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CARDIOLOGY CASEBOOK |
A 62-year-old Cuban-born woman presents to her primary care physician with pains in the right calf after walking 1 city block, of 5 months’ duration. Following an automobile accident the year before, she had developed a mild degree of spinal stenosis in the lower lumbar spine revealed by magnetic resonance imaging. On the basis of this finding, the patient had been treated as an orthopedic problem. Further questioning revealed additional history that included relief of her calf muscle pain after 1 minute of rest, essential hypertension for the past 5 years and diabetes mellitus type 2, of 6 years’ duration. With this history, the doctor was quite certain that peripheral artery disease (PAD) was responsible for the patient’s presenting symptoms. No cardiac or cerebrovascular symptoms were elicited on system review.
QUESTIONS
ANSWERS
1. a. palpation of the arteries in the inferior extremities
b. ABI
d. blood lipid profile
e. peripheral arterial angiography
f. stress thallium imaging
Atherosclerosis is a diffuse, multistaged and multigenic disease process that usually involves more than 1 vascular bed. Atherogenic relationships usually exist between vascular beds, especially in the older population. As the population ages, the prevalence and disabling effects of vascular disease in other arterial sites become clinically evident. It is generally unappreciated that PAD shares similarities with coronary and cerebral atherosclerotic disease, although flow dynamics and triggers may differ between these vascular beds. The greatest severity, the most serious symptoms and the gravest prognosis are seen when atherosclerotic disease involves the coronary circulation. The coronary, cerebral and aortic arteries are usually closely monitored and managed, whereas the peripheral arteries of the extremities are usually underdiagnosed and undertreated.1 In the majority of patients, PAD is only one of many atherosclerotic syndromes. PAD is defined as stenosis or occlusion of a peripheral arterial vessel by an atherosclerotic plaque, resulting in inadequate muscle perfusion and ischemia. Awareness of PAD is low and it is therefore underdiagnosed. Many cases go unrecognized until claudication or an event occurs.2 PAD affects men and women equally and is more common in the black population.2 PAD is present in 12% of persons over 60 years old and in 20% of those over 75 years of age. Atherosclerotic disease of the iliofemoral and crural (infrapopliteal) vessels is the primary substrate for symptomatic PAD.
The diagnosis of PAD is made by a focused history and physical examination aided by noninvasive and occasionally invasive studies. The majority of physicians, when obtaining a cardiac history and examining the heart and lungs, rarely elicit symptoms of PAD nor do they palpate the peripheral arteries in the inferior extremities.3 The diagnosis of intermittent claudication (IC), the sine qua non for PAD, can be elusive because key questions often go unasked. IC is described as a cramp or tightness or severe fatigue of the exercising muscle usually relieved promptly after 1 or 2 minutes of rest. The degree of exercise that induces IC is usually constant for any given patient. Although the calf is the most frequent site of IC, the muscles of the lower back, buttocks, hips, thighs and arches of the feet may also be affected. Obstruction of the iliac artery and its branches may cause claudication in the buttocks, thighs and calves. Atherosclerotic iliac disease that is concurrent with femoral, popliteal or tibial disease will require therapy to improve iliac artery perfusion pressure to the distal artery it supplies. The external iliac artery courses below the inguinal ligament to become the common femoral artery, which branches into the superficial and deep femoral arteries. The superficial femoral artery is a common site for atherosclerotic disease. Crural or infrapopliteal arteries (anterior and posterior tibial [PT], peroneal) provide blood flow to the muscles of the calf and foot. Involvement of 1 crural artery rarely produces claudication; symptoms of ischemia are usually a result of 3-vessel disease (in the absence of iliofemoral disease). Lesions in these arteries are typically proximal, sequential and lead to distal manifestations, such as nonhealing foot ulcers.
Inferior extremity arteries in patients age 30 or older should be routinely examined by palpation during physical examination and an ABI performed if indicated. Since the PAD risk factors are similar to those of the coronary and cerebral arteries, the early and easier diagnosis of PAD may trigger a search for atherosclerosis in other vascular beds and thus stimulate aggressive risk reduction therapy. For example, during examinations for PAD, a search for disease in the other arterial systems should be included. Similarly, auscultation of the carotid arteries for bruits, auscultation of the abdomen for stenotic renal artery bruits or abdominal aortic bruits and palpation of the abdomen to assess for local widening of an abdominal aortic aneurysm should be done. Femoral, popliteal, PT and dorsalis pedis (DP) pulses should be examined by palpation. However, it is important to note that an abnormal or absent PT pulse is more sensitive and specific for PAD than an abnormal or absent DP, because the incidence of congenital absence of the DP pulse is higher (10% of the population with whites > blacks) than the incidence of congenital absence of the PT pulse (<1% of the population). Peripheral pulses should be graded on a 0-to-2 scale (2 = normal, 1 = normal, 0 = absent). The lower extremities and feet should be inspected for signs of chronic ischemia, infection, ulcerations, fissures, fungus or xanthomas.
The ABI is easily obtainable, objective and a valid measure of arterial occlusive disease in the lower extremities. The ABI is obtained by using a Doppler probe that measures systolic blood pressure in the right and left brachial, DP and PT arteries. Pressures are taken twice. The ABI is derived by dividing the average pressures in each leg by the average brachial pressures. Normally, the ankle (DP, PT) systolic blood pressure is greater than the brachial systolic blood pressure, resulting in an ankle/brachial pressure ratio greater than 1. A ratio of less than 0.9 is usual with claudication and is highly sensitive and specific for angiographic arterial disease. The lower the ratio, the more severe the disease and the higher the risk of cardiovascular events. A value of 0.4 or less is seen initially in critical leg ischemia. A high ratio greater than 1.3 indicates a noncompressible calcified artery. An exercise ABI can be performed when there are symptoms of IC and the resting ABI is normal. The combined use of segmental limb systolic pressure measurements may help to localize areas of stenosis.
Many primary care physicians who perform histories and physical examinations do not include evaluation of the peripheral arteries and very few use Doppler-derived ABIs. Doppler ultrasonography analyzes arterial velocity and pulse waveforms. Loss of the normal triphasic wave pattern and peak velocity can localize the area of stenosis. Pulse volume recordings measure changes in blood volume in different segments of each limb during each cardiac cycle. When used in combination with segmental systolic pressure measurements, pulse volume recordings can provide 95% accuracy in detecting angiographic disease.
Magnetic resonance angiography (MRA) is based on the comparison of contrast formation by inflow of unsaturated blood into surrounding saturated perivascular tissue. Acquisition of images is possible in 2-dimensional and 3-dimensional modes. MRA protocols have been accurate in assessing lower extremity arterial disease. MRA and CT angiography help define anatomy and can differentiate between small tight lesions and long occlusions with collateralized vessels. MRA is consistent in detecting infrapopliteal arteries not visible on angiography4 and accurate in detecting occlusion or stenosis greater than 50% in the entire arterial tree of the inferior extremity. Flow-induced artifacts have been reduced with electrocardiographic triggering. Three-dimensional gadolinium contrast and digital subtraction techniques improve image definition. MRA techniques remain unstandardized and the role of MRA in clinical practice continues to evolve.4
Other noninvasive modalities, such as positive-emission tomography scanning and nuclear medicine techniques (techniques that directly measure arterial blood flow and measure changes in muscular perfusion: lipoprotein levels, hypoxia, biochemical marker analysis) have been considered in the evaluation of PAD, but have serious methodological limitations or lack specificity and/or sensitivity for localizing diseased arterial segments and evaluating the severity of the lesion. Peripheral angiography, long considered the reference standard to detect and assess PAD and performed when planning surgical revascularization, is being replaced by newer noninvasive techniques. The accuracy of angiography in evaluating popliteal disease is limited: The complication rate remains 0.8% with a mortality rate of 0.16%.1 To prevent nephrotoxicity in patients with renal insufficiency, carbon dioxide angiography may be performed.
The differential diagnosis of PAD includes chronic compartment syndrome seen in athletes, osteoarthritis of the hip or knee, rheumatologic-connective tissue diseases and spinal stenosis often seen in the elderly and in whom pain occurs with standing and is relieved with lumbar spinal flexion. Depression and neuropathies may alter the symptoms of PAD. The key to the diagnosis of PAD that differentiates PAD from other causes of inferior extremity symptoms is the prompt relief of pain after 1 or 2 minutes of rest.
A blood lipid profile should be obtained promptly and appropriate strict lipid reduction measures started without delay. Stress thallium imaging with electrocardiographic or echocardiographic testing is advisable in all who have an established diagnosis of PAD. Atherosclerotic heart disease is prevalent in patients with PAD and exposure can be life saving.
2. a. diabetes, hyperlipidemia
b. cigarette smoking
c. elevated fibrinogen level
d. HTN, HHCY
Risk factors that potentiate PAD include advancing age (>40) and any tobacco use (cigarette, cigar, pipe, chewing tobacco); all are risks for atherosclerosis in any or all vascular sites. Diabetes mellitus, HTN, hyperlipidemia (elevated levels of low-density lipoprotein, low levels of high-density lipoprotein, elevated levels of lipoprotein[a]), elevated fibrinogen levels and HHCY all are significant risk factors. Regular physical exercise and moderate alcohol intake are therapeutic for PAD.
PAD is often a manifestation of more serious systemic atherosclerosis. Forty percent of patients with coronary artery disease have symptomatic PAD. The greater the severity of PAD, the more likely the coexistence of coronary artery disease. Mortality from cardiovascular atherosclerotic disease is closely linked with the presence and severity of PAD and contributes significantly to morbidity and mortality. In a report of patients over 55 years of age with PAD, the 5-year mortality was 30% and the incidence of nonfatal events (myocardial infarction, cerebral vascular accident) was 20%.1 Therapy for atherosclerosis in any arterial system is a multifaceted problem.
3. b. exercise
a. risk factor reduction
c. medication
d. revascularization
Early symptomatic improvement is usual with an initial walking exercise program and that progress is often appreciated by patients and gives them realistic hope for a favorable prognosis. A sedentary lifestyle is a cardiovascular risk factor. A regular exercise-training program is the primary and the initial recommended treatment for patients with IC of the inferior extremities. Patients should be advised to walk until IC develops, then attempt to walk a little further with the pain, then rest until pain resolves and begin walking again to tolerance. Exercise improves the maximal walking distances and the quality of life. Regular walking exercise improves oxygen extraction in the legs and significantly increases the average initial claudication distance, as well as the overall maximum walking distance. A supervised exercise program has been reported to increase the average walking distance to the onset of claudication by 179% and the normal walking distance by 122%. In 1 study,5 maximum benefits occurred when walks lasted 30 minutes 3 times per week for 6 months. At submaximal workload, exercise training improves walking efficacy by decreasing oxygen consumption.
Due to the association of specific risk factors with the development of systemic atherosclerosis, patients with PAD are considered prime candidates for secondary risk prevention strategies. Diabetes is an intense risk factor for PAD: The diagnosis of diabetes alone is sufficient to warrant initiation of PAD prophylaxis, even in the absence of symptoms. Strict control of blood sugar can prevent microvascular complications often associated with diabetes. The effect on macrovascular complications is less clear. Weight reduction to the patient’s normal weight for height and age may serve to eliminate diabetes type 2 (author’s observations).
Tobacco use enhances the atherosclerotic process. The severity of PAD is directly proportional to the number of cigarettes smoked. PAD is 3 times more prevalent in smokers than in nonsmokers.1 Discontinuing tobacco use slows the progression of ischemic disease, increases the ABI and walking distance and reduces the risk of myocardial infarction and cardiovascular death, especially in patients over age 70.
Drug therapy is essential for all stages of HTN regardless of the presence of PAD. HTN is a major risk factor for PAD and over time PAD may contribute to HTN. All patients with HTN with or without atherosclerotic heart disease should be treated with triple therapy, that is, a low-dose diuretic, a ß-blocker, and an angiotensin-converting enzyme inhibitor. At times ß-blocker therapy, which leaves 
-adrenergic effects unopposed, may unmask or increase IC of PAD.1
Target levels in lipid control must be achieved when managing atherosclerotic disease, which can be present in any of the arterial beds. Reaching target levels involves lowering cholesterol levels below 200 mg/dL, raising high density lipoprotein levels above 50 mg/dL, lowering low density lipoprotein levels below 100 mg/dL and lowering triglycerides levels to below 150 mg/dl by use of a statin drug in therapeutic doses. Moderate doses are effective when a long-acting niacin is added, a combination that has proven to be most effective. Statin drug therapy improves endothelial function, stabilizes arterial plaques and eliminates inflammation, which is a marker for unstable plaques.6 Lipoprotein(a) levels can be reduced with nicotinic acid (niacin) therapy or apheresis. The reduction in serum lipids can stabilize and may result in some regression of femoral atherosclerotic plaques.6 A low-cholesterol-forming and weight-reducing diet in the overweight patients is essential and often not sufficiently stressed.
High serum levels of HCY are due to genetic alterations in HCY metabolism, altered B12 metabolism, or dietary folate deficiency. HHCY increases the risk of cardiovascular death as well as PAD. HCY facilitates the oxidation of low-density lipoprotein cholesterol, which adds to endothelial injury and promotes an atherogenic milieu. Folate and vitamin B12 supplementation is effective and lowers serum HCY concentration.
Pharmacological therapy for PAD includes platelet inhibition and drugs that increase the walking distance to claudication. Aspirin is the most economical and frequently used platelet inhibitor. The US Food and Drug Administration recommends aspirin in doses of 50 to 325 mg daily in the prevention of complications of atherosclerosis in any vascular bed. Aspirin is a first-line antiplatelet agent that prevents ischemic events in PAD, coronary disease and cerebrovascular disease. It is also effective in maintaining vascular-graft patency.
The thienopyridines, ticlopidine and clopidogrel inhibit platelet activation by blocking platelet receptors. Ticlopidine reduces the severity of claudication and the need for surgical intervention; however, the secondary risks of thrombocytopenia, neutropenia and thrombotic thrombocytopenia are relatively high and have restricted its widespread use. Clopidogrel is similar in action and has fewer hematological side effects than ticlopidine. Clopidogrel is more effective and has a better safety profile than aspirin (incidence of gastrointestinal hemorrhage 1.99% with clopidogrel versus 2.66% with aspirin).7 In combination, clopidogrel and ticlopidine are additive platelet inhibitors. Rare cases of thrombotic thrombocytopenic purpura and severe neutropenia have been reported and therefore periodic blood testing may be advised.
The vasodilator drugs pentoxifylline and cilostazol were designed to limit symptoms of IC. Pentoxifylline, used in the treatment of claudication, lowers plasma fibrinogen concentrations, improves the shapes of red and white blood cells and has antiplatelet actions. However, reports show little effect on increasing walking distance. Cilostazol, used in the treatment of claudication, is a type 3 phosphodiesterase inhibitor that increases intracellular concentrations of cyclic adenosine monophosphate. Cilostazol, a vasodilator, inhibits platelet aggregation and formation of arterial thrombi, inhibits smooth muscle proliferation, increases ABI values and raises levels of high-density lipoprotein cholesterol. It improves IC in patients with stable PAD (compared with placebo and pentoxifylline). Cilostazol has not been evaluated in the heart failure population, but the increase in mortality associated with the use of this class of drugs (eg, milrinone, vesnarinone) in patients with heart failure restricts its use in those with a low left ventricular ejection fraction or heart failure.
Progressive symptoms, crippling claudication and limb ischemia warrant more aggressive interventions. Options include injection of endothelial growth factors and satisfactory collateral vessel growth around occluded vessels; percutaneous and surgical revascularization to relieve ischemic symptoms and salvage an affected limb; and percutaneous endovascular interventions, such as peripheral angioplasty with the use of drug-eluding stents. Endovascular interventions are also used as an adjunct to surgery, by limiting the extent of surgical reconstruction; however, only a small number of patients actually require surgical intervention. Surgical revascularization poses a peri-operative risk of myocardial infarction and cardiovascular death in those who have coexisting cardiovascular disease. Iliac balloon angioplasty has a high rate of initial success and long-term patency. Long-term success of percutaneous iliac intervention is dependent on the quality of distal arterial runoff. Early results were affected by the degree of vascular stenosis (partial or total occlusion); however, technical advances and new guidewires have made impressive long-term results possible. Stenting of the iliac artery is used primarily to improve long-term outcomes of iliac angioplasty in situations of residual stenosis or flow-limiting dissection.8 Indications for percutaneous revascularization include wound healing, crippling claudication and the improvement of proximal flow before femoral-distal bypass procedures.
In uncomplicated cases of iliac arterial disease, primary stenting is not considered superior to balloon angioplasty alone. Distal embolization, commonly a serious complication with thrombolysis in acute myocardial infarction, is also a common and serious complication associated with recanalization of the iliac artery. Percutaneous revascularization of the superficial femoral artery is initially successful but is associated with high rates of restenosis. The length of the stenotic lesion determines the outcome; short lesions having better long-term results than long lesions (>10 cm). Distal runoff also predicted late patency. Indications for percutaneous peripheral revascularization include limiting claudication not responsive to conservative measures in patients at high operative risk and improving wound healing. Primary stenting of the superficial femoral artery as in iliac disease segment was not shown to be superior to angioplasty alone and is reserved for flow-limiting dissection or inadequate angioplasty results. Percutaneous revascularization below the knee is limited to persons with critical limb ischemia who are at high surgical risk. Revascularization of the crural vessels is also indicated to promote wound healing and to preserve distal runoff following proximal intervention. Modern equipment increases high interventional success rates, resulting in improved distal arterial runoff and limb salvage, despite the concomitant high rates of late restenosis and reocclusion.
SUMMARY
The peripheral vascular system makes up the largest single "organ system" and holds many biological secrets that, when unlocked, can open doors for new treatments for all vascular beds, including those of the coronary and cerebral arteries. The coronary and noncoronary circulations are inseparable and interdependent. Cardiologists as well as primary care physicians should have a global view in the management of patients with PAD. The treatment of atherosclerosis in any of the arterial beds is a multifactorial problem.
PAD is underrecognized. Antiplatelet and lipid-lowering therapy is underutilized in patients with PAD. Clopidogrel, an antiplatelet drug, has proven to prevent adverse cardiovascular events in patients with PAD. Therapeutic angiogenesis has been reported to improve severe claudication.
ACKNOWLEDGMENT
Supported in part by a grant from the Applebaum Foundation in loving memory of Joseph Applebaum.
Reprint requests: Louis Lemberg, MD, University of Miami School of Medicine, Division of Cardiology (D-39), P O Box 016960, Miami, Fla 33101.
McDermott MM, Greenland P, Liu K, et al. Leg symptoms in peripheral arterial disease: associated clinical characteristics and functional impairment. JAMA. 2001;286:1599–1605.
Reilly MD, Mohler ER. Cilostazol: treatment of intermittent claudication. Ann Pharmacother. 2001;35:48–56.[Abstract]
This article has been cited by other articles:
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  L. G. Futterman and L. Lemberg Seminal Changes in the Management of the Acute Coronary Event: Current Concepts Am. J. Crit. Care., January 1, 2003; 12(1): 73 - 76. [Full Text] [PDF]
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