within such a small participant group that it would be right to ask whether a fundamental error has been made. Absent any error it is also right to ask: What is really happening? What is the real risk posed by statin therapy?"
There is prior evidence from the literature implicating a relationship between statins and ALS -- a study of the FDA's adverse event reports [10] as well as a study showing that high cholesterol protects against ALS [19]. My next essay will be on the subject of statin drugs' likely adverse effects on the nervous system: I will argue that statins increase risk not just to ALS but to multiple sclerosis, Parkinson's disease, and Alzheimer's.
My research indicates that, if you rigorously follow all of your doctor's advice, you will be facing severe muscle damage sooner or later. The statin drug's impact on the mitochondria and on the cell walls of the muscle cells is such that even modest exercise can lead to rhabdomyolysis. For some it will be obvious right away that the side effects are too damaging and the statin therapy must be terminated. For others, the damage will happen more insidiously, and will not become apparent until years after statin therapy was initiated. But often patients will find that the symptoms remain after the drug is stopped -- it will be too late to repair the muscle damage. Or, worse, they will develop kidney failure or heart failure as a consequence.
Statin drugs have many adverse side effects, but probably the most frequent complaints concern muscle pain and muscle weakness. In this essay, I have developed a physiological explanation for the mechanism responsible for this side effect. It is due to the fact that statins interfere with the synthesis of not only cholesterol, but also coenzyme Q10 and the dolichols. Statins also reduce the bioavailability to the cells of both fatty acids and all dietary antioxidants, due to the sharp reduction in serum levels of LDL, which delivers these essential nutrients to the cells.
Without sufficient coenzyme Q10, muscle cells suffer from an impaired ability to generate energy to fuel their contractions. They are forced to cannibalize their own proteins to survive. At the same time, powerful oxidative agents are generated which damage the myoglobin in the cell, rendering it both ineffective to transport oxygen and toxic to the cell wall. The oxidized myoglobin, known as "Ferryl myoglobin" is toxic to the fatty acids that are the main component of the cell wall. With insufficient cholesterol in the cell wall, the cell can't hold a charge, and this also causes it to waste energy. The lysosomes are unable to digest debris because they can't maintain a sufficiently acidic environment. The problem is further compounded by profound shortages of cholesterol, which would have offered further protection against oxidative damage to the fatty acids and ion leakage in the cell wall, the mitochondrial wall, and the lysosome wall. Eventually the cell disintegrates and the myoglobin is released into the blood stream. It makes its way to the kidneys, which try to dispose of it. But the Ferryl myoglobin is also toxic to the kidneys, which leads to severe kidney disease.
The low-fat diet and the exercise regime will both increase the likelihood that the statin drug will cause problems. Vigorous exercise increases the energy needs of the muscles, while the low-fat diet reduces even further the bioavailability of fatty acids to replace damaged cell walls. Furthermore, cell walls composed of unsaturated fats are more vulnerable to attack by the Ferryl myoglobin than those composed of saturated fats.
Because the heart is also a muscle, it also suffers from damage due to exposure to statins. This leads to a reduced likelihood of recovering from a diastolic heart attack, and an increased chance of developing heart failure. Damaged cells of the respiratory system lead to an increased risk of both pneumonia and interstitial lung disease, both of which are very dangerous for someone with a weak heart.
The JUPITER trial revealed that the treatment group had a 25% increased risk for diabetes, and I have explained above why this would be true. Diabetes is a significant risk factor for heart disease, so this outcome is disturbing, and one wonders whether the trial was terminated early to avoid making this number even worse. Dr. William Davis, a cardiologist who believes that statins should be a last resort in treating heart disease, has this to say about the JUPITER trial: "I view the foisting of Crestor via the JUPITER argument on the public as taking full advantage of the helpless situation many Americans find themselves in: Reduce fat intake, eat more healthy whole grains and . . . cholesterol and CRP skyrocket! 'You need Crestor! See, I told you it was genetic,' says the doctor after attending the nice AstraZeneca-sponsored drug dinner." ( Dr. Davis' Blog Post on JUPITER)
The news has just come out that even children are now being tested for high cholesterol, and it is being suggested that they should be put on a statin drug if they can not control their cholesterol levels (Children Taking Statins??). I find this news to be extremely disturbing, especially since none of the controlled statin trials have been conducted on children. We have no idea what negative consequences statin drugs might have on the developing nervous system of a child. However, it has been shown that statins can completely destroy the nervous system of an embryo [13].
A remarkable recent publication by Jeff Cable (December, 2009) [7] analyzes a set of 885 self-reported adverse effects of statin therapy by patients. Although the reports covered a wide range of known side effects of statins, including cognitive impairment, muscle pain and weakness, skin problems and sexual dysfunction, what was most disturbing was the large number of reports of severe neurological damage. Most distressing was the fact that there were a total of 17 reports of ALS with 2 additional reports related to motor neuron deterioration, which he counts together as 1 to give a total of 18. In ALS, nerve cells waste away or die, and can no longer send messages to muscles. This eventually leads to muscle weakening, twitching, and ultimately paralysis. As the disease progresses, swallowing and breathing become difficult. Most victims die within five years of diagnosis.
The author's comments related to neurological disorders and ALS are quoted here: "One fragment of information that was gained from the patient accounts is the apparent incidence of major neurodegenerative diseases which may well have been precipitated by statin therapy. ... The rarest of these conditions is ALS and yet in just 351 reports there were enough cases to have made the prediction (based upon incidence statistics) that an expected three million six hundred thousand accounts would have to be written before eighteen ALS/MND cases would have been revealed. This is such an astonishingly high number of cases to report within such a small participant group that it would be right to ask whether a fundamental error has been made. Absent any error it is also right to ask: What is really happening? What is the real risk posed by statin therapy?"
There is prior evidence from the literature implicating a relationship between statins and ALS -- a study of the FDA's adverse event reports [10] as well as a study showing that high cholesterol protects against ALS [19]. My next essay will be on the subject of statin drugs' likely adverse effects on the nervous system: I will argue that statins increase risk not just to ALS but to multiple sclerosis, Parkinson's disease, and Alzheimer's.
Acknowledgements for Essay on Statins and Muscle Damage
I would like to thank Glyn Wainwright for pointing me to both his own excellent review paper and the very informative and fascinating article by Haines [20] on proton and sodium leaks through lipid bilayers, which played a crucial role in my arguments for statin damage to muscles.
References for Essay on Statins and Muscle Damage
[1] A Arduini, L. Eddy, and P. Hochstein, "Detection of ferryl myoglobin in the isolated ischemic rat heart," Free-Radic-Biol-Med. (1990) Vol. 9, No. 6, pp. 511-3.
[2] M. Baciu, S.C. Sebai, O. Ces, X. Mulet, J.A. Clarke, G.C. Shearman, and R.V. Law, Templer RH, Plisson C, Parker CA, Gee A. "Degradative transport of cationic amphiphilic drugs across phospholipid bilayers." Philos Transact A Math Phys Eng Sci. (2006) Oct 15, Vol. 364(1847), pp. 2597-614.
[3] M.W. Bolt,J. W. Card, W.J. Racz, J.F. Brien and T.E. Massey, "Disruption of Mitochondrial Function and Cellular ATP Levels by Amiodarone and N-Desethylamiodarone in Initiation of Amiodarone-Induced Pulmonary Cytotoxicity," JPET (2001) September 1, Vol. 298, No. 3, pp. 1280-1289.
[4] S.L. Bonting, P.J. van Breugel, F.J. Daemen, "Influence of the lipid environment of the properties of rhodopsin in the photoreceptor membrane," Adv. Exp. Med. Biol. (1977) Vol. 83, pp. 175-89.
[5] P. Brancaccio, N. Maffulli, and F.M. Limongelli, "Creatine kinase monitoring in sport medicine" British Medical Bulletin (2007) Vol. 81-82. No. 1, pp. 209-230; doi:10.1093/bmb/ldm014
[6] E. Bruckert, G. Hayem, S. Dejager, et al. "Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients -- the PRIMO study." Cardiovasc Drugs Ther (2005) Vol. 19, pp. 403-14.
[7] J. Cable, "Adverse Events of Statins -- An Informal Internet-based Study," JOIMR (2009, December, Vol. 7, No. 1; http://www.joimr.org/JOIMR_Vol7_No1_Dec2009.pdf.
[8] L.P. Cahalin, PT, PhD, et al., CHEST 2009: American College of Chest Physicians Annual Meeting, Poster 592. Presented November 4, 2009.
[9] J.C. Chatham, "Lactate - the forgotten fuel!" J Physiol. (2002) July 15; 542(Pt 2), p. 333. doi: 10.1113/jphysiol.2002.020974.
[10] E. Colman, A. Szarfman, J. Wyeth, et al., "An evaluation of a data mining signal for amyotrophic lateral sclerosis and statins detected in FDA"s spontaneous adverse event reporting system," Pharmacoepidemiol Drug Saf (2008) Vol. 17, pp. 1060-76.
[11] B.E. Corkey, J.T. Deeney, G.C. Yaney, K. Tornheim, and M. Prentki, "The Role of Long-Chain Fatty Acyl-CoA Esters in Beta-Cell Signal Transduction," American Society for Nutritional Sciences, (2000) pp. 299S-304S.
[12] S. Dublin, M.L. Jackson, J.C. Nelson, N.S. Weiss, E.B. Larson, and L.A. Jackson, "Statin use and risk of community acquired pneumonia in older people: population based case-control study," BMJ (2009) Vol. 338, p. b2137 ; doi:10.1136/bmj.b2137
[13] R.J. Edison and M. Muenke, "Central nervous system and limb anomalies in case reports of first-trimester statin exposure," N Engl J Med (2004) Vol. 350, pp. 1579-1582.
[14] J.L. Farber, "Mechanisms of cell injury by activated oxygen species." Environ Health Perspect. (1994) December; Vol. 102 (Suppl 10), pp. 17-24.
[15] A.B. Fernandez, R.H. Karas, A.A. Alsheikh-Ali, and P.D. Thompson, "Statins and interstitial lung disease: a systematic review of the literature and of food and drug administration adverse event reports." Chest, (2008) Oct, Vol. 134 No. 4, pp. 824-30. Epub 2008 Aug 8.
[16] K. Folkers, P. Langsjoen, R. Willis, P. Richardson,L.J. Xia,C.Q. Ye, and H. Tamagawa, "Lovastatin decreases coenzyme Q levels in humans," PNAS (1990) November 1, Vol. 87, No. 22, pp. 8931-8934.
[17] C. Gaugler, "Lipofuscin", Stanislaus Journal of Biochemical Reviews
May (1997).
[18] Ghirlanda G, Oradei A, Manto A, Lippa S, Uccioli L, Caputo S, Greco A, Littarru G (1993). "Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study". J Clin Pharmacol 33 (3): 226-9. PMID 8463436.
[19] M.R. Goldstein, L. Mascitelli, and F. Pezzetta, "Dyslipidemia is a protective factor in amyotrophic lateral sclerosis," Neurology (2008) Vol. 71, p. 956.
[20] T. H. Haines, "Do Sterols Reduce Proton and Sodium Leaks through Lipid Bilayers?" Progress in Lipid Research (2001) Vol.40, pp. 299-324.
[21] S. Jamil and P. Iqbal, "Rhabdomyolysis induced by a single dose of a statin." Heart (2004) Jan; Vol. 90 No. 1, p. e3.
[22] N. Kucerka, D. Marquardt, T.A. Harroun, M-P Nieh, S. R. Wassall, and J. Katsaras, "The Functional Significance of Lipid Diversity: Orientation of Cholesterol in Bilayers is Determined by Lipid Species," J. Am. Chem. Soc. (2009) Vol. 131, pp. 16358-16359.
[23] J.M. Land, J.A. Morgan-Hughes, and J.B.Clark, " Mitochondrial myopathy: biochemical studies revealing a deficiency of NADH-cytochrome b reductase activity." J. Neurol. Sci. 50: 1-13, 1981.
[24] S. Lantuejoul, E. Brambilla, C. Brambilla, and G. Devouassoux, "Statin-induced Fibrotic Nonspecific Interstitial Pneumonia," Eur Respir J. (2002) Vol. 19, pp. 577-580.
[25] R.S. Lees and A.M. Lees, "Rhabdomyolysis from the Coadministration of Lovastatin and the Antifungal Agent Itraconazole," NEJM (1995) Vol. 333, pp. 664-665.
[26] S.R. Majumdar, F.A. McAlister, D.T. Eurich, R.S. Padwal, and T.J. Marrie, "Statins and outcomes in patients admitted to hospital with community acquired pneumonia: population based prospective cohort study," BMJ (2006) Vol. 333, p. 999.
[27] M.G. Mohaupt, MD, R.H. Karas, MD PhD, E.B. Babiychuk, PhD, V. Sanchez-Freire, K. Monastyrskaya, PhD, L. Iyer, PhD, H. Hoppeler, MD, F. Breil and A. Draeger, MD "Association between statin-associated myopathy and skeletal muscle damage," CMAJ (2009) July 7 Vol. 181 No. 1-2 ; doi:10.1503/cmaj.081785.
[28] A. Mordente, S. A. Santini, G. A. D. Miggiano, G. E. Martorana, T. Petitti, G. Minotti, and B. Giardina, "The Interaction of Short Chain Coenzyme Q analogs with Different Redox States of Myoglobin," The Journal of Biological Chemistry, (1994) Vol. 269, Mo. 44, pp. 27394-27400.
[29] R.A. Oleka, J. Antosiewicza, J. Popinigisa, R. Gabbianellib, D. Fedelib and G. Falcionib, "Pyruvate but not lactate prevents NADH-induced myoglobin oxidation," Free Radical Biology and Medicine (2005) June; Vol. 38, Issue 11, pp. 1484-1490; doi:10.1016/j.freeradbiomed.2005.02.018.
[30] D. Papahadjopoulosa "Na+-K+ discrimination by “pure” phospholipid membranes," Biochimica et Biophysica Acta (BBA) (1971) Vol. 241, Issue 1, 6 July 1971, pp. 254-259
[31] R.P. Patel, U. Diczfalusy, S. Dzeletovic, M.T. Wilson and V.M. Darley-Usmar, "Formation of oxysterols during oxidation of low density lipoprotein by peroxynitrite, myoglobin, and copper, "Journal of Lipid Research (1996) Vol. 37, pp. 2361-2371.
[32] S. Pitkanen, A. Feigenbaum,, R. Laframboise, and B.H. Robinson, "NADH-coenzyme Q reductase (complex I) deficiency: heterogeneity in phenotype and biochemical findings," J. Inherit. Metab. Dis. (1996) Vol. 19, pp. 675-686.
[33] E.Y. Plotnikov, A.A. Chupyrkina, I.B. Pevzner, N.K. Isaev, and D.B. Zorov, "Myoglobin causes oxidative stress, increase of NO production and dysfunction of kidney's mitochondria," Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (2009) Vol. 1792, Issue 8, August pp. 796-803; doi:10.1016/j.bbadis.2009.06.005
[34] T. Pozefsky, R G Tancredi, R T Moxley, J Dupre, and J D Tobin "Effects of brief starvation on muscle amino acid metabolism in nonobese man." J Clin Invest. (1976) February, Vol. 57, No. 2, pp. 444-449. doi: 10.1172/JCI108295.
[35] S.I. Rao, A. Wilks, M. Hamberg, and P.R. Ortiz de Montellano, "The Lipoxygenase Activity of Myoglobin," The Journal of Biological Chemistry (1994) Vol. 269, No. 10, pp. 7210-7216.
[36] M. Rizzo, G.A. Spinas, G.B. Rinia and K. Berneis, "Is diabetes the cost to pay for a greater cardiovascular prevention?" International Journal of Cardiology (2009), article in press; doi:10.1016/j.ijcard.2009.03.001
[37] A. Shahapurkar, S. M. Tarvade, N. M. Dedhia, S. Bichu, "Exertional Myoglobinuria Leading to Acute Renal Failure: A Case Report" Indian Journal of Nephrology (2004) Vol. 14, pp. 198-199.
[38] Y. Shimomura, M. Suzuki, S. Sugiyama, Y. Hanaki, and T. Ozawa, "Protective effect of coenzyme Q10 on exercise-induced muscular injury." Biochem Biophys Res Commun. (1991) Apr 15;176(1):349-55.
[39] J.P. Silva, M. Kohler, C. Graff, A. Oldfors, M.A. Magnuson, P.O. Berggren, and N.G. Larsson, "Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes" Nat Genet. (2000) Nov; Vol. 26, No. 3, pp. 336-40.
[40] H. Sinzinger, R. Wolfram, and B.A. Peskar, "Muscular side effects of statins," J Cardiovasc Pharmacol (2002) Vol. 40, pp. 163-71.
[41] R. Sukhija, MD, S.Prayaga, MD, M. Marashdeh, MD, Z. Bursac, PhD, MPH, P. Kakar, MD, D. Bansal MD, R. Sachdeva, MD, S.H. Kesan, MD, and J.L. Mehta, MD, PhD, "Effect of Statins on Fasting Plasma Glucose in Diabetic and Nondiabetic Patients" Journal of Investigative Medicine (2009) March; Vol. 57, Issue 3, pp. 495-499; doi: 10.231/JIM.0b013e318197ec8b
[42] A. Termana and U.T. Brunk "The Aging Myocardium: Roles of Mitochondrial Damage and Lysosomal Degradation," Heart, Lung and Circulation (2005) June, Vol. 14, Issue 2, pp. 107-114; doi:10.1016/j.hlc.2004.12.023
[43] G. Wainwright, L. Mascitelli, and M.R. Goldstein, "Cholesterol-lowering Therapy and Cell Membranes. Stable Plaque at the Expense of Unstable Membranes?" Arch. Med. Sci. (2009) Vol. 5, No. 3, pp. 289-295.
[44] T. Walker, J. McCaffery and C. Steinfort, "Potential link between HMG-CoA reductase inhibitor (statin) use and interstitial lung disease," MJA (2007) Vol. 186, No. 2, pp. 91-94.
[45] P.L. Yeagle, The Biology of Cholesterol (1988) 242 pp. CRC Press, Boca Raton, FL.
[46] F. Xia, L. Xie, A. Mihic, X. Gao, Y. Chen, H.Y. Gaisano and R.G. Tsushima, "Inhibition of Cholesterol Biosynthesis Impairs Insulin Secretion and Voltage-Gated Calcium Channel Function in Pancreatic Beta-Cells," Endocrinology (2008) Vol. 149, No. 10, pp. 5136-5145.
[47] R.A. Zager and K.M. Burkhart, "Differential effects of glutathione and cysteine on Fe2+, Fe3+, H2O2 and myoglobin-induced proximal tubular cell attack," Kidney Inernational (1998) Vol. 53, No 6, pp. 1661-1672. doi:10.1046/j.1523-1755.1998.00919.x
[2] M. Baciu, S.C. Sebai, O. Ces, X. Mulet, J.A. Clarke, G.C. Shearman, and R.V. Law, Templer RH, Plisson C, Parker CA, Gee A. "Degradative transport of cationic amphiphilic drugs across phospholipid bilayers." Philos Transact A Math Phys Eng Sci. (2006) Oct 15, Vol. 364(1847), pp. 2597-614.
[3] M.W. Bolt,J. W. Card, W.J. Racz, J.F. Brien and T.E. Massey, "Disruption of Mitochondrial Function and Cellular ATP Levels by Amiodarone and N-Desethylamiodarone in Initiation of Amiodarone-Induced Pulmonary Cytotoxicity," JPET (2001) September 1, Vol. 298, No. 3, pp. 1280-1289.
[4] S.L. Bonting, P.J. van Breugel, F.J. Daemen, "Influence of the lipid environment of the properties of rhodopsin in the photoreceptor membrane," Adv. Exp. Med. Biol. (1977) Vol. 83, pp. 175-89.
[5] P. Brancaccio, N. Maffulli, and F.M. Limongelli, "Creatine kinase monitoring in sport medicine" British Medical Bulletin (2007) Vol. 81-82. No. 1, pp. 209-230; doi:10.1093/bmb/ldm014
[6] E. Bruckert, G. Hayem, S. Dejager, et al. "Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients -- the PRIMO study." Cardiovasc Drugs Ther (2005) Vol. 19, pp. 403-14.
[7] J. Cable, "Adverse Events of Statins -- An Informal Internet-based Study," JOIMR (2009, December, Vol. 7, No. 1; http://www.joimr.org/JOIMR_Vol7_No1_Dec2009.pdf.
[8] L.P. Cahalin, PT, PhD, et al., CHEST 2009: American College of Chest Physicians Annual Meeting, Poster 592. Presented November 4, 2009.
[9] J.C. Chatham, "Lactate - the forgotten fuel!" J Physiol. (2002) July 15; 542(Pt 2), p. 333. doi: 10.1113/jphysiol.2002.020974.
[10] E. Colman, A. Szarfman, J. Wyeth, et al., "An evaluation of a data mining signal for amyotrophic lateral sclerosis and statins detected in FDA"s spontaneous adverse event reporting system," Pharmacoepidemiol Drug Saf (2008) Vol. 17, pp. 1060-76.
[11] B.E. Corkey, J.T. Deeney, G.C. Yaney, K. Tornheim, and M. Prentki, "The Role of Long-Chain Fatty Acyl-CoA Esters in Beta-Cell Signal Transduction," American Society for Nutritional Sciences, (2000) pp. 299S-304S.
[12] S. Dublin, M.L. Jackson, J.C. Nelson, N.S. Weiss, E.B. Larson, and L.A. Jackson, "Statin use and risk of community acquired pneumonia in older people: population based case-control study," BMJ (2009) Vol. 338, p. b2137 ; doi:10.1136/bmj.b2137
[13] R.J. Edison and M. Muenke, "Central nervous system and limb anomalies in case reports of first-trimester statin exposure," N Engl J Med (2004) Vol. 350, pp. 1579-1582.
[14] J.L. Farber, "Mechanisms of cell injury by activated oxygen species." Environ Health Perspect. (1994) December; Vol. 102 (Suppl 10), pp. 17-24.
[15] A.B. Fernandez, R.H. Karas, A.A. Alsheikh-Ali, and P.D. Thompson, "Statins and interstitial lung disease: a systematic review of the literature and of food and drug administration adverse event reports." Chest, (2008) Oct, Vol. 134 No. 4, pp. 824-30. Epub 2008 Aug 8.
[16] K. Folkers, P. Langsjoen, R. Willis, P. Richardson,L.J. Xia,C.Q. Ye, and H. Tamagawa, "Lovastatin decreases coenzyme Q levels in humans," PNAS (1990) November 1, Vol. 87, No. 22, pp. 8931-8934.
[17] C. Gaugler, "Lipofuscin", Stanislaus Journal of Biochemical Reviews
May (1997).
[18] Ghirlanda G, Oradei A, Manto A, Lippa S, Uccioli L, Caputo S, Greco A, Littarru G (1993). "Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study". J Clin Pharmacol 33 (3): 226-9. PMID 8463436.
[19] M.R. Goldstein, L. Mascitelli, and F. Pezzetta, "Dyslipidemia is a protective factor in amyotrophic lateral sclerosis," Neurology (2008) Vol. 71, p. 956.
[20] T. H. Haines, "Do Sterols Reduce Proton and Sodium Leaks through Lipid Bilayers?" Progress in Lipid Research (2001) Vol.40, pp. 299-324.
[21] S. Jamil and P. Iqbal, "Rhabdomyolysis induced by a single dose of a statin." Heart (2004) Jan; Vol. 90 No. 1, p. e3.
[22] N. Kucerka, D. Marquardt, T.A. Harroun, M-P Nieh, S. R. Wassall, and J. Katsaras, "The Functional Significance of Lipid Diversity: Orientation of Cholesterol in Bilayers is Determined by Lipid Species," J. Am. Chem. Soc. (2009) Vol. 131, pp. 16358-16359.
[23] J.M. Land, J.A. Morgan-Hughes, and J.B.Clark, " Mitochondrial myopathy: biochemical studies revealing a deficiency of NADH-cytochrome b reductase activity." J. Neurol. Sci. 50: 1-13, 1981.
[24] S. Lantuejoul, E. Brambilla, C. Brambilla, and G. Devouassoux, "Statin-induced Fibrotic Nonspecific Interstitial Pneumonia," Eur Respir J. (2002) Vol. 19, pp. 577-580.
[25] R.S. Lees and A.M. Lees, "Rhabdomyolysis from the Coadministration of Lovastatin and the Antifungal Agent Itraconazole," NEJM (1995) Vol. 333, pp. 664-665.
[26] S.R. Majumdar, F.A. McAlister, D.T. Eurich, R.S. Padwal, and T.J. Marrie, "Statins and outcomes in patients admitted to hospital with community acquired pneumonia: population based prospective cohort study," BMJ (2006) Vol. 333, p. 999.
[27] M.G. Mohaupt, MD, R.H. Karas, MD PhD, E.B. Babiychuk, PhD, V. Sanchez-Freire, K. Monastyrskaya, PhD, L. Iyer, PhD, H. Hoppeler, MD, F. Breil and A. Draeger, MD "Association between statin-associated myopathy and skeletal muscle damage," CMAJ (2009) July 7 Vol. 181 No. 1-2 ; doi:10.1503/cmaj.081785.
[28] A. Mordente, S. A. Santini, G. A. D. Miggiano, G. E. Martorana, T. Petitti, G. Minotti, and B. Giardina, "The Interaction of Short Chain Coenzyme Q analogs with Different Redox States of Myoglobin," The Journal of Biological Chemistry, (1994) Vol. 269, Mo. 44, pp. 27394-27400.
[29] R.A. Oleka, J. Antosiewicza, J. Popinigisa, R. Gabbianellib, D. Fedelib and G. Falcionib, "Pyruvate but not lactate prevents NADH-induced myoglobin oxidation," Free Radical Biology and Medicine (2005) June; Vol. 38, Issue 11, pp. 1484-1490; doi:10.1016/j.freeradbiomed.2005.02.018.
[30] D. Papahadjopoulosa "Na+-K+ discrimination by “pure” phospholipid membranes," Biochimica et Biophysica Acta (BBA) (1971) Vol. 241, Issue 1, 6 July 1971, pp. 254-259
[31] R.P. Patel, U. Diczfalusy, S. Dzeletovic, M.T. Wilson and V.M. Darley-Usmar, "Formation of oxysterols during oxidation of low density lipoprotein by peroxynitrite, myoglobin, and copper, "Journal of Lipid Research (1996) Vol. 37, pp. 2361-2371.
[32] S. Pitkanen, A. Feigenbaum,, R. Laframboise, and B.H. Robinson, "NADH-coenzyme Q reductase (complex I) deficiency: heterogeneity in phenotype and biochemical findings," J. Inherit. Metab. Dis. (1996) Vol. 19, pp. 675-686.
[33] E.Y. Plotnikov, A.A. Chupyrkina, I.B. Pevzner, N.K. Isaev, and D.B. Zorov, "Myoglobin causes oxidative stress, increase of NO production and dysfunction of kidney's mitochondria," Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (2009) Vol. 1792, Issue 8, August pp. 796-803; doi:10.1016/j.bbadis.2009.06.005
[34] T. Pozefsky, R G Tancredi, R T Moxley, J Dupre, and J D Tobin "Effects of brief starvation on muscle amino acid metabolism in nonobese man." J Clin Invest. (1976) February, Vol. 57, No. 2, pp. 444-449. doi: 10.1172/JCI108295.
[35] S.I. Rao, A. Wilks, M. Hamberg, and P.R. Ortiz de Montellano, "The Lipoxygenase Activity of Myoglobin," The Journal of Biological Chemistry (1994) Vol. 269, No. 10, pp. 7210-7216.
[36] M. Rizzo, G.A. Spinas, G.B. Rinia and K. Berneis, "Is diabetes the cost to pay for a greater cardiovascular prevention?" International Journal of Cardiology (2009), article in press; doi:10.1016/j.ijcard.2009.03.001
[37] A. Shahapurkar, S. M. Tarvade, N. M. Dedhia, S. Bichu, "Exertional Myoglobinuria Leading to Acute Renal Failure: A Case Report" Indian Journal of Nephrology (2004) Vol. 14, pp. 198-199.
[38] Y. Shimomura, M. Suzuki, S. Sugiyama, Y. Hanaki, and T. Ozawa, "Protective effect of coenzyme Q10 on exercise-induced muscular injury." Biochem Biophys Res Commun. (1991) Apr 15;176(1):349-55.
[39] J.P. Silva, M. Kohler, C. Graff, A. Oldfors, M.A. Magnuson, P.O. Berggren, and N.G. Larsson, "Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes" Nat Genet. (2000) Nov; Vol. 26, No. 3, pp. 336-40.
[40] H. Sinzinger, R. Wolfram, and B.A. Peskar, "Muscular side effects of statins," J Cardiovasc Pharmacol (2002) Vol. 40, pp. 163-71.
[41] R. Sukhija, MD, S.Prayaga, MD, M. Marashdeh, MD, Z. Bursac, PhD, MPH, P. Kakar, MD, D. Bansal MD, R. Sachdeva, MD, S.H. Kesan, MD, and J.L. Mehta, MD, PhD, "Effect of Statins on Fasting Plasma Glucose in Diabetic and Nondiabetic Patients" Journal of Investigative Medicine (2009) March; Vol. 57, Issue 3, pp. 495-499; doi: 10.231/JIM.0b013e318197ec8b
[42] A. Termana and U.T. Brunk "The Aging Myocardium: Roles of Mitochondrial Damage and Lysosomal Degradation," Heart, Lung and Circulation (2005) June, Vol. 14, Issue 2, pp. 107-114; doi:10.1016/j.hlc.2004.12.023
[43] G. Wainwright, L. Mascitelli, and M.R. Goldstein, "Cholesterol-lowering Therapy and Cell Membranes. Stable Plaque at the Expense of Unstable Membranes?" Arch. Med. Sci. (2009) Vol. 5, No. 3, pp. 289-295.
[44] T. Walker, J. McCaffery and C. Steinfort, "Potential link between HMG-CoA reductase inhibitor (statin) use and interstitial lung disease," MJA (2007) Vol. 186, No. 2, pp. 91-94.
[45] P.L. Yeagle, The Biology of Cholesterol (1988) 242 pp. CRC Press, Boca Raton, FL.
[46] F. Xia, L. Xie, A. Mihic, X. Gao, Y. Chen, H.Y. Gaisano and R.G. Tsushima, "Inhibition of Cholesterol Biosynthesis Impairs Insulin Secretion and Voltage-Gated Calcium Channel Function in Pancreatic Beta-Cells," Endocrinology (2008) Vol. 149, No. 10, pp. 5136-5145.
[47] R.A. Zager and K.M. Burkhart, "Differential effects of glutathione and cysteine on Fe2+, Fe3+, H2O2 and myoglobin-induced proximal tubular cell attack," Kidney Inernational (1998) Vol. 53, No 6, pp. 1661-1672. doi:10.1046/j.1523-1755.1998.00919.x
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