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Peripheral Arterial Disease and Cholesterol: Addressing the Lipid Connection

Low-density lipoprotein cholesterol (LDL-C) serves as an important atherogenic risk factor in the development of peripheral arterial disease (PAD). We have chosen to examine the relationship between LDL-C levels and PAD for several reasons. Although LDL-C levels have been shown to be associated with atherostenotic disease at other arterial beds, the LDL-C levels specific to patients with PAD have only been reported in one large study. This data is of critical importance, not only because improvement of LDL-C levels may be an important measure of systemic atherosclerosis risk reduction in PAD patients, but also because patients with PAD suffer from a significantly increased mortality rate. Due to some statistics that believe that patients with PAD have the same risk of cardiovascular morbidity and/or mortality as those who have already suffered a myocardial infarct, the National Cholesterol Education Program (NCEP) guidelines can classify these patients as having a CHD equivalent, and thus recommend the same reductions of LDL-C levels to less than 100 mg/dL and even lower in some cases. Therefore, adherence to current guidelines for LDL-C management is imperative for the prevention of adverse cardiovascular events in PAD patients.

Understanding Peripheral Arterial Disease

High levels of cholesterol can also lead to the formation of atherosclerotic plaque within the abdominal aorta, the major source of arteries supplying the lower extremities. This plaque removes the oxygen supply that the muscles need during and after physical activity, and causes pain in the legs. A reduction in blood supply to the feet can result in sores and wounds that do not heal.

The cholesterol comes from a variety of sources, either produced in the liver or taken in by food, and it is carried to cells through the blood by lipoproteins. Diets high in saturated fats raise LDL cholesterol and lower HDL cholesterol, and are a significant risk factor for PAD. This type of diet provides more cholesterol to cells than they need, and the excess is deposited in the arterial walls.

Peripheral artery disease is a common manifestation of atherosclerosis in the arteries supplying the legs. It is similar to coronary artery disease and carotid artery disease in its causes, mechanisms, and adverse effects on health. Atherosclerosis is a condition where fatty deposits (plaque) build up on the inside of the artery wall. The plaque is composed of cholesterol, fatty substances, cellular waste products, and fibrin (a clotting material in the blood). High levels of cholesterol in the blood promote this condition, and the result is a reduction in blood supply to the legs and feet.

Understanding peripheral artery disease (PAD) and the connection between cholesterol and PAD is critical to preventing the disease and reducing its progression. An adequate comprehension of this problem could prompt the manifestation of cholesterol in susceptible individuals and result in more effective treatments to reduce lipid levels in these patients.

Risk Factors

The last risk factor we can control is obesity and physical inactivity. Losing weight can lower the risk of PAD and increase pain-free walking time. High weight puts more demand on the arteries to supply blood to areas of the body. This increases blood pressure and makes the heart work harder. Physical activity has the same effect. Regular exercise and a healthy diet can help lower blood pressure, cholesterol, blood sugar, and the medium to high-risk categories of general PAD. The beneficial effects of exercise have been known to decrease the risk of PAD by 80 percent. Although exercise can cause increased leg pain at first, PAD patients are encouraged to walk, as studies have shown it leads to a more active lifestyle and can actually decrease symptoms in the long run.

High blood pressure is another risk factor for PAD; it forces the heart to work harder, and if left untreated, can lead to damage of arterial walls. This makes it easier for cholesterol to deposit into the arteries because damaged arteries become inflamed. High cholesterol levels also increase the risk of PAD. Cholesterol is carried through the blood attached to proteins called lipids. There are high-density lipoproteins (HDL) and low-density lipoproteins (LDL). HDL is known as the good cholesterol and is believed to remove bad cholesterol from the arteries and carry it to the liver to be excreted. The general belief is the higher the HDL level, the lower the risk of heart disease. LDL is known as the bad cholesterol, which causes cholesterol buildup on the artery walls. This leads to atherosclerosis and increased risk of heart attack, stroke, and PAD.

The second most modifiable risk factor is diabetes. It is common for diabetics to have lower extremity artery disease 10-15 years earlier than the rest of the population. PAD is also more extensive and severe in the diabetic population. High blood sugar levels over time damage the arteries and the nerves that control the arteries. This damage makes the arteries to the lower extremities more susceptible to obstruction from atherosclerosis and makes the patient more vulnerable to infection and problems in wound healing.

In PAD, atherosclerosis affects arteries that carry blood to the legs, arms, kidneys, or brain. The earliest and most modifiable risk factor is cigarette smoking. Smokers have approximately a 10-fold increased risk for PAD. Chemically, nicotine leads to constriction of the arteries and increased heart rate. The carbon monoxide in cigarette smoke damages the artery lining. In addition, smoking promotes the deposit of bad cholesterol in the artery wall by decreasing the good cholesterol. People who smoke a pack of cigarettes a day have a four times higher risk of developing the disease than nonsmokers.

The risk factors for PAD are the same as those for atherosclerosis, as PAD is, in fact, a form of atherosclerosis. Atherosclerosis is a degenerative process that may begin as early as age 10, but rarely causes problems before men are in their 40s and women are in their 50s. As people age, the risk of atherosclerosis increases.

Symptoms

The most common symptom of peripheral arterial disease is intermittent claudication. This is pain in the legs which occurs while walking and is relieved by rest. The location of the pain can help determine the site of the arterial disease. If pain occurs in the calf muscles, it is most commonly due to superficial femoral artery disease. Pain in the buttock or thigh is typically due to aortoiliac artery disease. Pain in the foot or ankle may be due to more distal vessel disease. The nature of the pain may also give information about the severity of the disease. Those with mild disease will typically experience cramp-like pain, while those with more severe disease will experience pain at rest. Another common symptom of lower limb arterial disease is erectile dysfunction. This is commonly caused by aortoiliac artery disease.

Diagnosis

If the healthcare providers could increase their suspicion that patients may have PAD, more patients could be diagnosed and subsequently treated for the disease. The diagnosis of intermittent claudication caused by PAD is not difficult and can be confirmed by an exercise test, measurement of the ABI or angiography. Unfortunately, many patients, especially those with atypical leg symptoms or those who are sedentary, are not questioned about the presence of leg discomfort. If leg pain is mentioned, the symptom is often attributed to aging or arthritis. Healthcare providers should question all patients about leg symptoms and should perform a careful examination of the foot and leg when patients complain of any lower extremity discomfort. Specific questioning about location, duration, and character of leg symptoms can help to differentiate intermittent claudication from other musculoskeletal disorders. An office treadmill exercise test is a simple and non-invasive means of diagnosing intermittent claudication. Most patients with PAD will have reproducible leg symptoms and an observable impairment of gait at a constant walking pace. Alternative modes of exercise testing, such as a stationary bicycle, can also be used for those who are unable to walk on a treadmill. The ABI is a useful screening test for PAD and has an overall accuracy of 95%. It is a ratio of the systolic blood pressure in the ankle to the systolic blood pressure in the arm. A normal ABI is between 0.9 and 1.3. An ABI of <0.9 is indicative of PAD, and the severity of the disease is inversely related to the ABI. Patients with severe PAD or those who have ABI that is suggestive or indicative of PAD may benefit from angiography. Although angiography is an invasive procedure and is usually reserved for patients who are candidates for intervention, it is the most accurate test to define the location and extent of anatomic disease in the arterial system of the lower extremities. An alternative non-invasive method of evaluating anatomic disease is by using magnetic resonance angiography or CT angiography. In summary, the diagnosis of PAD begins with healthcare providers being attentive to patients’ complaints of leg discomfort. Such examinations can lead to a simple test such as an exercise treadmill test or measuring the ABI, which can confirm the diagnosis of PAD.

The Role of Cholesterol in Peripheral Arterial Disease

Cholesterol in Peripheral Arterial Disease is an organic lipid and though it is essential to life, it is often thought of in negative terms. It is carried in our bloodstream by low-density lipoproteins (LDL) and high-density lipoproteins (HDL). LDL cholesterol is what is known as the “bad” cholesterol. If there is too much of it in the bloodstream, it will slowly build up on the walls of the arteries feeding the heart and brain. This can form plaque, which is a thick, hard deposit that can clog arteries and make them less flexible. This condition is known as atherosclerosis and is a form of PAD, which can affect the arteries in the legs, arms, head, or internal organs. HDL cholesterol is the “good” cholesterol and is so called because it carries LDL cholesterol away from the arteries and back to the liver where it is broken down. High levels of LDL cholesterol and low levels of HDL cholesterol in the bloodstream are a high-risk factor for PAD.

Types of Cholesterol

Cholesterol is a waxy, fat-like substance found in the walls of cells in all parts of the body, from the nervous system to the liver to the blood. Although it is necessary for many functions of the body, a high level of cholesterol present in the blood can lead to the formation of plaque. This substance can narrow or block the blood vessels, leading to Peripheral Arterial Disease (P.A.D.) or have an effect on other cardiovascular diseases. Usually, cholesterol is carried through the bloodstream by molecules called lipoproteins. There are two main types of lipoproteins: low-density lipoproteins (LDL) and high-density lipoproteins (HDL). High levels of LDL cholesterol and low levels of HDL cholesterol have been shown to be associated with an increased risk of heart disease and are a strong positive risk factor for atherosclerosis, the narrowing of the arteries. This is why it is very important for individuals with P.A.D. to monitor their cholesterol levels and make sure that they are in the healthy range. This can be done with a blood test called a lipoprotein profile. This is usually done after a 9-12 hour fast and will give information about total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. High levels of total cholesterol and LDL cholesterol are associated with an increased chance of getting P.A.D. and having a worsening of lower extremity blood flow.

Cholesterol and Arterial Plaque

Mention the word cholesterol and most people will think of fat, heart disease and a heart attack. Though many will argue that cholesterol is bad and it must be eradicated from our bodies, it is in fact necessary for normal bodily function. Cholesterol is a type of fat that is essential for the body. It is used to insulate nerve fibers and is in the formation of cell membranes. Cholesterol is also used in the production of hormones. It has been estimated that the liver produces around 80% of the body’s cholesterol supply and it is also absorbed from the food that we eat. Cholesterol is carried in the bloodstream in the form of lipoproteins. There are two types of lipoprotein, a high density and a low-density lipoprotein. The high-density lipoprotein is known as HDL and is required for the body to function efficiently. HDL soaks up excess LDL in the bloodstream. LDL, which is low-density lipoprotein, is what delivers cholesterol to the cells. It is known as bad cholesterol because high levels of LDL can cause the clogging of arteries. This occurs when the LDL carrying cholesterol circulating in the bloodstream invades the layer of cells that line the walls of the arteries. The invasion initiates a complex reaction, which leads to the formation of hard waxy substance in the arteries. This substance is known as plaque and plaque builds up on the interior walls of arteries and can reduce or block the flow of blood to the heart.

Cholesterol-Lowering Medications

Other medications to lower LDL cholesterol include bile acid sequestrants, nicotinic acid, and fibric acid derivatives. All of these medications work in different ways to lower LDL, but they are not as effective as statins. Some of them also have more side effects. People with PAD who need to lower their LDL cholesterol with medication should speak with their doctors about the best treatment plan for their individual health needs.

There are several different types of medications to lower LDL cholesterol. The most commonly prescribed medications are called statins. Statins work in the liver to block the formation of cholesterol. They can lower LDL by up to 60 percent and have been shown to be very effective at preventing heart attacks and strokes. At least one large study is underway to specifically determine if statin therapy can help to reduce heart attacks, strokes, and other cardiovascular events in people with PAD.

To avoid cardiovascular problems, it is important for PAD patients to lower their LDL cholesterol levels. Diet and exercise are always the first steps in any plan to raise HDL and lower LDL cholesterol. But, for many people with PAD and heart disease, cholesterol-lowering medications are also needed. Several large studies have shown that taking medication to lower LDL will decrease the risk of heart attack and stroke in people with PAD and other forms of heart disease.

Addressing the Lipid Connection

Dyslipidemia is one among the major risk factors for onset and progression of PAD. It creates an atherogenic lipid profile which in turn results in plaque formation and its progression in the peripheral arteries. These eventually lead to narrowing and occlusion of the lumen causing the symptoms of PAD. Hence addressing this lipid connection is paramount in managing PAD. Lifestyle modification is the initial step in managing dyslipidemia. This is achieved by diet therapy and increased physical activity. Diet which is low in saturated fats, trans fats and cholesterol is the primary recommendation. Increase in dietary fibre, omega-3 fatty acids and consuming a plant stanols/sterols-based diet can lead to better lipid profile. These dietary changes can bring reduction in the LDL-cholesterol by 8-10%. Weight reduction and increased physical activity are found to improve lipid and blood pressure abnormalities, and reduce the risk of diabetes in addition to treating PAD. For every 1kg of weight loss, there is reduction in LDL-cholesterol by 19mg/day. Hence the American Heart Association and National Cholesterol Education Program recommend weight reduction along with LDL-cholesterol lowering diet for patients with dyslipidemia and PAD. Regular physical activity such as brisk walking for >30min/day can increase HDL-cholesterol by 3-5% and decrease triglycerides by 5%. Physical activity can also reduce incidence of major cardiovascular events and improve claudication in patients with PAD. High intensity exercise such as supervised treadmill walking can improve functional performance in patients with PAD. Hence regular physical activity is becoming an important part of PAD rehabilitation which would help in improving the functional status of PAD patients. In spite of well-documented benefits of lifestyle modification, there is lack of such interventions in PAD patients with dyslipidemia. This is mainly because we are often more aggressive in managing the same problem with drugs rather than mere lifestyle change.

Lifestyle Changes

Regular aerobic exercise is an essential part of a healthy lifestyle. In patients with PAD, supervised exercise training should prove effective in improving walking distance. This can vary from the more severely impaired patient, who may be suitable for inpatient exercise therapy with or without revascularization, to less extensive disease where supervised treadmill walking exercise proves efficacious. In a general population, structural changes in the form of exercise facilities being more friendly to the walking impaired would be a useful addition to healthcare provision. Patients should be encouraged to walk further within their pain-free threshold (intermittent claudication distance) and to do this most days of the week. Upper body exercise is a useful alternative for those truly unable to walk. Household and gardening activities should also be encouraged as part of the increase in overall activity and cholesterol lowering has been documented with modest changes in activity such as these. These measures will also help to prevent the development of obesity, a state undesirable in all forms of PAD. Gradual increases to a programme of more vigorous intensity exercise in fitter patients help to further reduce cardiac risk. This type of exercise can exacerbate claudication symptoms and it is useful for patients to be reminded that they are not at increased risk of limb loss when exercising. A comprehensive review of the effects of exercise training in these patients can be found elsewhere. High-intensity statin therapy in patients with PAD is supported by the Heart Protection Study which shows reductions in major cardiovascular events and revascularization. This includes benefit in patients with no established vascular disease but at high risk, a state which can be argued true for all patients with a diagnosis of symptomatic PAD. Use of ezetimibe as additional therapy among these patients is yet to be supported by clinical trials or evidence but its ability to further lower LDL cholesterol would suggest specific benefit in this group.

Medications and Treatments

Fibric acid derivatives have been used in the treatment of atherogenic lipid disorders and also have effects on inflammation and reverse cholesterol transport. Despite the fact that they have been shown to increase HDL and lower LDL, they have not been found to be beneficial in preventing cardiovascular events and have not been compared with placebo in patients with PAD. This is also the case with bile acid sequestrants, of which there is no good evidence on their benefits for patients with PAD.

The most widely used group of pharmaceuticals for PAD is statins, which are cholesterol-lowering medications. In addition to lowering cholesterol, statins also have anti-inflammatory effects which are beneficial to the arterial wall. The Heart Protection Study, which included a subgroup of patients with PAD, found that use of simvastatin lowered the risk of a major coronary event and stroke requiring revascularization by 24%. The study found that the benefits of statin therapy were consistent in the PAD subgroup whether or not they had a history of coronary disease, highlighting the impact of these medications on individuals with PAD. Despite the fact that statins have consistently proven to be an effective therapy for PAD, one retrospective study of 501 patients found that only 39% of patients were on a statin at the time they were admitted to hospital for peripheral vascular intervention. High intensity statin therapy is recommended for all patients with PAD to lower the risk of cardiovascular events, and a target LDL level of under 100 mg/dl with an option to use high dose statins to achieve an LDL of under 70 mg/dl in patients with PAD or a history of myocardial infarction is recommended. Unfortunately, it is well known that many patients with PAD have multiple co-existing medical conditions and the use of multiple medications can lead to poor compliance with statins. High intensity statin therapy has been associated with an increase in the incidence of new onset diabetes, which has also raised concerns regarding its use in atherogenic cohorts. Patient and physician education regarding the benefits of statins in PAD is important, and improved compliance will be seen if patients notice an improvement in their symptoms on the medication.

Importance of Regular Monitoring

To determine whether cholesterol-lowering treatment should continue, the patient’s lipid levels should be reassessed 6 weeks to 3 months after drug initiation or dosage adjustment, and every 6-12 months thereafter. The cost and effort expended on regular monitoring are justified by the high probability of treatment success and the potential consequences of not achieving and maintaining goal cholesterol levels. Three basic factors affect the choice of monitoring strategy: the drug’s expected effects on lipoprotein levels, reliability of the test, and cost. In general, the more a drug lowers LDL-C, the greater the expected benefit. Therefore, frequency of monitoring should be highest soon after treatment initiation or dosage adjustment, and can be reduced to once or twice yearly if LDL-C is nearing goal. This approach is applicable when reliable tests are being used. However, reliability of lipid tests vary. For example, the ultracentrifugation beta quantification method for LDL-C is precise but rarely used due to its expense and technical demands. On the other hand, the often used calculated method (LDL-C = TC – HDL-C – TG/5) can be unreliable in certain patients, particularly those with low TG and high cholesterol. Still, the cost of monitoring can be reduced at any given level of reliability by using simpler lipid tests or panels. For example, one can switch from monitoring both lipid levels and liver enzymes to monitoring lipids alone. The key in all cases is to maintain good adherence to the National Cholesterol Education Programme (NCEP) goal lipid levels while minimizing the cost of monitoring. Periodic assessments of patient adherence and response to treatment can be made by comparing on-treatment lipid levels to baseline levels and the NCEP treatment thresholds.

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