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Stroke and Cerebrovascular Disease
A stroke, previously known medically as a cerebrovascular accident (CVA), is the rapidly developing loss of brain function(s) due to disturbance in the blood supply to the brain. This can be due to ischemia (lack of blood flow) caused by blockage (thrombosis, arterial embolism), or a hemorrhage (leakage of blood). As a result, the affected area of the brain is unable to function, leading to inability to move one or more limbs on one side of the body, inability to understand or formulate speech, or an inability to see one side of the visual field.
A stroke is a medical emergency and can cause permanent neurological damage, complications, and lead to death. It is the leading cause of adult disability in the United States and Europe and it is the second leading cause of death worldwide. Risk factors for stroke include advanced age, hypertension (high blood pressure), previous stroke or transient ischemic attack (TIA), diabetes, high cholesterol, cigarette smoking and atrial fibrillation. High blood pressure is the most important modifiable risk factor of stroke.
A silent stroke is a stroke that does not have any outward symptoms, and the patient is typically unaware they have suffered a stroke. Despite not causing identifiable symptoms a silent stroke still causes damage to the brain, and places the patient at increased risk for both transient ischemic attack and major stroke in the future. Conversely those who have suffered a major stroke are at risk of having silent strokes.In a broad study in 1998, more than 11 million people were estimated to have experienced a stroke in the United States. Approximately 770,000 of theses strokes were symptomatic and 11 million were first-ever silent MRI infarcts or hemorrhages. Silent strokes typically cause lesions which are detected via the use of neuroimaging such as MRI. Silent stroke are estimated to occur at five times the rate of symptomatic stroke.The risk of silent stroke increases with age but may also affect younger adults and children, especially those with acute anemia.
An ischemic stroke is occasionally treated in a hospital with thrombolysis (also known as a "clot buster"), and some hemorrhagic strokes benefit from neurosurgery. Treatment to recover any lost function is termed stroke rehabilitation, ideally in a stroke unit and involving health professions such as speech and language therapy, physical therapy and occupational therapy. Prevention of recurrence may involve the administration of antiplatelet drugs such as aspirin and dipyridamole, control and reduction of hypertension, and the use of statins. Selected patients may benefit from carotid endarterectomy and the use of anticoagulants.
3 Signs and symptoms
3.1 Early recognition
3.3 Associated symptoms
6.1 Physical examination
6.3 Underlying etiology
7.1 Risk factors
7.1.1 Blood pressure
7.1.2 Atrial fibrillation
7.1.3 Blood lipids
7.1.4 Diabetes mellitus
7.1.5 Anticoagulation drugs
7.1.7 Nutritional and metabolic interventions
8.1 Stroke unit
8.2 Treatment of ischemic stroke
8.2.2 Mechanical thrombectomy
8.2.3 Angioplasty and stenting
8.3 Secondary prevention of ischemic stroke
8.4 Treatment of hemorrhagic stroke
9 Care and rehabilitation
13 External Links
15 Further reading
The traditional definition of stroke , devised by the World Health Organization in the 1970s, is a "neurological deficit of cerebrovascular cause that persists beyond 24 hours or is interrupted by death within 24 hours". This definition was supposed to reflect the reversibility of tissue damage and was devised for the purpose, with the time frame of 24 hours being chosen arbitrarily. The 24-hour limit divides stroke from transient ischemic attack, which is a related syndrome of stroke symptoms that resolve completely within 24 hours. With the availability of treatments that, when given early, can reduce stroke severity, many now prefer alternative concepts, such as brain attack and acute ischemic cerebrovascular syndrome (modeled after heart attack and acute coronary syndrome respectively), that reflect the urgency of stroke symptoms and the need to act swiftly.
A slice of brain from the autopsy of a person who suffered an acute middle cerebral artery (MCA) strokeStrokes can be classified into two major categories: ischemic and hemorrhagic. Ischemic strokes are those that are caused by interruption of the blood supply, while hemorrhagic strokes are the ones which result from rupture of a blood vessel or an abnormal vascular structure. About 87% of strokes are caused by ischemia, and the remainder by hemorrhage. Some hemorrhages develop inside areas of ischemia ("hemorrhagic transformation"). It is unknown how many hemorrhages actually start as ischemic stroke.
Main articles: Cerebral infarction and Brain ischemia.
In an ischemic stroke, blood supply to part of the brain is decreased, leading to dysfunction of the brain tissue in that area. There are four reasons why this might happen:
1.Thrombosis (obstruction of a blood vessel by a blood clot forming locally)
2.Embolism (obstruction due to an embolus from elsewhere in the body, see below),
3.Systemic hypoperfusion (general decrease in blood supply, e.g. in shock)
Stroke without an obvious explanation is termed "cryptogenic" (of unknown origin); this constitutes 30-40% of all ischemic strokes.
There are various classification systems for acute ischemic stroke. The Oxford Community Stroke Project classification (OCSP, also known as the Bamford or Oxford classification) relies primarily on the initial symptoms; based on the extent of the symptoms, the stroke episode is classified as total anterior circulation infarct (TACI), partial anterior circulation infarct (PACI), lacunar infarct (LACI) or posterior circulation infarct (POCI). These four entities predict the extent of the stroke, the area of the brain affected, the underlying cause, and the prognosis. The TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification is based on clinical symptoms as well as results of further investigations; on this basis, a stroke is classified as being due to (1) thrombosis or embolism due to atherosclerosis of a large artery, (2) embolism of cardiac origin, (3) occlusion of a small blood vessel, (4) other determined cause, (5) undetermined cause (two possible causes, no cause identified, or incomplete investigation).
Main articles: Intracranial hemorrhage and intracerebral hemorrhage
CT scan showing an intracerebral hemorrhage with associated intraventricular hemorrhage. Intracranial hemorrhage is the accumulation of blood anywhere within the skull vault. A distinction is made between intra-axial hemorrhage (blood inside the brain) and extra-axial hemorrhage (blood inside the skull but outside the brain). Intra-axial hemorrhage is due to intraparenchymal hemorrhage or intraventricular hemorrhage (blood in the ventricular system). The main types of extra-axial hemorrhage are epidural hematoma (bleeding between the dura mater and the skull), subdural hematoma (in the subdural space) and subarachnoid hemorrhage (between the arachnoid mater and pia mater). Most of the hemorrhagic stroke syndromes have specific symptoms (e.g. headache, previous head injury).
Signs and symptoms
Stroke symptoms typically start suddenly, over seconds to minutes, and in most cases do not progress further. The symptoms depend on the area of the brain affected. The more extensive the area of brain affected, the more functions that are likely to be lost. Some forms of stroke can cause additional symptoms. For example, in intracranial hemorrhage, the affected area may compress other structures. Most forms of stroke are not associated with headache, apart from subarachnoid hemorrhage and cerebral venous thrombosis and occasionally intracerebral hemorrhage.
Various systems have been proposed to increase recognition of stroke by patients, relatives and emergency first responders. A systematic review, updating a previous systematic review from 1994, looked at a number of trials to evaluate how well different physical examination findings are able to predict the presence or absence of stroke. It was found that sudden-onset face weakness, arm drift (e.g. if a person, when asked to raise both arms, involuntarily lets one arm drift downward) and abnormal speech are the findings most likely to lead to the correct identification of a case of stroke (+ likelihood ratio of 5.5 when at least one of these is present). Similarly, when all three of these are absent, the likelihood of stroke is significantly decreased (â€“ likelihood ratio of 0.39). While these findings are not perfect for diagnosing stroke, the fact that they can be evaluated relatively rapidly and easily make them very valuable in the acute setting.
Proposed systems include FAST (stroke) (face, arm, speech, and time), as advocated by the Department of Health (United Kingdom) and The Stroke Association, the American Stroke Association (www.strokeassociation.org) , National Stroke Association (US www.stroke.org), the Los Angeles Prehospital Stroke Screen (LAPSS) and the Cincinnati Prehospital Stroke Scale (CPSS). Use of these scales is recommended by professional guidelines.
For people referred to the emergency room, early recognition of stroke is deemed important as this can expedite diagnostic tests and treatments. A scoring system called ROSIER (recognition of stroke in the emergency room) is recommended for this purpose; it is based on features from the medical history and physical examination.
If the area of the brain affected contains one of the three prominent central nervous system pathwaysâ€”the spinothalamic tract, corticospinal tract, and dorsal column (medial lemniscus), symptoms may include:
hemiplegia and muscle weakness of the face
reduction in sensory or vibratory sensation
In most cases, the symptoms affect only one side of the body (unilateral). Depending on the part of the brain affected, the defect in the brain is usually on the opposite side of the body. However, since these pathways also travel in the spinal cord and any lesion there can also produce these symptoms, the presence of any one of these symptoms does not necessarily indicate a stroke.
In addition to the above CNS pathways, the brainstem also consists of the 12 cranial nerves. A stroke affecting the brain stem therefore can produce symptoms relating to deficits in these cranial nerves:
altered smell, taste, hearing, or vision (total or partial)
drooping of eyelid (ptosis) and weakness of ocular muscles
decreased reflexes: gag, swallow, pupil reactivity to light
decreased sensation and muscle weakness of the face
balance problems and nystagmus
altered breathing and heart rate
weakness in sternocleidomastoid muscle with inability to turn head to one side
weakness in tongue (inability to protrude and/or move from side to side)
If the cerebral cortex is involved, the CNS pathways can again be affected, but also can produce the following symptoms:
aphasia (difficulty with verbal expression, auditory comprehension, reading and/or writing Broca's or Wernicke's area typically involved)
dysarthria (motor speech disorder resulting from neurological injury)
apraxia (altered voluntary movements)
visual field defect
memory deficits (involvement of temporal lobe)
hemineglect (involvement of parietal lobe)
disorganized thinking, confusion, hypersexual gestures (with involvement of frontal lobe)
anosognosia (persistent denial of the existence of a, usually stroke-related, deficit)
If the cerebellum is involved, the patient may have the following:
altered movement coordination
vertigo and or disequilibrium
Loss of consciousness, headache, and vomiting usually occurs more often in hemorrhagic stroke than in thrombosis because of the increased intracranial pressure from the leaking blood compressing the brain.
If symptoms are maximal at onset, the cause is more likely to be a subarachnoid hemorrhage or an embolic stroke.
In thrombotic stroke a thrombus (blood clot) usually forms around atherosclerotic plaques. Since blockage of the artery is gradual, onset of symptomatic thrombotic strokes is slower. A thrombus itself (even if non-occluding) can lead to an embolic stroke (see below) if the thrombus breaks off, at which point it is called an "embolus." Two types of thrombosis can cause stroke:
Large vessel disease involves the common and internal carotids, vertebral, and the Circle of Willis. Diseases that may form thrombi in the large vessels include (in descending incidence): atherosclerosis, vasoconstriction (tightening of the artery), aortic, carotid or vertebral artery dissection, various inflammatory diseases of the blood vessel wall (Takayasu arteritis, giant cell arteritis, vasculitis), noninflammatory vasculopathy, Moyamoya disease and fibromuscular dysplasia.
Small vessel disease involves the smaller arteries inside the brain: branches of the circle of Willis, middle cerebral artery, stem, and arteries arising from the distal vertebral and basilar artery. Diseases that may form thrombi in the small vessels include (in descending incidence): lipohyalinosis (build-up of fatty hyaline matter in the blood vessel as a result of high blood pressure and aging) and fibrinoid degeneration (stroke involving these vessels are known as lacunar infarcts) and microatheroma (small atherosclerotic plaques).
Sickle cell anemia, which can cause blood cells to clump up and block blood vessels, can also lead to stroke. A stroke is the second leading killer of people under 20 who suffer from sickle-cell anemia.
An embolic stroke refers to the blockage of an artery by an arterial embolus, a travelling particle or debris in the arterial bloodstream originating from elsewhere. An embolus is most frequently a thrombus, but it can also be a number of other substances including fat (e.g. from bone marrow in a broken bone), air, cancer cells or clumps of bacteria (usually from infectious endocarditis).
Because an embolus arises from elsewhere, local therapy solves the problem only temporarily. Thus, the source of the embolus must be identified. Because the embolic blockage is sudden in onset, symptoms usually are maximal at start. Also, symptoms may be transient as the embolus is partially resorbed and moves to a different location or dissipates altogether.
Emboli most commonly arise from the heart (especially in atrial fibrillation) but may originate from elsewhere in the arterial tree. In paradoxical embolism, a deep vein thrombosis embolises through an atrial or ventricular septal defect in the heart into the brain.
Cardiac causes can be distinguished between high and low-risk:
High risk: atrial fibrillation and paroxysmal atrial fibrillation, rheumatic disease of the mitral or aortic valve disease, artificial heart valves, known cardiac thrombus of the atrium or ventricle, sick sinus syndrome, sustained atrial flutter, recent myocardial infarction, chronic myocardial infarction together with ejection fraction <28 percent, symptomatic congestive heart failure with ejection fraction <30 percent, dilated cardiomyopathy, Libman-Sacks endocarditis, Marantic endocarditis, infective endocarditis, papillary fibroelastoma, left atrial myxoma and coronary artery bypass graft (CABG) surgery
Low risk/potential: calcification of the annulus (ring) of the mitral valve, patent foramen ovale (PFO), atrial septal aneurysm, atrial septal aneurysm with patent foramen ovale, left ventricular aneurysm without thrombus, isolated left atrial "smoke" on echocardiography (no mitral stenosis or atrial fibrillation), complex atheroma in the ascending aorta or proximal arch
Systemic hypoperfusion is the reduction of blood flow to all parts of the body. It is most commonly due to cardiac pump failure from cardiac arrest or arrhythmias, or from reduced cardiac output as a result of myocardial infarction, pulmonary embolism, pericardial effusion, or bleeding. Hypoxemia (low blood oxygen content) may precipitate the hypoperfusion. Because the reduction in blood flow is global, all parts of the brain may be affected, especially "watershed" areas - border zone regions supplied by the major cerebral arteries. A watershed stroke refers to the condition when blood supply to these areas is compromised. Blood flow to these areas does not necessarily stop, but instead it may lessen to the point where brain damage can occur. This phenomenon is also referred to as "last meadow" to point to the fact that in irrigation the last meadow receives the least amount of water.
Cerebral venous sinus thrombosis leads to stroke due to locally increased venous pressure, which exceeds the pressure generated by the arteries. Infarcts are more likely to undergo hemorrhagic transformation (leaking of blood into the damaged area) than other types of ischemic stroke.
It generally occurs in small arteries or arterioles and is commonly due to hypertension, intracranial vascular malformations (including cavernous angiomas or arteriovenous malformations), cerebral amyloid angiopathy, or infarcts into which secondary haemorrhage has occurred. Other potential causes are trauma, bleeding disorders, amyloid angiopathy, illicit drug use (e.g. amphetamines or cocaine). The hematoma enlarges until pressure from surrounding tissue limits its growth, or until it decompresses by emptying into the ventricular system, CSF or the pial surface. A third of intracerebral bleed is into the brain's ventricles. ICH has a mortality rate of 44 percent after 30 days, higher than ischemic stroke or even the very deadly subarachnoid hemorrhage (which, however, also may be classified as a type of stroke).
Micrograph showing cortical pseudolaminar necrosis, a finding seen in strokes on medical imaging and at autopsy. H&E-LFB stain.
Micrograph of the superficial cerebral cortex showing neuron loss and reactive astrocytes in a person that suffered a stroke. H&E-LFB stain.Ischemic stroke occurs due to a loss of blood supply to part of the brain, initiating the ischemic cascade. Brain tissue ceases to function if deprived of oxygen for more than 60 to 90 seconds and after approximately three hours, will suffer irreversible injury possibly leading to death of the tissue, i.e., infarction. (This is why TPAs (e.g. Streptokinase, Altapase) are given only until three hours since the onset of the stroke.) Atherosclerosis may disrupt the blood supply by narrowing the lumen of blood vessels leading to a reduction of blood flow, by causing the formation of blood clots within the vessel, or by releasing showers of small emboli through the disintegration of atherosclerotic plaques. Embolic infarction occurs when emboli formed elsewhere in the circulatory system, typically in the heart as a consequence of atrial fibrillation, or in the carotid arteries, break off, enter the cerebral circulation, then lodge in and occlude brain blood vessels. Since blood vessels in the brain are now occluded, the brain becomes low in energy, and thus it resorts into using anaerobic respiration within the region of brain tissue affected by ischemia. Unfortunately, this kind of respiration produces less adenosine triphosphate (ATP) but releases a by-product called lactic acid. Lactic acid is an irritant which could potentially destroy cells since it is an acid and disrupts the normal acid-base balance in the brain. The ischemia area is referred to as the "ischemic penumbra".
Then, as oxygen or glucose becomes depleted in ischemic brain tissue, the production of high energy phosphate compounds such as adenosine triphosphate (ATP) fails, leading to failure of energy-dependent processes (such as ion pumping) necessary for tissue cell survival. This sets off a series of interrelated events that result in cellular injury and death. A major cause of neuronal injury is release of the excitatory neurotransmitter glutamate. The concentration of glutamate outside the cells of the nervous system is normally kept low by so-called uptake carriers, which are powered by the concentration gradients of ions (mainly Na+) across the cell membrane. However, stroke cuts off the supply of oxygen and glucose which powers the ion pumps maintaining these gradients. As a result the transmembrane ion gradients run down, and glutamate transporters reverse their direction, releasing glutamate into the extracellular space. Glutamate acts on receptors in nerve cells (especially NMDA receptors), producing an influx of calcium which activates enzymes that digest the cells' proteins, lipids and nuclear material. Calcium influx can also lead to the failure of mitochondria, which can lead further toward energy depletion and may trigger cell death due to apoptosis.
Ischemia also induces production of oxygen free radicals and other reactive oxygen species. These react with and damage a number of cellular and extracellular elements. Damage to the blood vessel lining or endothelium is particularly important. In fact, many antioxidant neuroprotectants such as uric acid and NXY-059 work at the level of the endothelium and not in the brain per se. Free radicals also directly initiate elements of the apoptosis cascade by means of redox signaling.
These processes are the same for any type of ischemic tissue and are referred to collectively as the ischemic cascade. However, brain tissue is especially vulnerable to ischemia since it has little respiratory reserve and is completely dependent on aerobic metabolism, unlike most other organs.
Brain tissue survival can be improved to some extent if one or more of these processes is inhibited. Drugs that scavenge reactive oxygen species, inhibit apoptosis, or inhibit excitatory neurotransmitters, for example, have been shown experimentally to reduce tissue injury due to ischemia. Agents that work in this way are referred to as being neuroprotective. Until recently, human clinical trials with neuroprotective agents have failed, with the probable exception of deep barbiturate coma. However, more recently NXY-059, the disulfonyl derivative of the radical-scavenging spintrap phenylbutylnitrone, is reported to be neuroprotective in stroke. This agent appears to work at the level of the blood vessel lining or endothelium. Unfortunately, after producing favorable results in one large-scale clinical trial, a second trial failed to show favorable results.
In addition to injurious effects on brain cells, ischemia and infarction can result in loss of structural integrity of brain tissue and blood vessels, partly through the release of matrix metalloproteases, which are zinc- and calcium-dependent enzymes that break down collagen, hyaluronic acid, and other elements of connective tissue. Other proteases also contribute to this process. The loss of vascular structural integrity results in a breakdown of the protective blood brain barrier that contributes to cerebral edema, which can cause secondary progression of the brain injury.
As is the case with any type of brain injury, the immune system is activated by cerebral infarction and may under some circumstances exacerbate the injury caused by the infarction. Inhibition of the inflammatory response has been shown experimentally to reduce tissue injury due to cerebral infarction, but this has not proved out in clinical studies.
Head CT showing deep intracerebral hemorrhage due to bleeding within the cerebellum, approximately 30 hours old.Hemorrhagic strokes result in tissue injury by causing compression of tissue from an expanding hematoma or hematomas. This can distort and injure tissue. In addition, the pressure may lead to a loss of blood supply to affected tissue with resulting infarction, and the blood released by brain hemorrhage appears to have direct toxic effects on brain tissue and vasculature.
Stroke is diagnosed through several techniques: a neurological examination (such as the Nihss), CT scans (most often without contrast enhancements) or MRI scans, Doppler ultrasound, and arteriography. The diagnosis of stroke itself is clinical, with assistance from the imaging techniques. Imaging techniques also assist in determining the subtypes and cause of stroke. There is yet no commonly used blood test for the stroke diagnosis itself, though blood tests may be of help in finding out the likely cause of stroke.
A physical examination, including taking a medical history of the symptoms and a neurological status, helps giving an evaluation of the location and severity of a stroke. It can give a standard score on e.g. the NIH stroke scale.
For diagnosing ischemic stroke in the emergency setting:
CT scans (without contrast enhancements)
For diagnosing hemorrhagic stroke in the emergency setting:
CT scans (without contrast enhancements)
For detecting chronic hemorrhages, MRI scan is more sensitive.
For the assessment of stable stroke, nuclear medicine scans SPECT and PET/CT may be helpful. SPECT documents cerebral blood flow and PET with FDG isotope the metabolic activity of the neurons.
When a stroke has been diagnosed, various other studies may be performed to determine the underlying etiology. With the current treatment and diagnosis options available, it is of particular importance to determine whether there is a peripheral source of emboli. Test selection may vary, since the cause of stroke varies with age, comorbidity and the clinical presentation. Commonly used techniques include:
an ultrasound/doppler study of the carotid arteries (to detect carotid stenosis) or dissection of the precerebral arteries
an electrocardiogram (ECG) and echocardiogram (to identify arrhythmias and resultant clots in the heart which may spread to the brain vessels through the bloodstream)
a Holter monitor study to identify intermittent arrhythmias
an angiogram of the cerebral vasculature (if a bleed is thought to have originated from an aneurysm or arteriovenous malformation)
blood tests to determine hypercholesterolemia, bleeding diathesis and some rarer causes such as homocysteinuria
Given the disease burden of strokes, prevention is an important public health concern. Primary prevention is less effective than secondary prevention (as judged by the number needed to treat to prevent one stroke per year). Recent guidelines detail the evidence for primary prevention in stroke. Because stroke may indicate underlying atherosclerosis, it is important to determine the patient's risk for other cardiovascular diseases such as coronary heart disease. Conversely, aspirin prevents against first stroke in patients who have suffered a myocardial infarction or patients with a high cardiovascular risk.
The most important modifiable risk factors for stroke are high blood pressure and atrial fibrillation (although magnitude of this effect is small: the evidence from the Medical Research Council trials is that 833 patients have to be treated for 1 year to prevent one stroke). Other modifiable risk factors include high blood cholesterol levels, diabetes, cigarette smoking (active and passive), heavy alcohol consumption and drug use, lack of physical activity, obesity and unhealthy diet. Alcohol use could predispose to ischemic stroke, and intracerebral and subarachnoid hemorrhage via multiple mechanisms (for example via hypertension, atrial fibrillation, rebound thrombocytosis and platelet aggregation and clotting disturbances). The drugs most commonly associated with stroke are cocaine, amphetamines causing hemorrhagic stroke, but also over-the-counter cough and cold drugs containing sympathomimetics.
No high quality studies have shown the effectiveness of interventions aimed at weight reduction, promotion of regular exercise, reducing alcohol consumption or smoking cessation. Nonetheless, given the large body of circumstantial evidence, best medical management for stroke includes advice on diet, exercise, smoking and alcohol use. Medication or drug therapy is the most common method of stroke prevention; carotid endarterectomy can be a useful surgical method of preventing stroke.
Hypertension accounts for 35-50% of stroke risk. Epidemiological studies suggest that even a small blood pressure reduction (5 to 6 mmHg systolic, 2 to 3 mmHg diastolic) would result in 40% fewer strokes. Lowering blood pressure has been conclusively shown to prevent both ischemic and hemorrhagic strokes. It is equally important in secondary prevention. Even patients older than 80 years and those with isolated systolic hypertension benefit from antihypertensive therapy. Studies show that intensive antihypertensive therapy results in a greater risk reduction. The available evidence does not show large differences in stroke prevention between antihypertensive drugs â€”therefore, other factors such as protection against other forms of cardiovascular disease should be considered and cost.
Patients with atrial fibrillation have a risk of 5% each year to develop stroke, and this risk is even higher in those with valvular atrial fibrillation. Depending on the stroke risk, anticoagulation with medications such as coumarins or aspirin is warranted for stroke prevention.
High cholesterol levels have been inconsistently associated with (ischemic) stroke. Statins have been shown to reduce the risk of stroke by about 15%. Since earlier meta-analyses of other lipid-lowering drugs did not show a decreased risk, statins might exert their effect through mechanisms other than their lipid-lowering effects.
Patients with diabetes mellitus are 2 to 3 times more likely to develop stroke, and they commonly have hypertension and hyperlipidemia. Intensive disease control has been shown to reduce microvascular complications such as nephropathy and retinopathy but not macrovascular complications such as stroke.
Oral anticoagulants such as warfarin have been the mainstay of stroke prevention for over 50 years. However, several studies have shown that aspirin and antiplatelet drugs are highly effective in secondary prevention after a stroke or transient ischemic attack. Low doses of aspirin (for example 75â€“150 mg) are as effective as high doses but have fewer side effects; the lowest effective dose remains unknown. Thienopyridines (clopidogrel, ticlopidine) "might be slightly more effective" than aspirin and have a decreased risk of gastrointestinal bleeding, but they are more expensive. Their exact role remains controversial. Ticlopidine has more skin rash, diarrhea, neutropenia and thrombotic thrombocytopenic purpura. Dipyridamole can be added to aspirin therapy to provide a small additional benefit, even though headache is a common side effect. Low-dose aspirin is also effective for stroke prevention after sustaining a myocardial infarction. Except for in atrial fibrillation, oral anticoagulants are not advised for stroke prevention â€”any benefit is offset by bleeding risk.
In primary prevention however, antiplatelet drugs did not reduce the risk of ischemic stroke while increasing the risk of major bleeding. Further studies are needed to investigate a possible protective effect of aspirin against ischemic stroke in women.
Surgical procedures such as carotid endarterectomy or carotid angioplasty can be used to remove significant atherosclerotic narrowing (stenosis) of the carotid artery, which supplies blood to the brain. There is a large body of evidence supporting this procedure in selected cases. Endarterectomy for a significant stenosis has been shown to be useful in the secondary prevention after a previous symptomatic stroke. Carotid artery stenting has not been shown to be equally useful. Patients are selected for surgery based on age, gender, degree of stenosis, time since symptoms and patients' preferences. Surgery is most efficient when not delayed too long â€”the risk of recurrent stroke in a patient who has a 50% or greater stenosis is up to 20% after 5 years, but endarterectomy reduces this risk to around 5%. The number of procedures needed to cure one patient was 5 for early surgery (within two weeks after the initial stroke), but 125 if delayed longer than 12 weeks.
Screening for carotid artery narrowing has not been shown to be a useful screening test in the general population. Studies of surgical intervention for carotid artery stenosis without symptoms have shown only a small decrease in the risk of stroke. To be beneficial, the complication rate of the surgery should be kept below 4%. Even then, for 100 surgeries, 5 patients will benefit by avoiding stroke, 3 will develop stroke despite surgery, 3 will develop stroke or die due to the surgery itself, and 89 will remain stroke-free but would also have done so without intervention.
The European Society of Cardiology and the European Association for Cardiovascular Prevention and Rehabilitation have developed an interactive tool for prediction and managing the risk of heart attack and stroke in Europe. HeartScore is aimed at supporting clinicians in optimising individual cardiovascular risk reduction. The Heartscore Programme is available in 12 languages and offers web based or PC version.
Treatment Stroke unit
Ideally, people who have had a stroke are admitted to a "stroke unit", a ward or dedicated area in hospital staffed by nurses and therapists with experience in stroke treatment. It has been shown that people admitted to a stroke unit have a higher chance of surviving than those admitted elsewhere in hospital, even if they are being cared for by doctors without experience in stroke.
When an acute stroke is suspected by history and physical examination, the goal of early assessment is to determine the cause. Treatment varies according to the underlying cause of the stroke, thromboembolic (ischemic) or hemorrhagic. A non-contrast head CT scan can rapidly identify a hemorrhagic stroke by imaging bleeding in or around the brain. If no bleeding is seen, a presumptive diagnosis of ischemic stroke is made.
Treatment of ischemic stroke
An ischemic stroke is caused by a thrombus (blood clot) occluding blood flow to an artery supplying the brain. Definitive therapy is aimed at removing the blockage by breaking the clot down (thrombolysis), or by removing it mechanically (thrombectomy). The more rapidly blood flow is restored to the brain, the fewer brain cells die.
Other medical therapies are aimed at minimizing clot enlargement or preventing new clots from forming. To this end, treatment with medications such as aspirin, clopidogrel and dipyridamole may be given to prevent platelets from aggregating.
In addition to definitive therapies, management of acute stroke includes control of blood sugars, ensuring the patient has adequate oxygenation and adequate intravenous fluids. Patients may be positioned with their heads flat on the stretcher, rather than sitting up, to increase blood flow to the brain. It is common for the blood pressure to be elevated immediately following a stroke. Although high blood pressure may cause some strokes, hypertension during acute stroke is desirable to allow adequate blood flow to the brain.
In increasing numbers of primary stroke centers, pharmacologic thrombolysis ("clot busting") with the drug tissue plasminogen activator (tPA), is used to dissolve the clot and unblock the artery. However, the use of tPA in acute stroke is controversial. On one hand, it is endorsed by the American Heart Association and the American Academy of Neurology as the recommended treatment for acute stroke within three hours of onset of symptoms as long as there are not other contraindications (such as abnormal lab values, high blood pressure, or recent surgery). This position for tPA is based upon the findings of two studies by one group of investigators which showed that tPA improves the chances for a good neurological outcome. When administered within the first three hours, 39% of all patients who were treated with tPA had a good outcome at three months, only 26% of placebo controlled patients had a good functional outcome. A recent study using alteplase for thrombolysis in ischemic stroke suggests clinical benefit with administration 3 to 4.5 hours after stroke onset. However, in the NINDS trial 6.4% of patients with large strokes developed substantial brain hemorrhage as a complication from being given tPA. A recent study found the mortality to be higher among patients receiving tPA versus those who did not. Additionally, it is the position of the American Academy of Emergency Medicine that objective evidence regarding the efficacy, safety, and applicability of tPA for acute ischemic stroke is insufficient to warrant its classification as standard of care.
Intra-arterial fibrinolysis, where a catherter is passed up an artery into the brain and the medication is injected at the site of thrombosis, has been found to improve outcomes in people with acute ischemic stroke.[original research?]
Merci Retriever L5. Another intervention for acute ischemic stroke is removal of the offending thrombus directly. This is accomplished by inserting a catheter into the femoral artery, directing it into the cerebral circulation, and deploying a corkscrew-like device to ensnare the clot, which is then withdrawn from the body. Mechanical embolectomy devices have been demonstrated effective at restoring blood flow in patients who were unable to receive thrombolytic drugs or for whom the drugs were ineffective, though no differences have been found between newer and older versions of the devices. The devices have only been tested on patients treated with mechanical clot embolectomy within eight hours of the onset of symptoms.
Angioplasty and stenting
Angioplasty and stenting have begun to be looked at as possible viable options in treatment of acute ischemic stroke. In a systematic review of six uncontrolled, single-center trials, involving a total of 300 patients, of intra-cranial stenting in symptomatic intracranial arterial stenosis, the rate of technical success (reduction to stenosis of <50%) ranged from 90-98%, and the rate of major peri-procedural complications ranged from 4-10%. The rates of restenosis and/or stroke following the treatment were also favorable. This data suggests that a large, randomized controlled trial is needed to more completely evaluate the possible therapeutic advantage of this treatment.
Secondary prevention of ischemic stroke
Anticoagulation can prevent recurrent stroke. Among patients with nonvalvular atrial fibrillation, anticoagulation can reduce stroke by 60% while antiplatelet agents can reduce stroke by 20%. However, a recent meta-analysis suggests harm from anti-coagulation started early after an embolic stroke. Stroke prevention treatment for atrial fibrillation is determined according to the CHADS/CHADS2 system. The most widely used anticoagulant to prevent thromboembolic stroke in patients with nonvalvular atrial fibrillation is the oral agent Warfarin while dabigatran is a new alternative which does not require prothrombin time monitoring.
If studies show carotid stenosis, and the patient has residual function in the affected side, carotid endarterectomy (surgical removal of the stenosis) may decrease the risk of recurrence if performed rapidly after stroke.
Treatment of hemorrhagic stroke
Patients with intracerebral hemorrhage require neurosurgical evaluation to detect and treat the cause of the bleeding, although many may not need surgery. Anticoagulants and antithrombotics, key in treating ischemic stroke, can make bleeding worse and cannot be used in intracerebral hemorrhage. Patients are monitored for changes in the level of consciousness, and their blood pressure, blood sugar, and oxygenation are kept at optimum levels.
Care and rehabilitation
Stroke rehabilitation is the process by which patients with disabling strokes undergo treatment to help them return to normal life as much as possible by regaining and relearning the skills of everyday living. It also aims to help the survivor understand and adapt to difficulties, prevent secondary complications and educate family members to play a supporting role.
A rehabilitation team is usually multidisciplinary as it involves staff with different skills working together to help the patient. These include nursing staff, physiotherapy, occupational therapy, speech and language therapy, and usually a physician trained in rehabilitation medicine. Some teams may also include psychologists, social workers, and pharmacists since at least one third of the patients manifest post stroke depression. Validated instruments such as the Barthel scale may be used to assess the likelihood of a stroke patient being able to manage at home with or without support subsequent to discharge from hospital.
Good nursing care is fundamental in maintaining skin care, feeding, hydration, positioning, and monitoring vital signs such as temperature, pulse, and blood pressure. Stroke rehabilitation begins almost immediately.
For most stroke patients, physical therapy (PT) and occupational therapy (OT), speech-language pathology (SLP) are the cornerstones of the rehabilitation process. Often, assistive technology such as a wheelchair, walkers, canes, and orthosis may be beneficial. PT and OT have overlapping areas of working but their main attention fields are; PT involves re-learning functions as transferring, walking and other gross motor functions. OT focusses on exercises and training to help relearn everyday activities known as the Activities of daily living (ADLs) such as eating, drinking, dressing, bathing, cooking, reading and writing, and toileting. Speech and language therapy is appropriate for patients with the speech production disorders: dysarthria and apraxia of speech, aphasia, cognitive-communication impairments and/or dysphagia (problems with swallowing).
Patients may have particular problems, such as complete or partial inability to swallow, which can cause swallowed material to pass into the lungs and cause aspiration pneumonia. The condition may improve with time, but in the interim, a nasogastric tube may be inserted, enabling liquid food to be given directly into the stomach. If swallowing is still deemed unsafe, then a percutaneous endoscopic gastrostomy (PEG) tube is passed and this can remain indefinitely.
Stroke rehabilitation should be started as quickly as possible and can last anywhere from a few days to over a year. Most return of function is seen in the first few months, and then improvement falls off with the "window" considered officially by U.S. state rehabilitation units and others to be closed after six months, with little chance of further improvement. However, patients have been known to continue to improve for years, regaining and strengthening abilities like writing, walking, running, and talking. Daily rehabilitation exercises should continue to be part of the stroke patient's routine. Complete recovery is unusual but not impossible and most patients will improve to some extent : proper diet and exercise are known to help the brain to recover.
Disability affects 75% of stroke survivors enough to decrease their employability. Stroke can affect patients physically, mentally, emotionally, or a combination of the three. The results of stroke vary widely depending on size and location of the lesion. Dysfunctions correspond to areas in the brain that have been damaged.
Some of the physical disabilities that can result from stroke include muscle weakness, numbness, pressure sores, pneumonia, incontinence, apraxia (inability to perform learned movements), difficulties carrying out daily activities, appetite loss, speech loss, vision loss, and pain. If the stroke is severe enough, or in a certain location such as parts of the brainstem, coma or death can result.
Emotional problems resulting from stroke can result from direct damage to emotional centers in the brain or from frustration and difficulty adapting to new limitations. Post-stroke emotional difficulties include anxiety, panic attacks, flat affect (failure to express emotions), mania, apathy, and psychosis.
30 to 50% of stroke survivors suffer post stroke depression, which is characterized by lethargy, irritability, sleep disturbances, lowered self esteem, and withdrawal. Depression can reduce motivation and worsen outcome, but can be treated with antidepressants.
Emotional lability, another consequence of stroke, causes the patient to switch quickly between emotional highs and lows and to express emotions inappropriately, for instance with an excess of laughing or crying with little or no provocation. While these expressions of emotion usually correspond to the patient's actual emotions, a more severe form of emotional lability causes patients to laugh and cry pathologically, without regard to context or emotion. Some patients show the opposite of what they feel, for example crying when they are happy. Emotional lability occurs in about 20% of stroke patients.
Cognitive deficits resulting from stroke include perceptual disorders, speech problems, dementia, and problems with attention and memory. A stroke sufferer may be unaware of his or her own disabilities, a condition called anosognosia. In a condition called hemispatial neglect, a patient is unable to attend to anything on the side of space opposite to the damaged hemisphere.
Up to 10% of all stroke patients develop seizures, most commonly in the week subsequent to the event; the severity of the stroke increases the likelihood of a seizure.
Stroke could soon be the most common cause of death worldwide. Stroke is currently the second leading cause of death in the Western world, ranking after heart disease and before cancer, and causes 10% of deaths worldwide. Geographic disparities in stroke incidence have been observed, including the existence of a "stroke belt" in the southeastern United States, but causes of these disparities have not been explained.
The incidence of stroke increases exponentially from 30 years of age, and etiology varies by age. Advanced age is one of the most significant stroke risk factors. 95% of strokes occur in people age 45 and older, and two-thirds of strokes occur in those over the age of 65. A person's risk of dying if he or she does have a stroke also increases with age. However, stroke can occur at any age, including in childhood.
Family members may have a genetic tendency for stroke or share a lifestyle that contributes to stroke. Higher levels of Von Willebrand factor are more common amongst people who have had ischemic stroke for the first time. The results of this study found that the only significant genetic factor was the person's blood type. Having had a stroke in the past greatly increases one's risk of future strokes.
Men are 25% more likely to suffer strokes than women, yet 60% of deaths from stroke occur in women. Since women live longer, they are older on average when they have their strokes and thus more often killed (NIMH 2002). Some risk factors for stroke apply only to women. Primary among these are pregnancy, childbirth, menopause and the treatment thereof (HRT).
Hippocrates first described the sudden paralysis that is often associated with stroke. Episodes of stroke and familial stroke have been reported from the 2nd millennium BC onward in ancient Mesopotamia and Persia. Hippocrates (460 to 370 BC) was first to describe the phenomenon of sudden paralysis that is often associated with ischemia. Apoplexy, from the Greek word meaning "struck down with violence,â€ first appeared in Hippocratic writings to describe this phenomenon.
The word stroke was used as a synonym for apoplectic seizure as early as 1599, and is a fairly literal translation of the Greek term.
In 1658, in his Apoplexia, Johann Jacob Wepfer (1620â€“1695) identified the cause of hemorrhagic stroke when he suggested that people who had died of apoplexy had bleeding in their brains. Wepfer also identified the main arteries supplying the brain, the vertebral and carotid arteries, and identified the cause of ischemic stroke [also known as cerebral infarction] when he suggested that apoplexy might be caused by a blockage to those vessels.
Rudolf Virchow first described the mechanism of thromboembolism as a major factor.
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Coenzyme Q10, also known as ubiquinone, ubidecarenone, coenzyme Q, and abbreviated at times to CoQ10, CoQ, Q10, or Q, is a 1,4-benzoquinone, where Q refers to the quinone chemical group, and 10 refers to the number of isoprenyl chemical subunits in its tail.
This oil soluble, vitamin like substance is present in most eukaryotic cells, primarily in the mitochondria. It is a component of the electron transport chain and participates in aerobic cellular respiration, generating energy in the form of ATP. Ninety five percent of the human body's energy is generated this way. Therefore, those organs with the highest energy requirements - such as the heart, liver and kidney - have the highest CoQ10 concentrations. There are three redox states of Coenzyme Q10: fully oxidized (ubiquinone), semiquinone (ubisemiquinone), and fully reduced (ubiquinol). The capacity of this molecule to exist in a completely oxidized form and a completely reduced form enables it to perform its functions in electron transport chain and as an antioxidant respectively.
1 Discovery and History
2 Chemical properties
3 Biochemical role
3.1 CoQ10 and Electron Transport chain
3.2 Antioxidant Function of CoQ10
5 Absorption and metabolism
6 CoQ10 Deficiency and Toxicity
6.1 Clinical assessment techniques
6.2 Factors affecting CoQ levels
6.3 Inhibition by statins and beta blockers
7.1 Improving the bioavailability of CoQ10
7.1.1 Reduction of particle size
7.1.2 Softgel capsules with CoQ10 in oil suspension
7.1.3 Novel forms of CoQ10 with increased water solubility
8 Supplementation benefits
8.1 Mitochondrial disorders
8.2 Heart health
8.3 Migraine headaches
8.5 Cardiac arrest
8.6 Blood pressure
8.7 Periodontal disease
8.9 Radiation injury
8.10 Parkinson's disease
9 Coenzyme Q10 concentrations in foods and dietary intake
9.2 Effect of heat and processing
10 See also
12 External links
Discovery and History
Coenzyme Q10 was first discovered by Professor Fredrick L. Crane and colleagues at the University of Wisconsin - Madison Enzyme Institute in 1957. In 1958, its chemical structure was reported by Dr. Karl Folkers and coworkers at Merck; in 1968, Folkers became a Professor in the Chemistry Department at the University of Texas at Austin.In 1961 Peter Mitchel proposed the electron transport chain (which includes the vital protonmotive role of CoQ10) and he received a Nobel prize for the same in 1978. In 1972, Gian Paolo Littarru and Karl Folkers separately demonstrated a deficiency of CoQ10 in human heart disease. The 1980s witnessed a steep rise in the number of clinical trials due to the availability of large quantities of pure CoQ10 and methods to measure plasma and blood CoQ10 concentrations. The antioxidant role of the molecule as a free radical scavenger was widely studied by Lars Ernster. Numerous scientists around the globe started studies on this molecule since then in relation to various diseases including cardiovascular diseases and cancer.
The oxidized structure of CoQ10 is shown on the top right. The various kinds of Coenzyme Q can be distinguished by the number of isoprenoid subunits in their side chains. The most common Coenzyme Q in human mitochondria is CoQ10. Q refers to the quinone head and 10 refers to the number of isoprene repeats in the tail. The image below has three isoprenoid units and would be called Q3.
Electron transport chain ("UQ" visible in green near center). CoQ10 is found in the membranes of many organelles. Since its primary function in cells is in generating energy, the highest concentration is found on the inner membrane of the mitochondrion. Some other organelles that contain CoQ10 include endoplasmic reticulum, peroxisomes, lysosomes, and vesicles. In its reduced form (ubiquinol), Coenzyme Q10 acts as an important antioxidant in the body.
CoQ10 and Electron Transport chain
CoQ10, fat soluble and therefore mobile in cellular membranes, plays a unique role in the electron transport chain (ETC). In the inner mitochondrial membrane electrons from NADH and succinate pass through the ETC to the oxygen, which is then reduced to water. The transfer of electrons through ETC results in the pumping of H+ across the membrane creating a proton gradient across the membrane, which is used by ATP synthase (located on the membrane) to generate ATP. CoQ10 functions as an electron carrier from enzyme complex I and enzyme complex II to complex III in this process. This is crucial in the process, since no other molecule can perform this function. Thus, CoQ10 functions in every cell of the body to synthesize energy.
Antioxidant Function of CoQ10
The antioxidant nature of CoQ10 derives from its energy carrier function. As an energy carrier, the CoQ10 molecule is continuously going through an oxidation reduction cycle. As it accepts electrons, it becomes reduced. As it gives up electrons, it becomes oxidized. In its reduced form, the CoQ10 molecule holds electrons rather loosely, so this CoQ molecule will quite easily give up one or both electrons and, thus, act as an antioxidant. CoQ10 inhibits lipid peroxidation by preventing the production of lipid peroxyl radicals (LOO). Moreover, CoQH2 reduces the initial perferryl radical and singlet oxygen, with concomitant formation of ubisemiquinone and H2O2. This quenching of the initiating perferryl radicals, which prevent propagation of lipid peroxidation, protects not only lipids, but also proteins from oxidation. In addition, the reduced form of CoQ effectively regenerates vitamin E from the a - tocopheroxyl radical and, thereby interfering with the propagation step. Furthermore, during oxidative stress, interaction of H2O2 with metal ions bound to DNA generates hydroxyl radicals and CoQ efficiently prevents the oxidation of bases, in particular, in mitochondrial DNA (10). In contrast to other antioxidants, this compound inhibits both the initiation and the propagation of lipid and protein oxidation. It also regenerates other antioxidants such as vitamin E. The circulating CoQ10 in LDL prevents oxidation of LDL, therefore, by providing its benefits in cardiovascular diseases.
Starting from acetyl - CoA, a multistep process of mevalonate pathway produces farnesyl - PP (FPP), the precursor for cholesterol, CoQ, dolichol, and isoprenylated proteins. An important enzyme in this pathway is HMG Co A reductase, which is usually a target for intervention in cardiovascular complications. The long isoprenoid side chain of CoQ is synthesized by trans prenyltransferase, which condenses FPP with several molecules of isopentenyl PP (IPP), all in the trans configuration (11). The next step involves condensation of this polyisoprenoid side chain with 4 hydroxybenzoate, catalyzed by polyprenyl 4 hydroxy benzoate transferase. Hydroxybenzoate is synthesized from tyrosine or phenylalanine. In addition to their presence in mitochondria, these initial two reactions also occur in the endoplasmic reticulum and peroxisomes, indicating multiple sites of synthesis in animal cells (12). Increasing the endogenous biosynthesis of CoQ10 has attained attention in the recent years as a strategy to fight CoQ10 deficiency.
Genes involved include PDSS1, PDSS2, COQ2, and COQ8, CABC1.(13)
Absorption and metabolism
Absorption. CoQ10 is a crystalline powder that is insoluble in water. Absorption follows the same process as that of lipids and the uptake mechanism appears to be similar to that of vitamin E, another lipid soluble nutrient. This process in the human body involves the secretion of pancreatic enzymes and bile into the small intestines that facilitate emulsification and micelle formation that is required for the absorption of lipophilic substances. Food intake (and the presence of lipids) stimulates bodily biliary excretion of bile acids and greatly enhances the absorption of CoQ10. Exogenous CoQ10 is absorbed from the small intestinal tract and is best absorbed if it is taken with a meal. Serum concentration of CoQ10 in fed condition is higher than in fasting conditions.
Metabolism. Data on the metabolism of CoQ10 in animals and humans are limited. A study with 14C labeled CoQ10 in rats showed most of the radioactivity in the liver 2 hours after oral administration when the peak plasma radioactivity was observed, but it should be noted that CoQ9 is the predominant form of coenzyme Q in rats. It appears that CoQ10 is metabolised in all tissues, while a major route for its elimination is biliary and fecal excretion. After the withdrawal of CoQ10 supplementation, the levels return to normal within a few days, irrespective of the type of formulation used.
CoQ10 Deficiency and Toxicity
There are three major factors that lead to deficiency of CoQ10 in humans: insufficient dietary CoQ10, reduced biosynthesis, and increased utilization by the body. The literature is still inconclusive about whether biosynthesis or dietary intake is the major source of CoQ10. However, the biosynthesis is a multistep process requiring many other nutrients, and so a diet low in nutrients may lead to decreased biosynthesis. This implies that the normal levels established now may be suboptimal, given the fact that suboptimal nutrient intake is almost universal in humans. Biosynthesis also can be affected by aging and certain medications (statins, blood thinners, etc.). Some chronic disease conditions (cancer, heart disease, etc.) reduce the biosynthesis and increases the demand for CoQ10 in the body. Recent evidences suggest that mutations in some genes also lead to CoQ10 deficiency. Products of these genes are thought to be involved in the metabolic pathway leading to CoQ10 production. Toxicity is not usually observed with high doses of CoQ10. A daily dosage up to 3600 mg was found to be tolerated by healthy as well as unhealthy persons. However, some adverse effects are reported with very high intakes. They are mostly gastrointestinal problems. The observed safe level(OSL) risk assessment method indicated that the evidence of safety is strong at intakes up to 1200 mg per day, and this level is identified as the OSL.
Clinical assessment techniques
The routine clinical assessment of CoQ10 status is, in general, based on plasma measurements. Since CoQ10 is synthesised endogenously also, plasma concentrations may not adequately represent cellular concentrations. Other suitable targets that can act as surrogates for tissue CoQ10 levels are being investigated. Blood cells are considered to be a good target for analysing intracellular CoQ10 levels.
Factors affecting CoQ levels
Various factors reduce the concentration of CoQ10 in different organs; the following are known:
Use of statins reduce CoQ10 levels - see below.
Aging, in individuals older than 20 years, reduces CoQ10 levels in internal organs.
UV exposure reduces CoQ10 levels in the skin.
 Inhibition by statins and beta blockersCoenzyme Q10 shares a common biosynthetic pathway with cholesterol. The synthesis of an intermediary precursor of coenzyme Q10, mevalonate, is inhibited by some beta blockers, blood pressure lowering medication, and statins, a class of cholesterol lowering drugs. Statins can reduce serum levels of coenzyme Q10 by up to 40%. Some research suggests the logical option of supplementation with coenzyme Q10 as a routine adjunct to any treatment that may reduce endogenous production of coenzyme Q10, based on a balance of likely benefit against very small risk.
Some reports have been published on the pharmacokinetics of CoQ10. The plasma peak can be observed 2 - 6 hours after oral administration, mainly depending on the design of the study. In some studies, a second plasma peak was also observed at about 24 hours after administration, probably due to both enterohepatic recycling and redistribution from the liver to circulation. Tomono et al. used deuterium labelled crystalline CoQ10 to investigate pharmacokinetics in human and determined an elimination half time of 33 hours.
Improving the bioavailability of CoQ10
The importance of how drugs are formulated for bioavailability is well known. In order to find a principle to boost the bioavailability of CoQ10 after oral administration, several new approaches have been taken and different formulations, and forms have been developed and tested on animals or humans.
Reduction of particle size
The obvious strategy is reduction of the particle size to as low as the micro and nano scale. Nanoparticles have been explored as a delivery system for various drugs and an improvement of the oral bioavailability of drugs with poor absorption characteristics has been reported; the pathways of absorption and the efficiency were affected by reduction of particle size. This protocol has so far not proved to be very successful with CoQ10, although reports have differed widely. The use of the aqueous suspension of finely powdered CoQ10 in pure water has also revealed only a minor effect.
Softgel capsules with CoQ10 in oil suspension
A successful approach was to use the emulsion system to facilitate absorption from the gastrointestinal tract and to improve bioavailability. Emulsions of soybean oil (lipid microspheres) could be stabilised very effectively by lecithin and were utilised in the preparation of soft gelatine capsules. In one of the first such attempts, Ozawa et al. performed a pharmacokinetic study on beagle dogs in which the emulsion of CoQ10 in soybean oil was investigated; about two times higher plasma CoQ10 level than that of the control tablet preparation was determined during administration of a lipid microsphere. Although an almost negligible improvement of bioavailability was observed by Kommuru et al. with oil-based soft-gel capsules in a later study on dogs, the significantly increased bioavailability of CoQ10 was confirmed for several oil based formulations in most other studies.
Novel forms of CoQ10 with increased water solubility
Facilitating drug absorption by increasing its solubility in water is a common pharmaceutical strategy and has also been shown to be successful for Coenzyme Q10. Various approaches have been developed to achieve this goal, with many of them producing significantly better results over oil based soft gel capsules in spite of the many attempts to optimize their composition. Examples of such approaches are use of the aqueous dispersion of solid CoQ10 with tyloxapol polymer, formulations based on various solubilising agents, i.e., hydrogenated lecithin, and complexation with cyclodextrins; among the latter, complex with cyclodextrin has been found to have highly increased bioavailability. and is also used in pharmaceutical and food industry for CoQ10-fortification. Also some other novel carrier systems like liposomes, nanoparticles, dendrimers etc. can be used to increase the bioavailability of Coenzyme Q10.
Coenzyme Q10 is the 3rd most sold dietary ingredient in the United States after Omega 3 and multivitamins.
According to the Mayo Clinic, "CoQ10 has been used, recommended, or studied for numerous conditions, but remains controversial as a treatment in many areas." Further clinical results are needed to determine whether supplementation with coenzyme Q10 is beneficial for healthy people.
Mitochondrial disorders Supplementation of coenzyme Q10 is a treatment for some of the very rare and serious mitochondrial disorders and other metabolic disorders, where patients are not capable of producing enough coenzyme Q10 because of their disorder. Coenzyme Q10 is then prescribed by a physician.
Coenzyme Q10 helps to maintain a healthy cardiovascular system. There is evidence of CoQ10 deficiency in heart failure. Recently, CoQ10 plasma concentrations have been demonstrated as an independent predictor of mortality in chronic heart failure, CoQ10 deficiency being detrimental to the long term prognosis of chronic heart failure. CoQ10 is available as medicine in several European countries, but is in these countries also available as a food supplement. Oxidation of the circulating LDL is thought to play a key role in the pathogenesis of atherosclerosis, which is the underlying disorder leading to heart attack and ischemic strokes and CHD. Studies in the last decade have demonstrated that the content of Ubiquinol in human LDL affords protection against the oxidative modifications of LDL themselves, thus lowering their atherogenic potency.
Supplementation of coenzyme Q10 has been found to have a beneficial effect on the condition of some sufferers of migraine headaches. So far, three studies have been done, of which two were small, did not have a placebo group, were not randomized, and were open label, and one was a double blind, randomized, placebo controlled trial, which found statistically significant results despite its small sample size of 42 patients. Dosages were 150 to 300 mg/day.
It has been used effecitvely in the prophylaxis of migraines, especially in combination with a daily supplement of magnesium citrate 500 mg and riboflavin (vitamin B2) 400 mg.
CoQ10 is also being investigated as a treatment for cancer, and as relief from cancer treatment side effects.
Another recent study shows a survival benefit after cardiac arrest if coenzyme Q10 is administered in addition to commencing active cooling of the body to 90 to 93 degrees Fahrenheit (32 to 34 degrees Celsius).
There are several reports concerning the effect of CoQ10 on blood pressure in human studies.
A recent (2007) meta-analysis of the clinical trials of CoQ10 for hypertension reviewed all published trials of coenzyme Q10 for hypertension, and assessed overall efficacy, consistency of therapeutic action, and side-effect incidence. Meta-analysis was performed in 12 clinical trials (362 patients) comprising three randomized controlled trials, one crossover study, and eight open-label studies. The meta-analysis concluded that coenzyme Q10 has the potential in hypertensive patients to lower systolic blood pressure by up to 17 mm Hg and diastolic blood pressure by up to 10 mm Hg without significant side-effects.
Studies have shown that diseased gum tissue is deficient in CoQ10 compared to healthy gum tissue. Human clinical trials have suggested a link between oral administration of CoQ10 and improved gingival health, immune response in gum tissues, and a reversal of the diseased gum conditions. In addition to oral supplementation, topical application of CoQ10 on gum tissues has been shown to improve periodontitis and gingivitis conditions.
One study demonstrated that low dosages of coenzyme Q10 reduce oxidation and DNA double-strand breaks, and a combination of a diet rich in polyunsaturated fatty acids and coenzyme Q10 supplementation leads to a longer lifespan in rats. Coles and Harris demonstrated an extension in the lifespan of rats when they were given coenzyme Q10 supplementation. But multiple studies have since found no increase in lifespan or decrease in aging in mice and rats supplemented with coenzyme Q10. Another study demonstrated that coenzyme Q10 extends the lifespan of C. elegans (nematode).
A 2002 study reported that, in rat experiments, coenzyme Q10 taken as dietary supplement reduced radiation damage to the animals' blood.
A 2002 study in 80 Parkinson's disease patients found 1200 mg/day reduced the progression by 44%. and a phase III trial of 1200 mg/d and 2400 mg/d should run until 2011.
Coenzyme Q10 concentrations in foods and dietary intake
Detailed reviews on occurrence of CoQ10 and dietary intake were published recently. Besides endogenous synthesis, CoQ10 is also supplied to the organism by various foods. However, despite the scientific community's great interest in this compound, a very limited number of studies have been performed to determine the contents of CoQ10 in dietary components. The first reports on this issue were published in 1959, but the sensitivity and selectivity of the analytical methods at that time did not allow reliable analyses, especially for products with low concentrations. Developments in analytical chemistry have since enabled a more reliable determination of CoQ10 concentrations in various foods (Table below).
CoQ10 levels in selected foods  Food Coenzyme Q10 concentration [mg/kg]
liver 39 to 50
muscle 26 to 40
heart 11.8 to 128.2
liver 22.7 to 54.0
muscle 13.8 to 45.0
heart 116.2 to 132.2
sardine 5 to 64
red flesh 43 to 67
white flesh 11 to 16
salmon 4 to 8
soybean 54 to 280
olive 4 to 160
grapeseed 64 to 73
sunflower 4 to 15
sesame seeds 18 to 23
pistachio nuts 20
almond 5 to 14
parsley 8 to 26
broccoli 6 to 9
cauliflower 2 to 7
spinach up to 10
grape 6 to 7
Chinese cabbage 2 to 5
orange 1 to 2
Meat and fish are the richest source of dietary CoQ10 and levels over 50 mg/kg can be found in beef, pork and chicken heart, and chicken liver. Dairy products are much poorer sources of CoQ10 compared to animal tissues. Vegetable oils are also quite rich in CoQ10. Within vegetables, parsley, and perilla are the richest CoQ10 sources, but significant differences in their CoQ10 levels can be found in the literature. Broccoli, grape, and cauliflower are modest sources of CoQ10. Most fruit and berries represent a poor to very poor source of CoQ10, with the exception of avocado, with a relatively high CoQ10 content.
In the developed world, the estimated daily intake of CoQ10 has been determined at 3 to 6 mg per day, derived primarily from meat.
Effect of heat and processing
Cooking by frying reduces CoQ10 content by 14 to 32%.
Idebenone - synthetic analog with reduced oxidant generating properties
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