Aneurysms — balloon-like weakness of the blood vessels — are especially dangerous in the brain. While some pose no threat, others are at risk for bleeding and/or can steadily grow. They balloon out and fill with blood. This may compress nerves and tissues, triggering headaches and facial numbness.
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The worst-case scenario: Aneurysms can hemorrhage or burst, flooding the brain with blood. “This causes a really devastating type of stroke that, for one-third of patients, is potentially life-ending,” says neurosurgeon Peter Rasmussen, MD. Doctors treat aneurysms to prevent stroke in three major ways:
- Cerebral Aneurysms Fact Sheet
- What is a cerebral aneurysm?
- What are the symptoms?
- How are aneurysms classified?
- What causes a cerebral aneurysm?
- How are cerebral aneurysms diagnosed?
- What are the complications of a ruptured cerebral aneurysm?
- How are cerebral aneurysms treated?
- What is the prognosis?
- What research is being done?
- Where can I get more information?
- Ruptured brain aneurysm
- What is a ruptured aneurysm?
- What are the symptoms?
- What are the causes?
- Who is affected?
- How is a diagnosis made?
- What treatments are available?
- Clinical trials
- Recovery and prevention
- Sources & links
- How a surgeon cured a young girl’s “incurable” brain aneurysm
- Curcumin Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm by Inhibition of Inflammatory Response and ERK Signaling Pathways
- 1. Introduction
- 2. Materials and Methods
- 2.1. Ethics Statement
- 2.2. Animal Modal
- 2.3. Aortic Diameter Measurement and Aneurysms Diagnosis
- 2.4. Specimen Preparation and Staining
- 2.5. Immunohistochemistry
- 2.6. RT-PCR
- 2.7. Gelatin Zymography
- 2.8. Measurements of SOD and MDA Assays
- 2.9. Western Blot
- 2.10. Serum Lipids and Blood Pressure Measurement
- 2.11. Statistical Analysis
- 3. Results
- 3.1. Curcumin Reduced the Incidence and Severity of AngII-Induced AAA Formation in ApoE−/− Mice
- 3.2. Curcumin Decreased Remodeling of Aortic Wall and Inhibited Inflammatory Response in AngII-Induced AAA
- 3.3. Curcumin Inhibited MMP-2 and MMP-9 Expression and Activity
- 3.4. Curcumin Diminished ROS and ERK Signaling Pathways
- 3.5. Blood Pressure and Biological Measurements
- 4. Discussion
- Conflict of Interests
- Abdominal aortic aneurysms repaired without surgical incisions
- Comprehensive Stroke Program
- What is a brain aneurysm?
- Diagnosis of Brain Aneurysm
- Treatment of Brain Aneurysm
- Warning Signs/ Symptoms of Brain Aneurysm
- Frequently asked Questions About Brain Aneurysms
1. Surgical clipping
The most traditional procedure, surgical clipping requires general anesthesia and starts with an incision in your scalp.
“We make an opening, or a window, in the skull,” explains Dr. Rasmussen. “Using a powerful surgical microscope armed with a bright light, we locate the aneurysm, place a small metal spring-clip on it, and pinch it off.” After confirming the repair, surgeons close the wound.
“It may seem like a lot to go through,” he says. “But when you leave the hospital with your aneurysm repaired, you’ll be at exceedingly low — or no — risk of hemorrhage.”
In the mid-1990s, the technology for treating aneurysms advanced quickly. Guided by fluoroscopy or X-rays, surgeons could gently thread catheters through the body’s blood vessels up to the brain. Today, 70 to 80 percent of aneurysm patients can be treated with coiling or other endovascular techniques.
Typically, small, soft platinum coils — mounted on a wire sent through the catheter — are deposited in the aneurysm. “A clot forms around them, sealing the aneurysm from within,” says Dr. Rasmussen. For aneurysms with wide openings, stents can be added to keep the coils in place.
“Patients are briefly hospitalized, have minimal pain or discomfort and can return to work within a few days,” says Dr. Rasmussen.
3. Flow diverter
Giant carotid artery aneurysms once meant complex, lengthy, high-risk surgeries. The arrival of a special stent in the early 2010s changed all that.
“We can cover aneurysms with these stents in about 15 minutes,” says neurosurgeon Mark Bain, MD. “There is very little pain and a quick recovery period.” Cleveland Clinic endovascular neurosurgeons were among the first to use the flow diverter to treat giant aneurysms.
They advance the braided metal mesh tube through a catheter into the brain, lay it across the aneurysm opening, and expand it so that it’s flush with the vessel wall.
“The flow diverter does two things,” says Dr. Bain. “It causes the aneurysm to clot off and keeps an important blood vessel to the brain open.” In about six months, blood flow through the aneurysm ceases, and blood vessel cells grow over the stent to create a permanent seal.
An individual choice
All three procedures have their risks and benefits. And they are equally safe. “Your choice of treatment should be a personal one centered on the type of aneurysm, its location, your medical condition, and what’s right for you as a human being,” says Dr. Rasmussen.
In fact, not all aneurysms require treatment, he points out. Those that pose minimal risk can simply be watched over time.
Cerebral Aneurysms Fact Sheet
What is a cerebral aneurysm?
A cerebral aneurysm (also known as a brain aneurysm) is a weak or thin spot on an artery in the brain that balloons or bulges out and fills with blood. The bulging aneurysm can put pressure on the nerves or brain tissue. It may also burst or rupture, spilling blood into the surrounding tissue (called a hemorrhage). A ruptured aneurysm can cause serious health problems such as hemorrhagic stroke, brain damage, coma, and even death.
Some cerebral aneurysms, particularly those that are very small, do not bleed or cause other problems. These types of aneurysms are usually detected during imaging tests for other medical conditions. Cerebral aneurysms can occur anywhere in the brain, but most form in the major arteries along the base of the skull.
Brain aneurysms can occur in anyone and at any age. They are most common in adults between the ages of 30 and 60 and are more common in women than in men. People with certain inherited disorders are also at higher risk.
All cerebral aneurysms have the potential to rupture and cause bleeding within the brain or surrounding area. Approximately 30,000 Americans per year suffer a brain aneurysm rupture. Much less is known about how many people have cerebral aneurysms, since they don’t always cause symptoms. There are no proven statistics but a consensus of scientific papers indicate that between 3 and 5 percent of Americans may have an aneurysm in their lifetime.
What are the symptoms?
Most cerebral aneurysms do not show symptoms until they either become very large or rupture. Small unchanging aneurysms generally will not produce symptoms.
A larger aneurysm that is steadily growing may press on tissues and nerves causing:
- pain above and behind the eye
- paralysis on one side of the face
- a dilated pupil in the eye
- vision changes or double vision.
When an aneurysm ruptures (bursts), one always experiences a sudden and extremely severe headache (e.g., the worst headache of one’s life) and may also develop:
- double vision
- stiff neck
- sensitivity to light
- loss of consciousness (this may happen briefly or may be prolonged)
- cardiac arrest.
Sometimes an aneurysm may leak a small amount of blood into the brain (called a sentinel bleed). Sentinel or warning headaches may result from an aneurysm that suffers a tiny leak, days or weeks prior to a significant rupture. However, only a minority of individuals have a sentinel headache prior to rupture.
If you experience a sudden, severe headache, especially when it is combined with any other symptoms, you should seek immediate medical attention.
How are aneurysms classified?
There are three types of cerebral aneurysms:
- Saccular aneurysm. A saccular aneurysm is a rounded sac containing blood, that is attached to a main artery or one of its branches. Also known as a berry aneurysm (because it resembles a berry hanging from a vine), this is the most common form of cerebral aneurysm. It is typically found on arteries at the base of the brain. Saccular aneurysms occur most often in adults.
- Fusiform aneurysm. A fusiform aneurysm balloons or bulges out on all sides of the artery.
- Mycotic aneurysm. A mycotic aneurysm occurs as the result of an infection that can sometimes affect the arteries in the brain. The infection weakens the artery wall, causing a bulging aneurysm to form.
Aneurysms are also classified by size: small, large, and giant.
- Small aneurysms are less than 11 millimeters in diameter (about the size of a large pencil eraser).
- Large aneurysms are 11 to 25 millimeters (about the width of a dime).
- Giant aneurysms are greater than 25 millimeters in diameter (more than the width of a quarter).
What causes a cerebral aneurysm?
Cerebral aneurysms form when the walls of the arteries in the brain become thin and weaken. Aneurysms typically form at branch points in arteries because these sections are the weakest. Occasionally, cerebral aneurysms may be present from birth, usually resulting from an abnormality in an artery wall.
Risk factors for developing an aneurysm
Sometimes cerebral aneurysms are the result of inherited risk factors, including:
- genetic connective tissue disorders that weaken artery walls
- polycystic kidney disease (in which numerous cysts form in the kidneys)
- arteriovenous malformations (snarled tangles of arteries and veins in the brain that disrupt blood flow. Some AVMs develop sporadically, or on their own.)
- history of aneurysm in a first-degree family member (child, sibling, or parent).
Other risk factors develop over time and include:
- untreated high blood pressure
- cigarette smoking
- drug abuse, especially cocaine or amphetamines, which raise blood pressure to dangerous levels. Intravenous drug abuse is a cause of infectious mycotic aneurysms.
- age over 40.
Less common risk factors include:
- head trauma
- brain tumor
- infection in the arterial wall (mycotic aneurysm).
Additionally, high blood pressure, cigarette smoking, diabetes, and high cholesterol puts one at risk of atherosclerosis (a blood vessel disease in which fats build up on the inside of artery walls), which can increase the risk of developing a fusiform aneurysm.
Risk factors for an aneurysm to rupture
Not all aneurysms will rupture. Aneurysm characteristics such as size, location, and growth during follow-up evaluation may affect the risk that an aneurysm will rupture. In addition, medical conditions may influence aneurysm rupture.
Risk factors include:
- Smoking. Smoking is linked to both the development and rupture of cerebral aneurysms. Smoking may even cause multiple aneurysms to form in the brain.
- High blood pressure. High blood pressure damages and weakens arteries, making them more likely to form and to rupture.
- Size. The largest aneurysms are the ones most likely to rupture in a person who previously did not show symptoms.
- Location. Aneurysms located on the posterior communicating arteries (a pair of arteries in the back part of the brain) and possibly those on the anterior communicating artery (a single artery in the front of the brain) have a higher risk of rupturing than those at other locations in the brain.
- Growth. Aneurysms that grow, even if they are small, are at increased risk of rupture.
- Family history. A family history of aneurysm rupture suggests a higher risk of rupture for aneurysms detected in family members.
- The greatest risk occurs in individuals with multiple aneurysms who have already suffered a previous rupture or sentinel bleed.
How are cerebral aneurysms diagnosed?
Most cerebral aneurysms go unnoticed until they rupture or are detected during medical imaging tests for another condition.
If you have experienced a severe headache or have any other symptoms related to a ruptured aneurysm your doctor will order tests to determine if blood has leaked into the space between the skull bone and brain.
Several tests are available to diagnose brain aneurysms and determine the best treatment. These include:
- Computed tomography (CT). This fast and painless scan is often the first test a physician will order to determine if blood has leaked into the brain. CT uses x-rays to create two-dimensional images, or “slices,” of the brain and skull. Occasionally a contrast dye is injected into the bloodstream prior to scanning to assess the arteries, and look for a possible aneurysm. This process, called CT angiography (CTA), produces sharper, more detailed images of blood flow in the brain arteries. CTA can show the size, location, and shape of an unruptured or a ruptured aneurysm.
- Magnetic resonance imaging (MRI). An MRI uses computer-generated radio waves and a magnetic field to create two- and three-dimensional detailed images of the brain and can determine if there has been bleeding into the brain. Magnetic resonance angiography (MRA) produces detailed images of the brain arteries and can show the size, location, and shape of an aneurysm.
- Cerebral angiography. This imaging technique can find blockages in arteries in the brain or neck. It also can identify weak spots in an artery, like an aneurysm. The test is used to determine the cause of the bleeding in the brain and the exact location, size, and shape of an aneurysm. Your doctor will pass a catheter (long, flexible tube) typically from the groin arteries to inject a small amount of contrast dye into your neck and brain arteries. The contrast dye helps the X-ray create a detailed picture of the appearance of an aneurysm and a clear picture of any blockage in the arteries.
- Cerebrospinal fluid (CSF) analysis. This test measures the chemicals in the fluid that cushions and protects the brain and spinal cord (cerebrospinal fluid). Most often a doctor will collect the CSF by performing a spinal tap (lumbar puncture), in which a thin needle is inserted into the lower back (lumbar spine) and a small amount of fluid is removed and tested. The results will help detect any bleeding around the brain. If bleeding is detected, additional tests would be needed to identify the exact cause of the bleeding.
What are the complications of a ruptured cerebral aneurysm?
Aneurysms may rupture and bleed into the space between the skull and the brain (subarachnoid hemorrhage) and sometimes into the brain tissue (intracerebral hemorrhage). These are forms of stroke called hemorrhagic stroke. The bleeding into the brain can cause a wide spectrum of symptoms, from a mild headache to permanent damage to the brain, or even death.
After an aneurysm has ruptured it may cause serious complications such as:
- Rebleeding. Once it has ruptured, an aneurysm may rupture again before it is treated, leading to further bleeding into the brain, and causing more damage or death.
- Change in sodium level. Bleeding in the brain can disrupt the balance of sodium in the blood supply and cause swelling in brain cells. This can result in permanent brain damage.
- Hydrocephalus. Subarachnoid hemorrhage can cause hydrocephalus. Hydrocephalus is a buildup of too much cerebrospinal fluid in the brain, which causes pressure that can lead to permanent brain damage or death. Hydrocephalus occurs frequently after subarachnoid hemorrhage because the blood blocks the normal flow of cerebrospinal fluid. If left untreated, increased pressure inside the head can cause coma or death.
- Vasospasm. This occurs frequently after subarachnoid hemorrhage when the bleeding causes the arteries in the brain to contract and limit blood flow to vital areas of the brain. This can cause strokes from lack of adequate blood flow to parts of the brain.
Seizures. Aneurysm bleeding can cause seizures (convulsions), either at the time of bleed or in the immediate aftermath. While most seizures are evident, on occasion they may only be seen by sophisticated brain testing. Untreated seizures or those that do not respond to treatment can cause brain damage.
How are cerebral aneurysms treated?
Not all cerebral aneurysms require treatment. Some very small unruptured aneurysms that are not associated with any factors suggesting a higher risk of rupture may be safely left alone and monitored with MRA or CTA to detect any growth. It is important to aggressively treat any coexisting medical problems and risk factors.
Treatments for unruptured cerebral aneurysms that have not shown symptoms have some potentially serious complications and should be carefully weighed against the predicted rupture risk.
Treatment considerations for unruptured aneurysms
A doctor will consider a variety of factors when determining the best option for treating an unruptured aneurysm, including:
- type, size, and location of the aneurysm
- risk of rupture
- the person’s age and health
- personal and family medical history
- risk of treatment.
Individuals should also take the following steps to reduce the risk of aneurysm rupture:
- carefully control blood pressure
- stop smoking
- avoid cocaine use or other stimulant drugs.
Treatments for unruptured and ruptured cerebral aneurysms
Surgery, endovascular treatments, or other therapies are often recommended to manage symptoms and prevent damage from unruptured and ruptured aneurysms.
There are a few surgical options available for treating cerebral aneurysms. These procedures carry some risk such as possible damage to other blood vessels, the potential for aneurysm recurrence and rebleeding, and a risk of stroke.
- Microvascular clipping. This procedure involves cutting off the flow of blood to the aneurysm and requires open brain surgery. A doctor will locate the blood vessels that feed the aneurysm and place a tiny, metal, clothespin-like clip on the aneurysm’s neck to stop its blood supply. Clipping has been shown to be highly effective, depending on the location, size, and shape of the aneurysm. In general, aneurysms that are completely clipped do not recur.
- Platinum coil embolization. This procedure is a less invasive procedure than microvascular surgical clipping. A doctor will insert a hollow plastic tube (a catheter) into an artery, usually in the groin, and thread it through the body to the brain aneurysm. Using a wire, the doctor will pass detachable coils (tiny spirals of platinum wire) through the catheter and release them into the aneurysm. The coils block the aneurysm and reduce the flow of blood into the aneurysm. The procedure may need to be performed more than once during the person’s lifetime because aneurysms treated with coiling can sometimes recur.
- Flow diversion devices. Other endovascular treatment options include placing a small stent (flexible mesh tube) similar to those placed for heart blockages, in the artery to reduce blood flow into the aneurysm. A doctor will insert a hollow plastic tube (a catheter) into an artery, usually in the groin, and thread it through the body to the artery on which the aneurysm is located. This procedure is used to treat very large aneurysms and those that cannot be treated with surgery or platinum coil embolization.
Other treatments for a ruptured cerebral aneurysm aim to control symptoms and reduce complications. These treatments include:
- Antiseizure drugs (anticonvulsants). These drugs may be used to prevent seizures related to a ruptured aneurysm.
- Calcium channel-blocking drugs. Risk of stroke by vasospasm can be reduced with calcium channel-blocking drugs.
- . A shunt, which funnels cerebrospinal fluid from the brain to elsewhere in the body, may be surgically inserted into the brain following rupture if the buildup of cerebrospinal fluid (hydrocephalus) is causing harmful pressure on surrounding brain tissue.
Rehabilitative therapy. Individuals who have suffered a subarachnoid hemorrhage often need physical, speech, and occupational therapy to regain lost function and learn to cope with any permanent disability.
What is the prognosis?
An unruptured aneurysm may go unnoticed throughout a person’s lifetime and not cause symptoms.
After an aneurysm bursts, the person’s prognosis largely depends on:
- age and general health
- preexisting neurological conditions
- location of the aneurysm
- extent of bleeding (and rebleeding)
- time between rupture and medical attention
- successful treatment of the aneurysm.
About 25 percent of individuals whose cerebral aneurysm has ruptured do not survive the first 24 hours; another 25 percent die from complications within 6 months. People who experience subarachnoid hemorrhage may have permanent neurological damage. Other individuals recover with little or no disability. Diagnosing and treating a cerebral aneurysm as soon as possible will help increase the chances of making a full recovery.
Recovery from treatment or rupture may take weeks to months.
What research is being done?
The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. The NINDS is a component of the National Institutes of Health (NIH), the leading federal supporter of biomedical research in the world. As part of its mission, the NINDS conducts research on cerebral aneurysms and supports studies through grants to medical institutions across the country.
The NINDS-funded International Study of Unruptured Aneurysm Study collected natural history data that guides medical decision-making based on size and location of asymptomatic aneurysms.
Scientists have long known about the link between cerebral and aortic aneurysm (the aorta is the body’s main artery). However, they still do not fully understand the relationship between the two types of aneurysm. Recent genome-wide association studies (GWAS) provide molecular evidence for shared biological function and activities (pathophysiology) of these aneurysms. A specific site on chromosome 9p21 has been identified as increasing the risk for both cerebral and aortic aneurysms. This GWAS data, along with linkage data to other susceptible locations for genes or DNA sequences, indicate that individuals and families harboring one type of aneurysm may be at especially increased risk of the other.
Other scientists are studying additional chromosomes and chromosomal regions to identify aneurysm-related genes.
Cerebral aneurysms located at the posterior communicating artery and in the arteries in the back part of the brain (called the vertebral and basilar arteries) are common and have higher risk of rupture than aneurysms at other locations. NINDS-funded scientists are working to identify the features associated with rupture and use these factors to build a scoring scale to guide and support clinical decisions.
The risk of having an aneurysm burst is difficult to determine and there can be serious complications from surgical treatments. Researchers are developing a new model to diagnose brain aneurysms based on the presence of molecules that can potentially tell whether there is a high chance of an aneurysm burst. This procedure can be done by using brain imaging without the need to open the skull. Not only would this new tool be less invasive, it would also allow for people to be treated before an aneurysm bursts.
Hormones and medication
Studies indicate aspirin lessens inflammation in cerebral aneurysms and reduces the risk of rupture. However, aspirin also inhibits the blood cells (platelets) that are important in stopping bleeding once a rupture occurs. Researchers are using mouse models to examine how inflammation impacts the formation and rupture of cerebral aneurysms, and the molecular mechanisms that contribute to the protective effect of aspirin.
Cerebral aneurysms and subarachnoid hemorrhage are more common in postmenopausal women than in men. Estrogen replacement therapy reduces the risk for subarachnoid hemorrhage in post-menopausal women. Researchers are investigating exactly how estrogen protects women against developing aneurysms. They hypothesize protection primarily occurs through inflammatory cells.
Other research projects include studies of the effectiveness of microsurgical clipping and endovascular surgery to treat ruptured and unruptured aneurysms, the use of various types of coils and other materials to block the flow of blood into the aneurysm, and the influence of blood flow speed and pressure on the success or failure of treatment.
Where can I get more information?
For more information on neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute’s Brain Resources and Information Network (BRAIN) at:
P.O. Box 5801
Bethesda, MD 20824
Information also is available from the following organizations:
“Cerebral Aneurysms Fact Sheet”, NINDS, Publication date May 2018.
NIH Publication No. 18-NS-5506
Back to Cerebral Aneurysms Information Page
See a list of all NINDS disorders
Publicaciones en Español
Office of Communications and Public Liaison
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Bethesda, MD 20892
NINDS health-related material is provided for information purposes only and does not necessarily represent endorsement by or an official position of the National Institute of Neurological Disorders and Stroke or any other Federal agency. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.
All NINDS-prepared information is in the public domain and may be freely copied. Credit to the NINDS or the NIH is appreciated.
Ruptured brain aneurysm
An aneurysm is a balloon-like bulge of an artery wall. As an aneurysm grows it puts pressure on nearby structures and may eventually rupture. A ruptured aneurysm releases blood into the subarachnoid space around the brain. A subarachnoid hemorrhage (SAH) is a life-threatening type of stroke. Treatment focuses on stopping the bleeding and repairing the aneurysm with clipping, coiling, or bypass.
What is a ruptured aneurysm?
An aneurysm is a balloon-like bulge or weakening of an artery wall. (Similar to a balloon on the side of a garden hose.) As the bulge grows it becomes thinner and weaker. It can become so thin that the blood pressure within can cause it to leak or burst open. Aneurysms usually occur on larger blood vessels at the fork where an artery branches off. Types of aneurysms include (Fig. 1):
- Saccular – (most common, also called “berry”) the aneurysm bulges from one side of the artery and has a distinct neck at its base.
- Fusiform – the aneurysm bulges in all directions and has no distinct neck.
- Dissecting – a tear in the inner wall of the artery allows blood to split the layers and pool; often caused by a traumatic injury.
Figure 1. A ruptured aneurysm releases blood into the subarachnoid space around the brain causing a stroke (left). Different types of aneurysms (right).
When an aneurysm bursts, it releases blood into the spaces between the brain and the skull. This space is filled with cerebrospinal fluid (CSF) that bathes and cushions the brain. As blood spreads and clots it irritates the lining of the brain and damages brain cells. At the same time, the area of brain that previously received oxygen-rich blood from the affected artery is now deprived of blood, resulting in a stroke. A subarachnoid hemorrhage (SAH) is life threatening with a 40% risk of death.
Enclosed within the rigid skull, clotted blood and fluid buildup increases pressure that can crush the brain against the bone or cause it to shift and herniate. Blockage of the normal CSF circulation can enlarge the ventricles (hydrocephalus) causing confusion, lethargy, and loss of consciousness.
A complication that occurs 5 to 10 days after aneurysm rupture is vasospasm (Fig. 2). Irritating blood byproducts cause the walls of an artery to spasm and narrow, reducing blood flow to that region of the brain and causing a secondary stroke.
Figure 2. (left) When red blood cells break down, toxins can cause the walls of nearby arteries to spasm and narrow. The larger the SAH, the higher the risk of vasospasm. Figure 3. (right) CT scan shows blood (white star-shape) in the subarachnoid space from a ruptured aneurysm.
What are the symptoms?
Most aneurysms don’t have symptoms until they rupture. Rupture usually occurs while a person is active rather than asleep. If you experience the symptoms of a SAH, call 911 immediately!
- sudden onset of a severe headache (often described as “the worst headache of my life”)
- nausea and vomiting
- stiff neck
- sensitivity to light (photophobia)
- blurred or double vision
- loss of consciousness
What are the causes?
Risk factors for aneurysm rupture include smoking, high blood pressure, drug or alcohol abuse, genetic (family inherited), atherosclerosis, and lifestyle habits.
Who is affected?
About 2 to 5% of Americans may have or develop an aneurysm; of those, 15% have multiple aneurysms. Unruptured aneurysms are more common than ruptured. However, 85% of aneurysms are not diagnosed until after they bleed. Aneurysms are usually diagnosed between ages 35 to 60 and are more common in women.
How is a diagnosis made?
When a person is brought to the emergency room with a suspected ruptured aneurysm, doctors will learn as much as possible about his or her symptoms, current and previous medical problems, medications, and family history. The person’s condition is assessed quickly. Diagnostic tests will help determine the source of the bleeding.
- Computed Tomography (CT) scan is a noninvasive X-ray to view the anatomical structures within the brain and to detect blood in or around the brain (Fig 3). A CT angiography (CTA) involves the injection of contrast into the blood stream to view the arteries of the brain.
- Lumbar puncture is an invasive procedure in which a hollow needle is inserted in the low back to collect cerebrospinal fluid (CSF) from the spinal canal. The CSF is examined to detect blood from a suspected hemorrhage.
- Angiogram is an invasive procedure in which a catheter is inserted into an artery and passed through the blood vessels to the brain. Once the catheter is in place, contrast dye is injected into the bloodstream and x-rays are taken.
- Magnetic Resonance Imaging (MRI) scan is a noninvasive test that uses a magnetic field and radio-frequency waves to give a detailed view of the soft tissues of the brain. An MRA (Magnetic Resonance Angiogram) involves the injection of contrast into the blood stream to examine the blood vessels in addition to structures of the brain.
Your loved one may be unable to make decisions about treatment. So you may need to decide what’s best for him or her. The doctors may refer to the Hunt-Hess SAH scale as an indicator of the patient’s condition.
Hunt-Hess scale grades:
- Alert, no symptoms, mild headache or neck stiffness
- Aware of surroundings, moderate to severe headache, stiff neck, no neurologic defect except cranial nerve palsy
- Drowsy, weakness or partial or severe paralysis on one side of the body
- Dazed, total paralysis on one side of the body
- Comatose, with abnormal posture
What treatments are available?
Treatment may include lifesaving measures, symptom relief, repair of the bleeding aneurysm, and complication prevention. For 10 to 14 days following an aneurysm rupture, the patient will remain in the neuroscience intensive care unit (NSICU), where doctors and nurses can watch closely for signs of renewed bleeding, vasospasm, hydrocephalus, and other potential complications.
Pain medication will be given to alleviate headache and anticonvulsant medication may be prescribed to prevent or treat seizures.
Determining the best treatment for a ruptured aneurysm involves many factors, such as the size and location of the aneurysm as well as how stable is the patient’s current condition.
- Surgical clipping: an opening is cut in the skull, called a craniotomy, to locate the aneurysm. A small clip is placed across the “neck” of the aneurysm to block the normal blood flow from entering (Fig. 4). The clip is made of titanium and remains on the artery permanently.
Figure 4. A titanium clip is placed across the neck of an aneurysm so that the blood flows through the artery (arrow), and not into the aneurysm.
- Endovascular coiling: is performed during an angiogram in the radiology department. A catheter is inserted into an artery in the groin and then passed through the blood vessels to the aneurysm in the brain. Through the catheter, the aneurysm is packed with platinum coils or glue, which prevents blood flow into the aneurysm (Fig. 5).
Figure 5. The aneurysm is packed with platinum coils. The coils induce clotting (embolization), which seals off the aneurysm and prevents blood from entering.
- Artery occlusion and bypass if the aneurysm is large and inaccessible or the artery is too damaged, the surgeon may perform a bypass surgery. A craniotomy is cut to open the skull and clips are placed to completely block (occlude) the artery and aneurysm. The blood flow is then rerouted (bypassed) around the occluded artery by inserting a vessel graft. The graft is a small artery, usually taken from your leg, which is connected above and below the blocked artery so that blood flows through the graft.
Another method is to detach a donor artery from its normal position on the scalp and connect it above the blocked artery inside the skull. This is called a STA-MCA (superficial temporal artery to middle cerebral artery) bypass.
Clotted blood and fluid buildup in the subarachnoid space may cause hydrocephalus and elevated intracranial pressure. Blood pressure is lowered to reduce further bleeding and to control intracranial pressure. Excess cerebrospinal fluid (CSF) and blood may be removed with: 1) a lumbar drain catheter inserted into the subarachnoid space of the spinal canal in the low back, or 2) a ventricular drain catheter, which is inserted into the ventricles of the brain through a small hole in the skull.
Five to 10 days after a SAH, the patient may develop vasospasm. Vasospasm narrows the artery and reduces blood flow to the region of the brain that the artery feeds. Vasospasm occurs in 70% of patients after SAH. Of these, 30% have symptoms that require treatment.
A patient in the NSICU will be closely monitored for signs of vasospasm, which include weakness in an arm or leg, confusion, sleepiness, or restlessness. Transcranial doppler (TCD) ultrasounds are performed routinely to monitor for vasospasm (see SAH). TCDs are used to measure the blood flow through the arteries. This test can show which arteries are in spasm as well as the severity. To prevent vasospasm, patients are given the drug nimodipine while in the hospital. Additionally, the patient’s blood pressure and blood volume will be increased to force blood through the narrowed arteries.
If vasospasm is severe, patients may require an injection of medication directly into the artery to relax and stop the spasm. This is done through a catheter during an angiogram. Sometimes balloon angioplasty is used to stretch open the artery.
Clinical trials are research studies in which new treatments—drugs, diagnostics, procedures, and other therapies—are tested in people to see if they are safe and effective. Research is always being conducted to improve the standard of medical care. Information about current clinical trials, including eligibility, protocol, and locations, are found on the Web. Studies can be sponsored by the National Institutes of Health (see clinicaltrials.gov) as well as private industry and pharmaceutical companies (see www.centerwatch.com).
Recovery and prevention
The possibility of having a second bleed is 22% within the first 14 days after the first bleed. This is why neurosurgeons prefer to treat the aneurysm as soon as it is diagnosed, so that the risk of a rebleed is lessened.
Aneurysm patients may suffer short-term and/or long-term deficits as a result of a rupture or treatment. Some of these deficits may disappear over time with healing and therapy. After a patient is discharged from the hospital, treatment may be continued at a facility that offers personalized rehabilitation therapies following a serious brain injury. A doctor who specializes in rehabilitation will oversee this care, which can include physical, occupational, and speech therapy. The recovery process is long and may take months or years to understand the deficits you incurred and regain function.
If you have more questions, please contact Mayfield Brain & Spine at 800-325-7787 or 513-221-1100.
Brain Aneurysm Foundation
aneurysm: a bulge or weakening of an arterial wall.
coiling: a procedure to insert platinum coils into an aneurysm; performed during an angiogram.
craniotomy: surgical opening in the skull.
embolization: inserting material, coil or glue, into an aneurysm so blood can no longer flow through it.
subarachnoid hemorrhage (SAH): bleeding in the space between the brain and skull; may cause a stroke.
vasospasm: abnormal narrowing or tightening of arteries due to irritation by blood in the subarachnoid space.
updated > 1.2020
reviewed by > Andrew Ringer, MD, Craig Kilburg, MD, Mayfield Clinic, Cincinnati, Ohio
Mayfield Certified Health Info materials are written and developed by the Mayfield Clinic. We comply with the HONcode standard for trustworthy health information. This information is not intended to replace the medical advice of your health care provider.
How a surgeon cured a young girl’s “incurable” brain aneurysm
Jessica, her mom and the medical team who helped save her life. When 15-year-old Jessica Vargas from Cali, Colombia, started getting headaches two years ago, a brain scan told her family something they never wanted or expected to hear: Jessica had a large, complicated congenital aneurysm – a bulging blood vessel in her brain – on an artery that’s difficult to access and impossible to treat. Traditional invasive surgery would almost certainly be fatal, but not treating the aneurysm would be nearly as risky. The aneurysm could burst at any moment, leaving Jessica dead, blind or without the ability to taste or walk. Jessica was young and otherwise healthy, so doctors decided not to operate, monitoring it closely and hoping it would improve on its own. There are almost 500,000 deaths each year caused by brain aneurysms globally. Half of the victims are younger than 50. Ruptured brain aneurysms are fatal in about 40% of cases, but of those who survive, about 66% suffer some permanent neurological deficit. As they monitored the aneurysm, Jessica’s symptoms became more severe. She had difficulty swallowing and found it challenging to eat as she would consistently drop her silverware. “I couldn’t hold things, and I felt I couldn’t swallow well,” Jessica says. “I realized something was wrong with me.” When she had trouble walking, her family rushed her to the ER where a neurologist told Katherine Vargas, Jessica’s mom, there was nothing they could do. “The doctor bent her head, looked at me and said, ‘The girl will lose her sight, her mobility and she will become bedridden until the mass bursts, since it is unavoidable’,” says Katherine. The only alternative was a high-risk surgery. That’s when the medical team contacted Dr. Jorge Holguin, an Interventional Radiologist at Clínica Nuestra, a healthcare partner of Corazón y Aorta in Cali, Colombia. Corazón y Aorta specializes in cardiovascular surgery. They recently acquired an OEC 9900 mobile C-arm from GE Healthcare to perform diagnostic and interventional applications. Dr. Holguin knew he had the expertise and the tools to perform the surgery that could save Jessica’s life. Jessica Vargas pictured with her doctor, Jorge Holguin, an Interventional Radiologist at Clínica Nuestra, a healthcare partner of Corazón y Aorta in Cali, Colombia. “The equipment is enough to perform endovascular treatment and treat Jessica’s congenital disease, which otherwise wouldn’t have a good outcome,” says Dr. Luis Felipe Medina, head of the surgical team and scientific director at Corazón y Aorta in Colombia. The OEC 9900 has special software to amplify images of the aneurysm so doctors can use a catheter to prevent the aneurysm from bursting, a minimally invasive surgery with high success rates. The procedure involves placing a catheter through the groin into the artery containing the aneurysm. Platinum coils are released, which causes the aneurysm to clot, preventing more blood from filling the aneurysm. The equipment also ensures minimum radiation dose, a key consideration for a smaller, younger patient like Jessica. “The doctors were very realistic,” Katherine says. “They told me it was a hard procedure but they were going to try, as Jessica was young and deserves to live.” The surgery was a success. Jessica regained all of her senses, and it took her less than a month to walk again. Today, Jessica is fully healed and living without restrictions. “Jessica’s story is a lucky one,” says Dr. Medina. “Any surgically invasive treatment was impossible for her.” Corazón y Aorta specializes in cardiovascular surgery. They recently acquired an OEC 9900 mobile C-arm from GE Healthcare to perform diagnostic and interventional applications. Dr. Medina continues to use the OEC 9800 and 9900 for several patients at Corazón y Aorta, including those with complex pathologies such as aneurysms and thoracic aorta dissections that need immediate attention. Seeing the success of these procedures, the medical board is providing similar equipment and services in facilities across Cali to complement cardiovascular surgery. Indeed, clinicians throughout Cali are performing new types of minimally invasive interventions, allowing patients to recover more quickly than ever before. Jessica has also been inspired by her medical team. “I want to study neurology and be an example for those who have similar health issues,” she says. “Trust the doctors. They want to do what´s best for us, to help us and save lives.”
Curcumin Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm by Inhibition of Inflammatory Response and ERK Signaling Pathways
Background and Objectives. Curcumin has long been used to treat age-related diseases, such as atherosclerosis and coronary heart disease. In this study, we explored the effects of curcumin on the development of abdominal aortic aneurysm (AAA). Methods. ApoE−/− mice were randomly divided into 3 groups: AngII group, AngII + curcumin (AngII + Cur) group (100 mg/kg/d), and the control group. Miniosmotic pumps were implanted subcutaneously in ApoE−/− mice to deliver AngII for 28 days. After 4-week treatment, abdominal aortas with AAA were obtained for H&E staining, immunohistochemistry, and Western blotting. Results. The results showed that curcumin treatment significantly decreased the occurrence of AAA. The levels of macrophage infiltration, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factors-α (TNF-α) were significantly lower in AngII + Cur group than those in AngII group (all ). The level of superoxide dismutase (SOD) was significantly higher in AngII + Cur group than those in AngII group . The ERK1/2 phosphorylation in AngII + Cur group was significantly lower than that in AngII group . Conclusions. These results suggested that curcumin can inhibit the AngII-induced AAA in ApoE−/− mice, whose mechanisms include the curcumin anti-inflammation, antioxidative stress, and downregulation of ERK signaling pathway.
Abdominal aortic aneurysm (AAA) is a severe disease threatening the human health and often causes death by rupture. The main pathological process of AAA includes (1) increasing inflammatory response, especially the macrophage infiltration and monocyte chemoattractant protein-1 (MCP-1) expression, (2) activating matrix metalloproteinases (MMP) and depredating extracellular matrix, and (3) degeneration of vascular media and damaging or breaking of elastic fiber . It is documented that statins, angiotensin receptor blockers (ARB), tissue inhibitors of metalloproteinases (TIMP), and some traditional Chinese medicines are beneficial for the treatment of AAA. However, no specific medicine can cure the disease. At present, the surgery is the only effective treatment method for AAA.
Recent studies have demonstrated that the renin-angiotensin system (RAS), especially angiotensin II (AngII), plays an important role in the pathogenesis of atherosclerosis and AAA. Lu et al. reported that subcutaneous infusion of AngII increases the size of atherosclerotic plaque and AAA formation in apoE-deficient mice (ApoE−/− mice), suggesting that the imbalance of RAS is involved in the pathogenesis of AAA . The AngII-induced aneurysm formation in ApoE−/− mice mirrors many characteristics of the human AAA, such as increase of inflammatory response, enhancement of MMP activity, depredation of extracellular matrix, and rupture of aortic elastic layer. Furthermore, these studies showed that inhibition of RAS activation prevented AAA formation . Daugherty’s group demonstrated that the AT1 receptor antagonist, losartan, prevented the formation of AAA and AT2 receptor antagonist, PD123319, enhanced the severity of AAA . Another study reported that simvastatin prevented the AngII-induced AAA formation in ApoE−/− mice by inhibiting MMP-2 and MMP-9 activity, MCP-1 protein expression, and ERK activity, indicating that inflammatory response and MAPK activation are involved in the pathogenesis of AAA .
Curcuma is the source of the spice, turmeric, which is widely used in Asian countries, especially in India and China. A number of scientific evidences have demonstrated that curcumin has many beneficial effects on health, including antioxidative and anti-inflammatory effects. Recent study has demonstrated that curcumin has an important role in prevention and treatment of age-related diseases, such as atherosclerosis, coronary heart disease, diabetes mellitus, and others owing to its powerful antioxidant and anti-inflammatory activities . The common characteristics of age-related disease are a low grade inflammatory response driven by oxygen stress and curcumin is believed to participate in age-related diseases by counteracting the inflammatory state and inhibiting oxygen stress production. Therefore, it has been widely used as a daily health supplement and treatment in cardiovascular disease. It was reported that curcumin protects the endothelial cell activity, inhibits vascular smooth muscle cell (VSMC) proliferation, and decreases the inflammatory response in vascular wall . Quiles et al. found that Curcuma longa reduced oxidative stress production and prohibited the development of fatty streaks in aortic arch, thoracic aorta, and abdominal aorta in rabbits fed a high cholesterol diet .
Previous study found that curcumin could inhibit formation of rat aneurysm induced by calcium chloride method , but the result from other studies showed that calcium chloride-induced AAA did not reveal atherosclerotic plaque formation, vascular thrombus, and rupture, all of which represents classical features of human AAA .
The formation of aneurysm induced by the infusion of AngII has characteristic features that are much more similar to the human disease than other models of aneurysm induced by calcium chloride. The calcium chloride-induced AAA in rat only induces the formation of aneurysm, with no consideration of hyperlipidemia, gender, atherosclerosis, thrombus, rupture, and other complicated factors in human disease, but the aneurysm induced by AngII in ApoE−/− mice generally considers atherosclerosis, thrombus, hyperlipidemia, gender, and rupture, and it is more fit for studying the mechanisms and treatment of AAA .
In this study, we established the AAA induced by AngII infusion and then observed the effect of curcumin on the AAA in ApoE−/− mice. We hypothesized that curcumin prevents aneurysm development by inhibiting inflammatory response, MMP activity, and ERK signal pathway activation during AAA formation. We determined the effect of curcumin on the pathogenesis of AAA in ApoE−/− mice. Our results showed that curcumin treatment significantly prevented AAA formation.
2. Materials and Methods
2.1. Ethics Statement
This study conforms to the principles outlined in the Declaration of Helsinki and to Chinese legal dispositions. This experiment was implemented in accordance with the recommendations in the guide for the care and use of laboratory animals published by the People’s Republic of China (document number 55, 2001). All animal procedures were approved by the Committee on the Ethics of Animal Experiments of Shandong University.
2.2. Animal Modal
Male ApoE−/− mice on a C57BL/6J background strain were housed under barrier conditions with food and water. Thirty-six mice (24-week-old male) were randomly divided into 3 groups (, each): AngII alone group (infusion of AngII, 1000 ng/kg/min, Sigma, St. Louis, MO, USA), AngII + Cur group (100 mg/kg/d, Sigma-Aldrich, St. Louis, MO, USA), and control group (infusion of normal saline). The mice were anaesthetized by intraperitoneal injection of ketamine (150 mg/kg) and xylazine (10 mg/kg). Miniosmotic pumps (Alzet Model 2004, Durect Corp, Cupertino, CA, USA) were implanted subcutaneously in mice to deliver AngII (1000 ng/kg/min) or saline for 28 days according to the literature as described previously . Curcumin was dissolved in 1% carboxymethyl cellulose and was applied by daily oral gavage in AngII + Cur group. The curcumin treatment was initiated 1 week before AngII infusion and lasted for 28 days. At the end of experiment, the mice were anesthetized with xylazine 20 mg/kg and ketamine 100 mg/kg and the aortas were isolated for pathology examination.
2.3. Aortic Diameter Measurement and Aneurysms Diagnosis
Following anesthesia with xylazine 20 mg/kg and ketamine 100 mg/kg, the mice were cut open ventrally. Phosphate-buffered saline (PBS) was perfused into left ventricles and exited through the severed auricula dextra. Suprarenal region of abdominal aorta containing AAA was identified between the last pair of intercostal arteries and the right renal branch. After periadventitial tissues were removed from the aortic wall, the aortic wall was photographed and the maximal aortic diameter of the aorta was measured with a caliper. Aneurysms were defined and diagnosed by reference to the previous literature; the aneurysm diagnosis was made when the maximum diameter of the aorta exceeded 50% of the normal diameter.
The average diameter of normal suprarenal aorta in our control mice is ≈0.83 ± 0.04 mm. Therefore, we set a threshold of 1.25 mm as evidence of the incidence of aneurysm formation.
2.4. Specimen Preparation and Staining
The suprarenal region of abdominal aorta containing AAA was perfused with PBS and then either fixed in 10% buffered formalin solution or frozen in liquid nitrogen. For each mouse, one part of abdominal aorta containing AAA was used for histological examination and the other part was used for Western blotting and measurement of the oxidative radical.
The suprarenal aortas used for histological examination were harvested and dehydrated with different gradients of ethanol and then embedded with paraffin. Paraffin-embedded suprarenal aortas were cross-sectioned into pieces 4 μm thick. H&E and Verhoeff Van-Gieson (VVG) staining were performed according to previous routine method.
The suprarenal region of abdominal aorta containing AAAs was serially cross-sectioned. The macrophages infiltration, MCP-1, TNF-α, MMP-2, and MMP-9 expression were analyzed by immunohistochemistry as described previously. The primary antibodies were used as follows: macrophages, MCP-1, TNF-α, and ERK1/2 were identified with a rabbit anti-mouse polyclonal antibody (Abcam, USA). MMP-2 and MMP-9 were detected with a monoclonal antibody (1 : 50, Abcam, USA). The cross-sections were labeled with primary antibodies at 4°C overnight. After washing, the bound antibodies were conjugated with secondary antibodies at 37°C for 1 hour, and then the DAB substrate was administrated and incubated for 1-2 minutes. The sections were counterstained with hematoxylin and the result was acquired with image analysis system (Image-Pro Plus 5.0, Media Cybernetics, USA).
Total RNA was isolated from abdominal aortas containing AAAs using the TriZol method (Invitrogen, USA) according to the manufacturer’s protocol. The concentration of total RNA was quantified by spectrophotometry and the mRNAs were reverse-transcribed into cDNAs using iScript cDNA synthesis kit (Bio-Rad, Hercules, CA). Quantitative real-time RT-PCR was performed with an Applied Lightcycler2.0 detection system (Roche Applied Science, USA) involving the SYBR-based method in 20 μL reaction volume according to the manufacturer’s instructions. The PCR primers of TNF-α, MCP-1, and β-actin are as follows: TNF-α, 5′-CCTGTAGCCCACGTCGTAGC-3′ and 5′-TTGACCTCAGCGCTGAGTTG-3′; MCP-1, 5′-ACTGAAGCCAGCTCTCTCTTCCTC-3′ and 5′-TTCCTTCTTGGGTCAGCACAGAC-3′; β-actin, 5′-TGCTGTCCCTGTAGTCCTCT-3′ and 5′-AGGTCTTTACGGATGTCAACG-3′. Reaction specificity was demonstrated by analyzing melting curves and by gel electrophoresis of the amplicons. The relative changes in gene expression were analyzed using a comparative method described in the applied biosystems user bulletin. The data were analyzed with method.
2.7. Gelatin Zymography
The MMP-2 and MMP-9 activity were evaluated by methods of zymography according to previous literature . Abdominal aortas containing AAAs were homogenized in a buffer containing 50 mM Tris/HCl (pH 7.5), 150 mM NaCl, and 1% Nonidet P-40. The homogenate was centrifuged and the protein concentration was measured by Bradford assay (Bio-Rad, Philadelphia, USA). 20 μg of protein aliquots was used for each zymographic assay. The experiment of gelatine zymography was carried out under nonreducing conditions on 10% SDS-PAGE gel containing 0.1% (w/v) gelatin at 4°C. The gels were washed with a washing buffer containing 2.5% Triton X-100, incubated in reaction buffer (50 mM Tris-HCl, pH 7.4, 0.15 M NaCl, 5 mM CaCl2, 0.02% NaN3, and 0.05% Brij 35) at 37°C for 48 hours, and then stained with 2.5% Coomassie brilliant blue (Sigma Chemical Co., St. Louis, MO, USA). The band intensity was quantified by computer-assisted image analysis (Image-Pro Plus 5.0, Media Cybernetics, USA).
2.8. Measurements of SOD and MDA Assays
The SOD activity in the aneurysm was measured according to the method using a kit (NJBC, Nanjing, China). Tetrazolium salt can be made to form a red formazan dye by superoxide radicals generated by xanthine oxidase and hypoxanthine. The red formazan dye was measured and evaluated at the optical density at 550 nm by a spectrophotometer. The SOD activity was expressed as U/mg protein.
The MDA contents were measured according to thiobarbituric acid method. The procedure was carried out following the manufacturer’s instruction (NJBC, Nanjing, China). The samples were determined at a wavelength of 546 nm using a spectrophotometer, and the results were expressed in terms of nmol/mg protein.
2.9. Western Blot
ERK1/2 protein expression was detected by Western blot analysis. Mouse abdominal aortas containing AAAs were homogenized in a RIPA lysis buffer (Sigma Chemical Co.) containing protease inhibitors (Roche, Germany) and the total protein was extracted and detected. Twenty micrograms of each protein sample was electrophoresed on 14% SDS-PAGE. The protein was transferred onto a polyvinylidene difluoride (PVDF) membrane for 120 min at 250 mA. Following incubation in blocking solution, membranes were hybridized with 1 : 250 dilution of the primary anti-ERK1/2 antibodies (Santa Cruz Biotechnology, USA) overnight at 4°C. The membranes were then incubated with second antibodies for 60 min at room temperature. The visualization of immune-reactive bands was detected by enhanced chemiluminescence reagent. Quantification of the intensities of each band was performed by use of a MSF-300G Scanner (Microtek Lab, Nikon, Japan).
2.10. Serum Lipids and Blood Pressure Measurement
Serum cholesterol, low-density lipoprotein (LDL), and triglyceride (TG) level were measured by an enzymatic assay kit. The blood pressure was measured on mice using noninvasive tail-cuff systems (BP2010AUL, Softron) in the morning. Considering the procedure-induced anxiety, mice were acclimated to the blood pressure monitor and attemperator (TMC-213, Softron) for three days prior to these measurements. On the 27th day, six blood pressure values were taken on each mouse and averaged for analysis.
2.11. Statistical Analysis
Data analysis involved use of SPSS 11.5. Pearson’s chi-squared test was performed to compare the incidence of aneurysm. One way analysis of variance was used to test the difference of means among three groups for continuous variables. A value was considered statistically significant.
3.1. Curcumin Reduced the Incidence and Severity of AngII-Induced AAA Formation in ApoE−/− Mice
To evaluate the effect of curcumin on AngII-stimulated AAA formation, AngII-induced mice were treated with curcumin or vehicle. No aneurysms were present in saline-infused control ApoE−/− mice (). In contrast, the result showed that eleven of 12 (or 92%) of AngII-induced mice developed aortic aneurysms (Figures 1(a) and 1(b)). However, this effect of AngII was statistically decreased in mice treated with curcumin; the result showed that 6 of 12 (or 50%) developed the aortic aneurysms, indicating that curcumin treatment significantly decreased the occurrence of AAA (Figure 1(b)).
(c) Figure 1 Curcumin reduces the incidence of AngII-induced AAA formation in ApoE−/− mice. (a) Representative images of aortas aneurysm in three groups. (b) AAA incidencein two groups. versus AngII group. (c) Aortic diameter. versus AngII group or control group.
There was no statistical difference in the incidence of aneurysm rupture between AngII + Cur group and AngII group (Table 1). The diameter of abdominal aortas in AngII alone group ( mm, ) was significantly higher than that in control group ( mm, , ). In contrast, the administration of curcumin treatment in AngII + Cur group ( mm, , ) significantly decreased the aortic diameter compared to the AngII alone group (Figure 1(c)). The result demonstrated that curcumin treatment obviously attenuated the incidence and protected ApoE−/− mice against AngII-induced AAA formation and development.
|versus AngII or control group.|
Table 1 AAA formation and rupture in 3 groups of mice.
H&E staining from the region of the aorta demonstrated that AngII treatment gives rise to a thickening of the abdominal aortic wall and disruption of the media and adventitia. VVG staining proved the disruption of the elastin fibers in the AngII alone group and AngII + Cur group (Figure 2). However, the adventitial thickness and disruption of the media and adventitia were relatively less marked in AngII + Cur group. There are no intimal thickening and the elastin fibers in control aortas are intact and not disrupted (Figure 2).
(c) Figure 2 Curcumin prevents remodeling of the aortic wall. (a) The upper photos were H&E staining (40x, scale bars equal 200 μm) of abdominal aortic cross-section from each group. (b) The middle photos were VVG elastin staining. Scale bars equal 200 μm (40x, middle). (c) The bottom photos were the magnification of (b). Scale bars equal 20 μm (400x, bottom).
The result showed that AngII-infusion not only induced macrophage infiltration, but also increased MCP-1, TNF-α gene, and protein expression as evaluated by RT-PCR (Figures 3(b) and 3(c)) and immunohistochemical staining (Figures 3(a), 3(d), 3(e), and 3(f)). In contrast, the macrophage infiltration, MCP-1, TNF-α gene expression, and protein expression were significantly lower in AngII + Cur group than those in AngII alone group (all ), indicating that curcumin treatment inhibited the inflammatory response in the pathogenesis of AAA.
(f) Figure 3 Macrophage, MCP-1, and TNF-α gene and protein expression by RT-PCR and immunostaining in three groups. (a) Immunostaining (scale bars equal 20 μm, 400x) of abdominal aortic cross-section in three groups for macrophages (MC, macrophage) (top row), MCP-1 (second row), TNF-α (third row). ((b) and (c)) MCP-1 and TNF-α mRNA expression by real-time RT-PCR, versus AngII group. ((d), (e), and (f)) Quantification of the positive staining area of macrophages, MCP-1, and TNF-α. versus AngII group.
3.3. Curcumin Inhibited MMP-2 and MMP-9 Expression and Activity
The methods of immunohistochemistry and zymography were used to evaluate the MMP-2 and MMP-9 expression and MMP-2 and MMP-9 activity. The result showed that the staining of MMP-2 and MMP-9 by immunohistochemistry was extensive in AngII group as compared with that of AngII + Cur group (Figure 4(a)). The result also revealed that AngII-infusion in AngII group significantly increased the MMP-2 and MMP-9 activity by zymography (Figures 4(b)–4(d)). Conversely, curcumin treatment markedly inhibited MMP-2 and MMP-3 expression and activity in AngII + Cur group (all ).
(d) Figure 4 MMP-2 and MMP-9 protein expression and activity in three groups. (a) Immunostaining (scale bars equal 20 μm, 400x) of abdominal aortic cross-section from AngII, AngII + Cur, and control groups for MMP-2 and MMP-9 protein expression. (b) MMP-2 and MMP-9 activity by zymography. (c) Quantification of the MMP-9 activity. (d) Quantification of the MMP-2 activity. versus AngII group.
3.4. Curcumin Diminished ROS and ERK Signaling Pathways
The result showed that the SOD was lower in AngII alone group compared to that of the control group. In contrast, the level of SOD increased in AngII + Cur group as compared with that of AngII alone group (). In addition, the level of MDA was increased in AngII alone group as compared with that in the control group. Furthermore, curcumin treatment reduced the MDA level, and the level of MDA was statistically lower in AngII + Cur group than that in AngII alone group (Table 2, ). To explain the signaling pathways in aortic aneurysm, the ERK1/2 signaling pathways were evaluated. ERK1/2 phosphorylation in AAA of AngII alone group was significantly higher than that in AngII + Cur group (, Figures 5(b) and 5(c)); the result suggested that curcumin attenuated AAA pathogenesis at least by ERK1/2 signaling pathways.
Table 2 The levels of SOD and MDA in 3 groups of mice.
(c) Figure 5 ERK protein expression by immunohistochemistry and Western blot. (a) ERK protein expression by immunohistochemistry in abdominal aortic cross-section (scale bars equal 20 μm, 400x). (b) ERK protein expression by Western blot. (c) Quantitative analysis of results in (b). versus AngII alone group.
3.5. Blood Pressure and Biological Measurements
Systolic blood pressure was measured in three groups, and the results showed that the systolic blood pressure was significantly higher in AngII alone group and AngII + Cur group than that in control group (), whereas systolic blood pressure was not statistically different between AngII alone group and AngII + Cur group. In addition, there was no significant difference in total cholesterol, LDL, and TG among AngII alone group, AngII + Cur group, and control group (Table 3).
Table 3 Effect of curcumin on serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), systolic blood pressure, and heart rate levels in 3 groups of mice.
In the present study, we found that the incidence of AAA was significantly lower in AngII + Cur group than that in AngII alone group. Moreover, we demonstrated that the benefit of curcumin treatment on AAA is associated with the reduction of inflammatory response, decreased MMP-2 and MMP-9 activities, and inhibited ROS production. Furthermore, we reported that curcumin inhibits ERK phosphorylation in AAA.
RAS plays an important role in the pathogenesis of atherosclerosis and AAA. Previous studies have shown that AngII infusion induced AAA formation in ApoE−/− mice. In line with the previous findings, our results demonstrated that AngII infusion increased the rates of AAA formation in ApoE−/− mice. Thus, the AngII-induced AAA offered a good model to investigate the mechanism and pathogenesis of AAA in humans .
Inflammation response and the local chronic inflammation of the aortic wall are characterized signs in the pathogenesis of AAAs . Macrophage accumulation in the aortic wall is an early feature of AngII-induced AAAs and it presents in the whole process of AAA.
Our studies found that infusion of AngII induces marked inflammatory responses in the AAA which manifests increased macrophage infiltration and MCP-1 expression. However, curcumin administration inhibited MCP-1 expression and macrophage accumulation. In addition, curcumin also decreased TNF-α and IL-1 protein expression. Previous study also showed that curcumin decreased IL-1 and IL-6 level in C57Bl/6 mice induced AAAs with transient elastase perfusion ; the above result indicated that curcumin may prevent the formation of AAA by anti-inflammatory function.
It is well documented that MMPs play an essential role in the pathogenesis of AAA . MMPs are main enzymes that degrade the structural components of the ECM, and the formation and progression of AAA are accompanied by degradation of vascular ECM. Previous studies have shown that MMP activity is elevated in AAA. The level of circulating MMP-9 was significantly higher in patients with AAA than in those without AAA. Moreover, recent study reported that the level of MMP-9 in the plasma was statistically elevated in patients with ruptured AAA, compared to patients with nonruptured AAA . Strikingly, it was reported that the inhibition of MMP activity prevented the development of AAA. Thus, the elevated MMP activity-induced vascular middle layer degradation is critical for the pathogenesis of AAA. In this study, we showed that AngII-infusion significantly increased the activity and expression level of MMP-2 and MMP-9. Conversely, curcumin treatmentsignificantly inhibited activity of MMP-2 and MMP-9. It has been previously shown that the activity of MMPs can be modulated by many inflammatory factors and oxygen radical , so we speculated that mechanism of curcumin against MMP-2 and MMP-9 activities may be due to its anti-inflammatory and antioxidant effects. Taken together, these results suggest that one of the mechanisms of curcumin in preventing formation of AAA is by inhibition of activity of MMP-2 and MMP-9.
Increased oxidative stress is another important mechanism in the progression of AAA . It was reported that the production of oxidants is elevated and its antioxidants ability is decreased in AAA. Many studies have shown that curcumin has an important role in its elimination of reactive oxygen species. In this study, we found that the levels of superoxide dismutase (SOD) were significantly decreased, but the levels of malondialdehyde (MDA) were higher in the AngII group than those in AngII + Cur group; the result suggested that curcumin reduces oxidative stress production in AAA.
Oxidative stress can also influence the gene expression of signaling molecules such as MAPK and nuclear factor-κB (NF-κB). The previous study has shown that MAPK activation has been associated with macrophage infiltration in aneurysm and other inflammatory processes and with the activation of MMPs . Administration of CI1040, an inhibitor of ERK activation, attenuated the severity of aneurysm, macrophage infiltration, and MMP expression; the result has demonstrated that MAPK activation plays an important role in the pathogenesis of aneurysm . Fan et al. showed that curcumin attenuates AAA formation by inhibiting JNK phosphorylation . Zhang et al. found that the ERK was highly expressed in AngII-induced AAA formation. Another report found that simvastatin prevents AAA formation by inhibiting ERK phosphorylation . It remains elusive whether curcumin treatment affects ERK phosphorylation in AngII-induced AAA. Our data showed that ERK phosphorylation significantly increased in the AngII group than that in the AngII + Cur group. Thus, our result indicated that curcumin reduces AAA formation at least in part via the inhibition of ERK signaling pathway. Previous study showed that nuclear factor-κB (NF-κB) signaling, the major transcription factor in mediating inflammation, can be activated in aneurysm. Katagiri’s group established the mice model with endothelium transgenic expression of dominant-negative IκBα (E-DNIκB mice) and demonstrated that aneurysm formation is significantly inhibited in E-DNIκB mice; the mechanism refers to inhibition of vascular inflammatory response and matrix metalloproteinases activation . Study by Parodi et al. found that curcumin inhibits the NF-κB activation and reduces the formation of aneurysm . Previous study showed that curcumin attenuates cardiac inflammatory response, inhibits cardiomyocytic apoptosis, inhibits atherosclerosis, and prevents diabetic cardiomyopathy by inhibiting NF-κB activity . From the above study, we speculated that the complex signaling pathway including MAPK and NF-κB, the crosstalk between oxidative stress, and inflammation may be more important factor in the pathogenesis of aneurysms; the effect of curcumin on the treatment of aneurysm may be multiple-targeted including its anti-inflammatory and antioxidant effects by inhibition of multiple signaling pathways, including MAPK and NF-κB signaling pathway.
In summary, our study demonstrated that curcumin significantly reduced the incidence of AngII-induced AAA formation in ApoE−/− mice, and the protective effect of curcumin likely resulted from the reduced inflammatory response, decreased MMP-2 MMP-3 activity, and lowered ROS production. The mechanisms underlying these therapeutic effects involved downregulated ERK and AngII-ROS pathways. Thus, our study provides the new clue that daily use of curcumin is an effective approach to the prevention and treatment of AAA.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors would like to express their thanks to Dr. Xu Peng at Department of Medical Physiology, Texas A&M Health Science Center College of Medicine, Texas, USA, and Dr. Shengxian Jia at the Department of Surgery, Northwestern University, Chicago, USA. They also thank Hong Jiang, Xu Ping Wang, ShanYing Huang, FeiFei Xu, and Zhi Yang for their technical assistance. This study was supported by the National 973 Basic Research Program of China (no. 2013CB530700), the National Natural Science Foundation of China (no. 81170207), and the Program of State Chinese Medicine Administration Bureau (no. JDZX2012113).
Abdominal aortic aneurysms repaired without surgical incisions
Patients seeking treatment for abdominal aortic aneurysms may now undergo a repair procedure that does not require a surgical incision.
Boston Medical Center is one of only two sites in Boston offering the non-invasive, incisionless procedure for abdominal aortic aneurysms. To repair the artery, the surgeon utilizes a small puncture site in the skin, thus obviating the need for an incision. The patient typically goes home the day after surgery and has minimal, if any, discomfort.
“It is truly amazing that the operation to treat an abdominal aortic aneurysm can now be performed without any incisions,” said Alik Farber, MD, clinical chief of Vascular Surgery at BMC, and associate professor of surgery at BUSM. “At times, patients find it hard to believe that their aneurysm was repaired because the procedure is so non-invasive.”
An abdominal aortic aneurysm occurs when sections of the aortic wall weaken and are unable to support the force of blood flow, causing a bubble on the wall. As these bubbles get larger, they are prone to bursting, often resulting in death. Traditional treatment of aortic aneurysm involved an extensive surgical procedure involving a long abdominal incision until the late 1990s, when the Food and Drug Administration approved endovascular repair of abdominal aortic aneurysms (EVAR). With EVAR, which is minimally invasive, surgeons access the aneurysm through an incision made in the femoral artery.
Several years ago, surgeons began performing EVAR through a small puncture site in the skin above the femoral artery in the groin, rather than through a surgical groin incision. The graft is then inserted through the puncture site, under fluoroscopic guidance, and finally deployed in the aorta. The hole in the artery is closed using a series of percutaneously placed sutures. The skin puncture site is so small that it heals without any sutures.
“Once the graft is released, blood flows through the new graft,” Dr. Farber said. “The aneurysm slowly shrinks and is no longer a threat to the patient.”
About 80 percent of the patients with an abdominal aortic aneurysm who are evaluated at BMC are eligible for the new technique. Physicians determine eligibility using factors such as the aneurysm’s shape and location, and the amount of calcium in the wall of the aorta.
“We have performed incisionless EVAR in ten patients at BMC and have had excellent results,” Dr. Farber said. “Not everyone is a candidate for incisionless EVAR, however. Patients have to have large enough femoral arteries and minimal arterial calcification.”
Comprehensive Stroke Program
What is a brain aneurysm?
A brain aneurysm is a bulge or ballooning in a blood vessel in the brain. Most common in people between the ages of 35 and 65 years of age, aneurysms occur at the base of the brain and are usually caused by a defect in an artery that was present at birth.
A hemorrhage can occur when an aneurysm ruptures, leading to bleeding on the brain’s surface and into the space around the brain. This often happens without warning and can be life threatening. Before rupturing, aneurysms usually produce no symptoms or warning signs. Once an aneurysm ruptures you can experience “the worst headache ever.”
Once an aneurysm has ruptured, the goal is to prevent further bleeding and prevent brain damage.
Diagnosis of Brain Aneurysm
Because unruptured brain aneurysms often do not cause any symptoms, many are discovered in people who are being treated for a different condition.
If your doctor believes that you have a brain aneurysm, you may have the following tests:
- Computed tomography (CT) scan. A CT scan can help identify bleeding in the brain.
- Computed tomography angiogram (CTA) scan. CTA is a more precise method of evaluating blood vessels than a standard CT scan. CTA uses a combination of CT scanning, special computer techniques, and contrast material (dye) injected into the blood to produce images of blood vessels.
- Magnetic resonance angiography (MRA). Similar to CTA, MRA uses a magnetic field and pulses of radio wave energy to provide pictures of blood vessels inside the body. As with CTA and cerebral angiography, a dye is often used during MRA to make blood vessels show up more clearly.
- Cerebral angiogram. During this X-ray test, a catheter is inserted through a blood vessel in the groin or arm and moved up through the vessel into the brain. A dye is then injected into the cerebral artery. As with the above tests, the dye allows any problems in the artery, including aneurysms, to be seen on the X-ray. Although this test is more invasive and carries more risk than the above tests, it is a good way to locate small brain aneurysms (such as aneurysms that are less than 5 mm).
Treatment of Brain Aneurysm
Your doctor will determine the type of treatment you receive based on your age, size and location of the aneurysm, your overall health and any additional health concerns.
If you have an aneurysm with a low risk of rupture, you and your doctor may want to continue to observe your condition rather than do surgery. If your aneurysm is large or causing pain or other symptoms or if you have had a previous ruptured aneurysm, your doctor may recommend surgery.
The following procedures are used to treat both ruptured and unruptured brain aneurysms:
- Endovascular embolization: During this procedure, a small tube is inserted into the affected artery and positioned near the aneurysm. For coil embolization, soft metal coils are then moved through the tube into the aneurysm, filling the aneurysm and making it less likely to rupture. In mesh embolization, mesh is placed in the aneurysm, reducing blood flow to the aneurysm and making it less likely to rupture. These procedures are less invasive than surgery. But they involve risks, including rupture of the aneurysm.
- Surgical clipping: This surgery involves placing a small metal clip around the base of the aneurysm to isolate it from normal blood circulation. This decreases the pressure on the aneurysm and prevents it from rupturing. Whether this surgery can be done depends on the location of the aneurysm, its size, and your general health.
Aneurysms that have bled are very serious. Emergency treatment will include hospitalization, intensive care to relieve pressure in the brain and to maintain breathing and vital functions (such as blood pressure) and treatment to prevent rebleeding.
Warning Signs/ Symptoms of Brain Aneurysm
Unruptured brain aneurysms typically do not cause symptoms and are small. Large unruptured aneurysms can occasionally press on the brain or the nerves and may result in various symptoms. If you are experiencing any of the following symptoms, please contact your physician
- Localized headache
- Dilated pupils
- Blurred or double vision
- Pain above and behind eye
- Weakness and numbness
- Difficulty speaking
Aneurysms that have ruptured usually cause immediate symptoms. Seek medical attention immediately if you are experiencing any of the following symptoms:
- Sudden severe headache, the worst headache of your life
- Loss of consciousness
- Stiff neck
- Sudden blurred or double vision
- Sudden pain above/behind the eye or difficulty seeing
- Sudden change in mental status/awareness
- Sudden trouble walking or dizziness
- Sudden weakness and numbness
- Sensitivity to light (photophobia)
- Drooping eyelid
Frequently asked Questions About Brain Aneurysms
What causes a brain aneurysm?
Many aneurysms are genetic. Other causes include trauma or injury to the head, high blood pressure, infection, tumors, diseases of the vascular system, cigarette smoking and drug abuse. They can also be more common in people with other medical issues such as connective tissue disorders, polycystic kidney disease, and certain circulatory disorders.
Do all aneurysms need treatment?
No. Treatment depends on the location and size of the aneurysm but always check with your physician if you have any symptoms or suspect an aneurysm.
What are the symptoms of an aneurysm?
Aneurysms typically cause headaches or vision that is blurred but most remain silent until they are discovered accidently through brain imaging.
Does a ruptured aneurysm need treatment?
Can a ruptured aneurysm cause death?
Yes. When an aneurysms ruptures, blood leaks into the brain and causes pressure on brain tissue and cause permanent damage leading to death.
Is a brain aneurysm the same as a stroke?
A brain aneurysm is a ballooning or bulging of a blood vessel in the head. If this ruptures and bleeds, it is known as a hemorrhagic stroke.