Closed Reduction, Casting, and Traction

Authors: Koval, Kenneth J.; Zuckerman, Joseph D.

Title: Handbook of Fractures, 3rd Edition

Closed Reduction, Casting, and Traction

PRINCIPLES OF CLOSED REDUCTION

• Displaced fractures, including those that will undergo internal fixation, should be reduced to minimize soft tissue complications.
• Splints should respect the soft tissues.
  • Pad all bony prominences.
  • Allow for postinjury swelling.
• Adequate analgesia and muscle relaxation are critical for success.
• Fractures are reduced using axial traction and reversal of the mechanism of injury.
• One should attempt to correct or restore length, rotation, and angulation.
• Reduction maneuvers are often specific for a particular location.
• One should immobilize the joint above and below the injury.
• Three-point contact and stabilization are necessary to maintain most closed reductions.

COMMON SPLINTING TECHNIQUES

• “Bulky” Jones
  • Lower extremity splint, commonly applied for foot and ankle fractures, that uses fluffy cotton or abundant cast padding to help with postinjury swelling. The splint is applied using a posterior slab and a U-shaped slab applied from medial to lateral around the malleoli.
• Sugartong splint
  • Upper extremity splint for distal forearm fractures that uses a U-shaped slab applied to the volar and dorsal aspects of the forearm encircling the elbow (Fig. 1.1).
    
    
• Coaptation splint
  • Upper extremity splint for humerus fractures that uses a U-shaped slab applied to the medal and lateral aspects of the arm, encircling the elbow, and overlapping the shoulder.
• Ulnar gutter splint
• Volar/dorsal hand splint
• Thumb spica splint
• Posterior slab (ankle) with or without a U-shaped splint
• Posterior slab (thigh)

Visit the University of Ottawa web site for general casting techniques and specifics on placing specific splints and casts: http://www.med.uottawa.ca/procedures/cast/

CASTING

• The goal is semirigid immobilization with avoidance of pressure or skin complications.
  
  
• It is often a poor choice in the treatment of acute fractures owing to swelling and soft tissue complications.
  

  Figure 1.1. A sugar-tong plaster splint is wrapped around the elbow and forearm and is held using a circumferential gauze bandage. It should extend from the dorsal surface of the metacarpophalangeal joints to the volar surface of the fracture site (From Bucholz RW, Heckman JD, Court-Brown C, eds. Rockwood and Green’s Fractures in Adults, 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2006.)

  • Padding: This is placed from distal to proximal with a 50% overlap, a minimum two layers, and extra padding at the fibular head, malleoli, patella, and olecranon.
  • Plaster: Cold water will maximize the molding time.
    • 6-inch width for thigh
    • 4- to 6-inch width for leg
    • 4- to 6-inch width for arm
    • 2- to 4-inch width for forearm
  • Fiberglass
    • This is more difficult to mold but more resistant to water and use breakdown.
    • Generally, it is two to three times stronger for any given thickness.

Visit the University of Ottawa web site for general casting techniques and specifics on placing specific splints and casts: http://www.med.uottawa.ca/procedures/cast/

Below Knee Cast (Short Leg Cast)

• This should support the metatarsal heads.
• The ankle should be placed in neutral; apply with the knee in flexion.
• Ensure freedom of the toes.
• Build up the heel for walking casts.
  • Fiberglass is preferred for durability.
• Pad the fibula head and the plantar aspect of the foot.

Above Knee Cast (Long Leg Cast)

• Apply below the knee first.
• Maintain knee flexion at 5 to 20 degrees.
• Mold the supracondylar femur for improved rotational stability.
• Apply extra padding anterior to the patella.

Short and Long Arm Casts

• The metacarpophalangeal (MCP) joints should be free.
  • Do not go past the proximal palmar crease.
• The thumb should be free to the base of the metacarpal; opposition to the fifth digit should be unobstructed.
• Even pressure should be applied to achieve the best mold.
• Avoid molding with anything but the heels of the palm, to avoid pressure points.

COMPLICATIONS OF CASTS AND SPLINTS

• Loss of reduction
• Pressure necrosis, as early as 2 hours after cast/splint application
• Tight cast or compartment syndrome
  • Univalving: 30% pressure drop
  • Bivalving: 60% pressure drop
  • Cutting of cast padding to further reduce pressure
• Thermal injury
  • Avoid plaster thicker than 10 ply
  • Avoid water hotter than 24°C
  • Unusual with fiberglass
• Cuts and burns during cast removal
• Thrombophlebitis or pulmonary embolus: increased with lower extremity fracture and immobilization but prophylaxis debated
• Joint stiffness: joints should be left free when possible (i.e., thumb MCP for short arm cast) and placed in position of function when not possible to leave free

POSITIONS OF FUNCTION

• Ankle: neutral dorsiflexion (no equinus)
• Hand: MCP flexed (70 to 90 degrees), interphalangeal joints in extension (also called the intrinsic plus position) (Fig. 1.2)
  
  
  
  
  

TRACTION

• This allows constant controlled force for initial stabilization of long bone fractures and aids in reduction during operative procedures.
• The option for skeletal versus skin traction is case dependent.

Skin Traction

• Limited force can be applied, generally not to exceed 10 lb.
• This can cause soft tissue problems, especially in elderly patients or those with or rheumatoid-type skin.
• It is not as powerful when used during operative procedures for both length and rotational control.
  
  
  
  
• Bucks traction uses a soft dressing around the calf and foot attached to a weight off the foot of the bed.

  Figure 1.2. Position of function for the MCP joint.

  • This is an on option to provide temporary comfort in hip fractures.
  • A maximum of 10 lb of traction should be used.
  • Watch closely for skin problems, especially in elderly or rheumatoid patients.

Skeletal Traction (Fig. 1.3)

• This is more powerful, with greater fragment control, than skin traction.
• It permits pull up to 20% of body weight for the lower extremity.
• It requires local anesthesia for pin insertion if the patient is awake.
  • The anesthesia should be infiltrated down to the sensitive periosteum.
• It is the preferred method of temporizing long bone, pelvic, and acetabular fractures until operative treatment can be performed.
• Choice of thin wire versus Steinmann pin
  • Thin wire is more difficult to insert with a hand drill and requires a tension traction bow.
  • The Steinmann pin may be either smooth or threaded.
    • A smooth pin is stronger but it can slide through the skin.
    • A threaded pin is weaker and bends more easily with increasing weights, but it will not slide and will advance more easily during insertion.
    • In general, the largest pin available is chosen, especially if a threaded pin is selected.

Tibial Skeletal Traction

• The pin is placed 2 cm posterior and 1 cm distal to the tibial tubercle.
  • It may go more distal in osteopenic bone.
  P.7
  
  
• The pin is placed from lateral to medial to direct the pin away from the common peroneal nerve.

  Figure 1.3. Skeletal traction sites. Various sites for skeletal traction are available. The techniques range from traction in the olecranon to skull traction, as illustrated here. (Modified from Connolly J. Fractures and Dislocations: Closed Management. Philadelphia: WB Saunders, 1995.)

• The skin is released at the pins’ entrance and exit points.
• One should try to stay out of the anterior compartment.
  • One should use a hemostat to push the muscle posteriorly.
• A sterile dressing is applied next to the skin.

Femoral Skeletal Traction (Fig. 1.4)

• This is the method of choice for acetabular and proximal femur fractures (especially in ligamentously injured knees).
• The pin is placed from medial to lateral (directed away from the neurovascular bundle) at the adductor tubercle, slightly proximal to the femoral epicondyle.
  • The location of this pin can be determined from the AP knee radiograph using the patella as a landmark.
• One should spread through the soft tissue to bone to avoid injury to the superficial femoral artery.

Balanced Skeletal Traction

• This allows for suspension of the leg with longitudinal traction.
• It requires an overhead trapeze, a traction cord, and pulleys.
• It is often helpful in the initial stabilization of femur fractures.
  
  

  

  
  

Figure 1.4. (A) Technique of inserting skeletal pins for femoral traction. A skeletal traction pin is inserted in the distal femur from medial to the lateral. Local anesthetic is infiltrated down to the periosteum, and care is taken to avoid the neurovascular structures in the posteromedial aspect of the knee. A hand drill is used to insert the 3-mm Steinmann pin, and care is taken to avoid pinching of the skin, which can be painful. (B) The pin is padded, and a traction bow is attached. (Modified from Connolly J. Fractures and Dislocations: Closed Management. Philadelphia: WB Saunders, 1995.)

Calcaneal Skeletal Traction

• This is most commonly used with a spanning external fixation for “traveling traction,” or it may be used with a Bohler-Braun frame.
• The pin is placed from medial to lateral, directed away from the neurovascular bundle, 2 to 2.5 cm posterior and inferior to the medial malleolus.

Olecranon Traction

• This is rarely used today.
• A small to medium-sized pin is placed from medial to lateral in the proximal olecranon; the bone is entered 1.5 cm from the tip of the olecranon.
• The forearm and wrist are supported with skin traction with the elbow at 90 degrees of flexion.

Gardner Wells Tongs

• Used for cervical spine reduction and traction.
• Pins are placed one fingerbreadth above the pinna, slightly posterior to the external auditory meatus.
  P.9
  
  
• Traction is applied starting with 5 lb and increasing in 5-lb increments with serial radiographs and clinical examination.

Halo

• Indicated for certain cervical spine fractures as definitive treatment or supplementary protection to internal fixation.
• Disadvantages
  • Pin problems
  • Respiratory compromise
• Technique
  • Positioning of patient to maintain spine precautions
  • Fitting of halo ring
  • Preparation of pin sites
    • Anterior: above the eyebrow, avoiding the supraorbital artery, nerve, and sinus
    • Posterior: superior and posterior to the ear
  • Tightening of pins to 6 to 8 ft-lb
  • Retightening if loose
    • Pins only once at 24 hours after insertion
    • Frame as needed

Lipid Disorders-3

Lipid Disorders
CURRENT Diagnosis & Treatment in Cardiology

Lipid Disorders

Peter C. Chien, MD & William H. Frishman, MD

Treatment (cont'd)

D. PHARMACOLOGIC TREATMENT

1. Lipid-lowering drugs—
a. Bile acid sequestrants—The bile acid-binding resins cholestyramine, colestipol, and colesevelam are primarily used as second-line therapy and in combination with other agents to treat hypercholesterolemia without concurrent hypertriglyceridemia (Table 2–9 and Table 2–10). The Lipid Research Clinics Coronary Primary Prevention Trial demonstrated a reduction in myocardial infarctions and CAD deaths in hypercholesterolemic men without CAD using cholestyramine.

Table 2–9. The four major classes of lipid-modifying drugs.

Table 2–10. Therapeutic options for treatment of primary dyslipidemias.

(1) Mode of action—These agents bind bile acids in the intestinal lumen, interrupting the enterohepatic circulation of bile acids, which are subsequently excreted in the feces. Increased synthesis of bile acids from endogenous cholesterol is then stimulated, resulting in the depletion of the hepatic cholesterol pool. This, in turn, leads to a compensatory increase in the biosynthesis of cholesterol and in the number of specific high-affinity LDL receptors on the liver cell membrane. The increased number of high-affinity LDL receptors expressed on hepatocytes stimulates an enhanced rate of LDL catabolism from plasma and thereby lowers the concentration of this lipoprotein.
(2) Clinical use—With their interruption of the enterohepatic circulation of bile acids and consequent stimulation of endogenous LDL biosynthesis, bile acid resins may have a synergistic effect with concomitant administration of HMG-CoA reductase inhibitors. They are indicated as adjunct therapy to reduce serum cholesterol in patients with primary hypercholesterolemia. Their use should be preceded by dietary therapy, which should address both the specific type of hyperlipoproteinemia in the patient and the patient's body weight, because obesity has been shown to be a contributing factor in hyperlipoproteinemia. Resin use can cause a 5–20% increase in VLDL levels, hence, it should be restricted to hypercholesterolemic patients with only slightly increased triglyceride levels. The increase in VLDL seen with resin use usually starts during the first few weeks of therapy and disappears 4 weeks after the initial rise. It is thought that excessive increases in the VLDL particles may blunt the LDL-lowering effect of the drug by competitively binding the upregulated LDL receptors on the hepatocyte. The resins should, therefore, not be used in patients whose triglyceride levels exceed 3.5 mmol/L unless they are accompanied by a second drug with triglyceride-lowering effects; some suggest not using resins if the triglyceride level exceeds 2.5 mmol/L. A general rule of thumb is that the LDL concentration is seldom raised if the triglyceride level exceeds 7 mmol/L, and bile acid resin treatment would not be effective in this setting.
Cholestyramine and colestipol are powders that must be mixed with water or fruit juice before ingestion and are taken in two or three divided doses with or just after meals. Colestipol is also available in tablet form for greater ease of administration. Colesevelam is a newer bile acid resin, which may have fewer adverse effects and drug interactions than older resins due to its novel structure and higher affinity for bile acids. It should be noted that bile acid sequestrants can decrease absorption of some antihypertensive agents, including thiazide diuretics and propranolol. As a general recommendation, all other drugs should be administered either 1 h before or 4 h after the bile acid sequestrant. The cholesterol-lowering effect of 4 g of cholestyramine appears to be equivalent to 5 g of colestipol. The response to therapy is variable in each individual, but a 15–30% reduction in LDL cholesterol may be seen with colestipol (20 g/day), cholestyramine (16 g/day), or colesevelam (3.8 g/day) treatments. The fall in LDL concentration becomes detectable 4–7 days after the start of treatment, and approaches 90% of maximal effect in 2 weeks. The initial dose should be 4 g of cholestyramine, 5 g of colestipol, or 1.88 g of colesevelam twice a day, and if there is an inadequate response, the dosage can be titrated upward accordingly. Using more than the maximum dosage does not increase the antihypercholesterolemic effect of the drug appreciably, but because it does increase side effects, it decreases compliance. Because resins are virtually identical in action, the choice is based on potential drug interactions and patient preference, specifically taste and the ability to tolerate the ingestion of bulky material.
If resin treatment is discontinued, cholesterol levels return to pretreatment levels within a month. In patients with heterozygous hypercholesterolemia who have not achieved desirable cholesterol levels on resin-plus-diet therapy, the combination therapy of bile acid resins and HMG-CoA reductase inhibitors or nicotinic acid can further lower serum cholesterol, triglyceride, and LDL levels and increase serum HDL concentration.
(3) Side effects—The side effects of bile acid resins include constipation, gastrointestinal irritation or bleeding, cholelithiasis, liver function test abnormalities, myalgias, dizziness, vertigo, and anxiety.
b. Fibric acid derivatives—Fibric acid derivatives are a class of drugs that inhibit the production of VLDL while enhancing VLDL clearance, as a result of the stimulation of lipoprotein lipase activity. These drugs reduce plasma triglycerides and concurrently raise HDL-C levels. Their effects on LDL-C are less marked and more variable. The Helsinki Heart Study demonstrated not only decreased triglycerides, decreased LDL-C and increased HDL-C in men treated with gemfibrozil, but also a decrease in the number of myocardial infarctions compared with placebo.
(1) Mode of action—These drugs increase the activity of the enzyme lipoprotein lipase, enhancing the catabolism of VLDL and triglycerides and promoting the transfer of cholesterol to HDL. VLDL production also appears to be decreased. Gemfibrozil has a more pronounced inhibiting effect on VLDL synthesis than clofibrate. Because gemfibrozil and clofibrate reduce LDL-C concentrations by less than 10%, they cannot be considered first-line agents for the treatment of hypercholesterolemia.
(2) Clinical use—It is well established that fibric-acid derivatives are first-line therapy to reduce the risk of pancreatitis in patients with very high levels of plasma triglycerides. Results from the Helsinki Heart Study have also suggested that hypertriglyceridemic patients with low HDL values can derive a cardioprotective effect from gemfibrozil. A Veterans Administration study found that gemfibrozil confers a significant risk reduction in major cardiovascular events in patients with established CAD and low HDL levels as their primary lipid disorder. However, it is not currently recommended to treat isolated low HDL levels with pharmacologic intervention.
The newer generation of fibric acid derivatives, such as fenofibrate, may decrease total cholesterol and LDL levels to a greater extent than gemfibrozil or clofibrate. Fenofibrate also reduces lipoprotein(a) levels and increases LDL size and buoyancy, as does nicotinic acid. These drugs should not be used as first-line therapy for hypercholesterolemic patients unless hypertriglyceridemia is present; type IIb hyperlipidemic patients would benefit from this therapy. HMG-CoA reductase inhibitors combined with fibric acid derivatives are excellent therapy for severe type IIb hyperlipidemia, however, creatine phosphokinase (CPK) values must be closely monitored. Nicotinic acid or bile acid resins plus gemfibrozil are also a reasonable combination for type IIb disease, but HDL levels may drop slightly with the latter combination.
(3) Side effects—The Side effects of fibric acid derivatives include cholelithiasis, gastrointestinal disturbance, myalgias from myositis, and liver function test abnormalities.
c. Nicotinic acid—Nicotinic acid, a water-soluble vitamin that, at doses much higher than those at which its vitaminic actions occur, lowers VLDL and LDL levels and increases HDL levels. It has been shown to reduce overall morbidity and mortality caused by coronary heart disease and to produce regression of some of the signs of atheroma.
(1) Mode of action—The mode of action of nicotinic acid is unknown and appears to be independent of the drug's role as a vitamin. One of its important actions is believed to be partial inhibition of free fatty acid release from adipose tissue. Experiments show that nicotinic acid inhibits the accumulation of cyclic-adenosinemonophosphate (AMP) stimulated by lipolytic hormones; the cAMP concentration controls the activity of triglyceride lipase and thus lipolysis. Nicotinic acid decreases the synthesis of VLDL and LDL by the liver and has been reported to increase the rate of triglyceride removal from the plasma as a result of increased lipoprotein lipase activity.
(2) Clinical use—Through its beneficial effects on VLDL-TG, LDL-C and HDL-C levels, nicotinic acid is indicated for most forms of hyperlipoproteinemia (types II, III, IV, and V) and for patients with depressed HDL. It is the most potent medication among lipid-lowering agents for the augmentation of HDL levels. It is also particularly useful for patients who have elevated plasma VLDL-TG levels as a part of their lipid profile. It is important to remember, however, that a diet low in cholesterol and saturated fats is the foundation of therapy for hyperlipoproteinemia.
Nicotinic acid is available in 100-, 125-, 250-, and 500-mg tablets as well as in a time-release form. The typical dosage is 3–7 g/day given in three divided doses. Therapeutic effects of the drug are usually not seen until the patient reaches a total daily dose of at least 3 g. A greater response may be attained with periodic increases to a maximum of 7–8 g/day, although the incidence of adverse effects also increases with higher doses. In general, it is best to use the lowest dose that will achieve the desired alterations in plasma lipoprotein levels.
(3) Side effects and contraindications—Unfortunately, many patients cannot tolerate therapeutic doses of nicotinic acid, whose primary side effects are cutaneous flushing and gastrointestinal disturbance, and appropriate steps should be taken to minimize these untoward effects. Taking two aspirins 30 min before the nicotinic acid will reduce flushing; taking the nicotinic acid with meals can ameliorate dyspepsia.
Regardless of the dose, it is important to draw laboratory test samples at regular intervals to monitor potential adverse effects. These include assessment of liver function (bilirubin, alkaline phosphatase, and transaminase levels), uric acid levels, and serum glucose levels.
Nicotinic acid is contraindicated in patients with active peptic ulcer disease. Because the drug may also impair glucose tolerance, it is contraindicated in patients with poorly controlled diabetes. Nicotinic acid is also associated with reversible elevations of liver enzymes and uric acid and should not be used in patients with hepatic disease or a history of symptomatic gout.
Patients taking a time-release form of nicotinic acid have a lower incidence of flushing than do patients with unmodified nicotinic acid (this side effect is thought to be related to the rate of gastrointestinal absorption). This is outweighed, however, by the far greater incidence of gastrointestinal and constitutional symptoms experienced by patients on the time-release form. These include nausea, vomiting, diarrhea, fatigue, and impaired male sexual function. In addition, even with low doses, the time-release preparation may be associated with more hepatotoxicity, entailing greater alkaline phosphatase and transaminase elevations.
Other adverse effects of nicotinic acid include pruritus (which responds to aspirin), acanthosis nigricans, cardiac arrhythmias, gout, and myopathy.
d. Hepatic 3-methylglutaryl coenzyme A reductase inhibitors—These inhibitors (HMG-CoA) inhibit the conversion of HMG-CoA to mevalonic acid, a rate-limiting step in the synthesis of cholesterol in the liver and intestines, the two main sites for production of cholesterol in the body.
HMG-CoA reductase inhibitors produce the greatest reduction in levels of LDL cholesterol, the primary atherogenic lipoprotein, along with ameliorating HDL and triglyceride levels to a lesser extent. In modest daily doses, HMG-CoA reductase inhibitors reduce total and LDL-C at a rate of 15–50% and may reduce triglycerides by 10–30%. Although effective as monotherapy, HMG-CoA reductase inhibitors can be combined to good effect with bile acid sequestrants when a greater effect on cholesterol is required, or with fibric acid derivatives when an additive effect on triglyceride levels is desired. These combinations may, however, increase the risk of rhabdomyolysis.
(1) Mode of action—Most cholesterol that is endogenously produced is synthesized in the liver. HMG-CoA reductase inhibitors interrupt an early rate-limiting step in cholesterol synthesis: the conversion of HMG-CoA to mevalonic acid. Because the synthesis rates of LDL receptors are inversely related to the amount of cholesterol in cells, the action of HMG-CoA reductase inhibitors reduces cholesterol synthesis and cellular concentrations of cholesterol and increases the expression of LDL receptors in the liver. Furthermore, because LDL receptors are responsible for clearing about two thirds to three quarters of plasma LDL (and associated cholesterol), HMG-CoA reductase inhibitors may promote the clearance of LDL as well as VLDL remnants. By reducing cholesterol synthesis, they may also interfere with the hepatic formation of lipoproteins. As cholesterol synthesis is maximal at night, it is recommended that HMG-CoA reductase inhibitors be given at bedtime.
(2) Clinical use—HMG-CoA reductase inhibitors have revolutionized the treatment of hyperlipidemia by their potency, efficacy, and tolerability and have evolved into first-line therapy for most forms of hyperlipidemia. Numerous studies with reductase inhibitors involving primary and secondary prevention of CAD have demonstrated a reduction in CAD events, CAD mortality, cerebrovascular events, and mortality from all other causes. Increased LDL receptor activity and decreased LDL synthesis are responsible for the hypocholesterolemic effect of the drug. This increase in LDL receptor activity occurs in response to a decrement in cholesterol synthesis by HMG-CoA reductase inhibition. LDL may be reduced by either its increased clearance from the plasma or its decreased production.
Reductase inhibitors exhibit pleiotropic effects beyond the lowering of LDL cholesterol levels. The reduction in coronary events and mortality rates is not solely attributable to the attenuation of atherosclerosis and improvement in vessel patency. They are postulated to possess antiinflammatory properties, contribute to coronary plaque stabilization, and improve endothelial cell function, conditions that are increasingly recognized as emerging areas of therapy for the treatment of coronary artery disease. They also reduce C-reactive protein levels, which are markers of inflammation and strong predictors of coronary events. One primary prevention trial suggested that pravastatin use may delay or prevent the development of diabetes mellitus, which is intimately linked to a constellation of multiple CAD risk factors known as the metabolic syndrome. Some studies have indicated that reductase inhibitors may prevent the onset of congestive heart failure, osteoporosis, and Alzheimer's disease as well.
(3) Side effects, drug interactions, and contraindications—HMG-CoA reductase inhibitors are contraindicated in pregnancy, lactation, hypersensitivity to the drugs, and active liver disease.
Immunosuppressive drugs, fibric acid derivatives, nicotinic acid, and erythromycin all may increase the risk of rhabdomyolysis. Concurrent use with warfarin (Coumadin) may potentiate the anticoagulant effect. Bile acid sequestrants decrease the bioavailability of the drug. ACE inhibitors may cause hyperkalemia when used with HMG-CoA reductase inhibitors. Digoxin tends to raise simvastatin levels.
Although the HMG-CoA reductase inhibitors are well tolerated, 10% of patients experience unwanted side effects. Although liver enzymes are elevated in 0.5–2% of patients, the patients are asymptomatic, and values may revert to normal on discontinuation of treatment. It is recommended that treatment be stopped if enzymes increase to a level three times that of normal.
Myositis, myalgia, and myopathy have been reported with increased creatine kinase levels in 5% of patients. Creatine kinase may increase further with the combined use of HMG-CoA reductase inhibitors with fibrates or nicotinic acid. Cerivastatin has been discontinued from production due to a high incidence of rhabdomyolysis and death, especially when combined with gemfibrozil. Although the question of cataract induction has been brought up with the use of these agents, clinical studies with lovastatin have not shown an increase in lens opacity. Recently cases of peripheral neuropathy have been described with these agents.
e. Estrogens and progestogens—Women are at increased risk of atherosclerosis after menopause. This is thought to be due to the lack of the protective effect of estrogen on lipoproteins. In this connection, several investigators have observed reductions in total-C and LDL in women taking exogenous estrogens compared with women not receiving any estrogen supplements. Exogenous estrogens can also produce modest elevations in HDL cholesterol (Table 2–11). There is, however, an increased risk of endometrial hyperplasia, possibly leading to endometrial cancer, with unopposed estrogen therapy. Therefore, in treating a postmenopausal woman with an intact uterus, it is advisable to add progesterone to offset the possible carcinogenic effect of estrogen on the uterus. By doing so, however, the beneficial effects on the lipoprotein profile induced by estrogens tend to be lost (Table 2–12).

Table 2–11. Possible beneficial effects of estrogens in reducing the risk of coronary artery disease in postmenopausal women.

Table 2–12. Effects of estrogens and progestogens on lipids and lipoproteins.

The Heart Estrogen/Progestin Replacement Study concluded that hormone replacement therapy (HRT) for the secondary prevention of CAD did not confer a reduction in CAD events or CAD mortality rates overall in the 4.1-year average follow-up period. In addition, a higher rate of venous thromboembolism and gallbladder disease was noted in the patients taking HRT. A subsequent angiographic end-point study demonstrated no benefit with estrogen or the combination of estrogen and medroxyprogesterone on the progression of coronary atherosclerosis compared with placebo in postmenopausal women with established CAD. The Women's Health Initiative trial recently showed that the combination of a conjugated estrogen with methoxyprogesterone increased the rate of coronary events, strokes, breast cancers, and thromboembolic diseases despite significant reductions in LDL-C and HDL-C levels.
2. Combination drug therapy—When treating patients with most severe genetic dyslipidemias, such as heterozygous familial hypercholesterolemia or familial combined hyperlipidemia, it is common for single-drug therapy to fail to achieve satisfactory plasma lipoprotein levels, even with HMG-CoA reductase inhibitors. In this setting, combination drug therapy is often successful in controlling plasma lipid levels (see Table 2–10). With less severe disorders, it is beneficial sometimes to use a combination of low-dose therapeutic agents with complementary effects rather than high doses of either agent alone in order to minimize their individual dose-related toxicities.
Common lipid-modifying agents to be used in combination regimens are the bile acid resins cholestyramine, colestipol, and colesevelam. They have the advantage of not being absorbed and thus cause fewer drug interactions. When the resins are used in full doses in combination with niacin, LDL-C levels are reduced 32–55% in patients with familial hyperlipidemia. Niacin is poorly tolerated by some patients, however, particularly because of its side effects. Recently a combination niacin–lovastatin formulation has become available for use in the treatment of hyperlipidemia.
Bile acid sequestrants can also be used in combination with fibric acid derivatives; some studies have shown an LDL-C reduction of 36–42%. Bile acid sequestrants and HMG-CoA reductase inhibitors used together are highly effective in lowering plasma LDL-C concentrations. A study of cholestyramine and lovastatin use in 62 patients showed a mean reduction in total-C of 48% and LDL-C levels of 59%.
The antifungal agent ketoconazole has an inhibitory effect on several enzymes linked to cytochrome P450. Large doses of this compound have been demonstrated to reduce total-C and LDL-C levels substantially, probably through inhibition of cholesterol synthesis at the demethylation-of-lanosterol step. The effects of low-dose ketoconazole (400 mg) alone and in combination with cholestyramine (12 g/day) have led to reductions in LDL-C levels of 22% and 31-41%, respectively.
Gotto AM Jr, Kuller LH: Eligibility for lipid-lowering drug therapy in primary prevention. How do the Adult Treatment Panel II and Adult Treatment Panel III guidelines compare? Circulation 2002;105:136.
Gupta EK, Ito MK: Lovastatin and extended-release niacin combination product. The fast drug combination for the treatment of hyperlipidemia. Heart Dis 2002;4(2):124.
Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet 2002:360:7.
Herrington DM, Reboussin DM, Brosnihan KB et al: Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522.
Hulley S, Grady D, Bush T et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease on postmenopausal women. JAMA 1998;280:605.
The LIPID Study Group: Long-term effectiveness and safety of pravastatin in 9014 patients with coronary heart disease and average cholesterol concentrations: The LIPID trial follow up. Lancet 2002;359:1379.
Pasternak RC, Smith SC Jr, Bairey-Merz CN et al: ACC/AHA/ NHLBI Clinical advisory on the use of safety stains. J Am Coll Cardiol 2002:40:567.
Rubins HB, Robins SJ, Collins D et al: Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410.
Women's Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women's Health Initiative Randomized Controlled Trial. JAMA 2002;288:321.

Lipid Disorder-2

Lipid Disorders
CURRENT Diagnosis & Treatment in Cardiology

Peter C. Chien, MD & William H. Frishman, MD

Treatment

A. RATIONALE FOR TREATMENT

The rationale of treatment of hyperlipidemia is based on the hypothesis that abnormalities in lipid and lipoprotein levels are risk factors for CAD and that changes in blood lipids can decrease the risk of disease and complications. Levels of plasma cholesterol and LDL have consistently been shown to directly correlate with the risk of CAD. Since the promulgation of the previous NCEP (Adult Treatment Panel II) guidelines, the results of numerous studies involving the primary and secondary prevention of CAD with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported. These trials have overwhelmingly demonstrated a significant reduction in CAD events, CAD mortality, and mortality from all other causes, in addition to ameliorating LDL-C, HDL-C, and triglyceride levels. Data from the West of Scotland Coronary Prevention Study and from the Air Force/Texas Coronary Atherosclerosis Prevention Study have provided cogent evidence that primary prevention of CAD in hypercholesterolemic individuals reduces the incidence of coronary events and, in the former study, death from cardiovascular events. Secondary prevention trials such as the Scandinavian Simvastatin Survival Study (4S) and Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study have revealed that lowering LDL cholesterol levels can retard the progression of coronary atherosclerosis and reduce CAD events, CAD mortality, and cerebrovascular events. These compelling data have prompted a more aggressive approach to the treatment of hyperlipidemia, culminating in the new NCEP (Adult Treatment Panel III [ATP III]) guidelines (Table 2–4). Although ATP III maintains attention to intensive treatment of patients with CAD, its major new focus is on primary prevention in patients with multiple risk factors (Table 2–5).

Table 2–4. ATP III classification of LDL, total and HDL cholesterol (mg/dL).

Table 2–5. New features of ATP III.

Epidemiologic studies and clinical trials are consistent in supporting the observation that for individuals with serum cholesterol levels in the 6.47–7.76 mm/L (250–300 mg/dL) range, each l% reduction in serum cholesterol would yield about a 2% reduction in the rate of combined morbidity and mortality from coronary heart disease. The absolute magnitude of these benefits would even be greater in those individuals having other risk factors for CAD, such as cigarette smoking and hypertension. These risk relationships are the basis for recommending lower cholesterol cutpoints and goals for those who are at high risk for developing coronary heart disease.
Recent meta-analyses have indicated that triglycerides are an independent risk factor for the development of CAD. In addition, serum triglyceride levels are inversely related to HDL levels, and a reduction in triglyceride levels is associated with a rise in HDL. Raising HDL may protect against CAD, therefore providing an additional rationale for treating hypertriglyceridemia.
Downs JR, Clearfield M, Weis S et al: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:1615.
The Long-Term Intervention with Pravastatin in Ischemic Heart Disease (LIPID) Study Group: Prevention of cardiovascular events and death with pravastatin in patients with coronary artery disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1357.
Scandinavian Simvastatin Survival Study Group: Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383.
Shepherd J, Cobbe SM, Ford I et al: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301.
B. TREATMENT GUIDELINES

1. Hypercholesterolemia—The NCEP has classified all adult patients into those with desirable cholesterol values (5.17 mm/L [<200 mg/dL]), borderline high blood cholesterol values (5.17–6.l8 mm/L [200–239 mg/dL]), and high blood cholesterol values (6.21 mm/L [³240 mg/dL]) (see Table 2–4). LDL-C values of <2.58 mm/L (l00 mg/dL) are considered optimal; those between 2.58 and 3.36 mm/L (100–129 mg/dL) are near optimal; those between 3.36 and 4.11 mm/L (130–159 mg/dL) are borderline high; those between 4.13 and 4.88 mm/L (160–189 mg/dL) are high; and those greater than or equal to 4.91 mm/L (190 mg/dL) are very high. HDL-C values of less than 1.03 mm/L (40 mg/dL) are considered to be low, and those greater than or equal to 1.54 mm/L (60 mg/dL) are considered to be high.
The NCEP recommends an approach in adults based on LDL-cholesterol levels (Figure 2–2, Table 2–6). Management should always begin with dietary intervention, as outlined in Table 2–7. When response to diet is inadequate, the NCEP recommends the addition of pharmacologic therapy (Figure 2–3).

Figure 2–2. Model of steps in therapeutic lifestyle changes (TLC). Reprinted, with permission, from: Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults: Executive summary of the Third Report of the NCEP Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285; 2491 (Fig. 1).

Figure 2–3. Progression of drug therapy in primary prevention. Reprinted, with permission, from: Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults: Executive summary of the Third Report of the NCEP Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285; 2492 (Fig. 2).

Table 2–6. LDL cholesterol goals and cutpoints for therapeutic lifestyle changes (TLC) and drug therapy in different risk categories.

Table 2–7. Nutrient composition of the therapeutic lifestyle changes (TLC) diet.

2. Hypertriglyceridemia—Non-HDL cholesterol, comprising LDL and VLDL, is a secondary treatment goal in patients with hypertriglyceridemia (levels > 200 mg/dL). The non-HDL cholesterol goal is set at 30 mg/dL higher than the LDL target level. Triglyceride values of less than 1.69 mm/L (150 mg/dL) are regarded as optimal; those from 1.69 to 2.25 mm/L (150–199 mg/dL) are borderline high; those from 2.26 to 5.64 mm/L (200–499 mg/dL) are high; and values greater than or equal to 5.65 mm/L (500 mg/dL) are considered to be very high. A link between plasma triglycerides and disease is most apparent in patients with severe hypertriglyceridemia with chylomicronemia. These patients are prone to abdominal pain and pancreatitis. Both changes in lifestyle (control of weight, increased physical activity, restriction of alcohol, restriction of dietary fat to 10–20% of total caloric intake, reduction of high carbohydrate intake) and drug therapy are often required.
Much of hypertriglyceridemia (2.82–5.65 mm/L [250–500 mg/dL]) is due to various exogenous or secondary factors (see Table 2–2), which include alcohol, diabetes mellitus, hypothyroidism, obesity, chronic renal disease, and drugs. Changes in lifestyle or treatment of the primary disease process may be sufficient to reduce triglyceride levels.
Patients with high triglycerides that is familial in origin (type IV) are not at risk for premature CAD. Caloric restriction and increased exercise should be instituted as first-line therapies. Patients with familial combined hyperlipoproteinemia often have mild hypertriglyceridemia and are at risk of premature coronary heart disease. These patients should have dietary treatment first, followed, if necessary, by drugs. Patients with high triglycerides and clinical manifestations of CAD can be treated as though they have familial combined hyperlipoproteinemia.
3. Low serum HDL cholesterol—A low serum HDL cholesterol level has emerged as the strongest single lipoprotein predictor of coronary heart disease. Although clinical trials suggest that raising HDL will reduce the risk of CAD, the evidence is insufficient at this time to specify the goal of therapy. The major causes of reduced serum HDL-C are shown in Table 2–8. Clearly, attempts should be made to raise low HDL-C by nonpharmacologic means. When a low HDL is associated with an increased VLDL, therapeutic modification of the latter should be considered, but attempts to raise HDL levels by drugs when there are no other associated risk factors cannot be justified.

Table 2–8. Major causes of reduced serum HDL-cholesterol.


4. Coronary artery disease—
a. Myocardial infarction—Numerous trials have demonstrated the efficacy of employing HMG-CoA reductase inhibitors in the primary and secondary prevention of CAD. Lipid-lowering agents especially benefit hypercholesterolemic patients at the greatest risk for coronary events—those with CAD and CAD equivalents, such as diabetes mellitus, symptomatic cerebrovascular disease, abdominal aortic aneurysm, and peripheral vascular disease. The NCEP now classifies these conditions as tantamount to having established CAD because of their high prevalence of overt and subclinical atherosclerosis. The goal LDL for CAD and its equivalents is less than 2.6 mm/L (100 mg/dL), and dietary modification should be implemented in patients exceeding this target level, with concurrent initiation of drug therapy also being a consideration. Patients should obtain a fasting lipid profile within 24 h of the onset of an acute coronary syndrome or several weeks after the event because LDL levels may remain depressed and yield spurious results. It is recommended that drug therapy be initiated whenever a patient is hospitalized and found to have an LDL-C above 100 mg/dL.
b. Coronary artery bypass grafts—Progressive atherosclerosis has been identified as the single most important cause of occlusion of saphenous vein coronary artery grafts; it is found in approximately two thirds of grafts within 10 years. Low HDL-C, high LDL-C, and high apolipoprotein B are the most significant predictors of atherosclerotic disease in grafts. Many investigators believe that internal mammary artery bypass grafting is the coronary bypass procedure of choice because atherosclerosis progresses less rapidly with these grafts than with saphenous veins. Moreover, lipid-lowering therapy may improve the patency of bypass grafts. The Coronary Artery Bypass Graft Trial demonstrated that aggressive LDL reduction as compared to moderate LDL reduction attenuated the progression of atherosclerosis in saphenous vein coronary artery bypass grafts. It also concluded that low-dose warfarin was ineffective in achieving this end-point.
c. Coronary angioplasty—Restenosis after successful coronary angioplasty has been observed in 25–40% of patients undergoing this procedure. Restenosis after angioplasty appears to result from intimal smooth muscle cell proliferation. Placement of coronary stents has reduced angioplasty restenosis rates, CAD events, and the need for repeat revascularization procedures. Stent patency may be improved with the subsequent administration of glycoprotein IIb/IIIa inhibitors and other antiplatelet agents, such as aspirin and clopidogrel, along with HMG-CoA reductase inhibitors.
5. Diabetes mellitus—Although elevated triglycerides, low HDL-C, or both are common in patients with diabetes, clinical trial data support the identification of LDL-C as the primary focus of therapy. Diabetes is designated a CAD risk equivalent in ATP III, and the LDL goal should be below 100 mg/dL.
6. Metabolic syndrome—Factors that characterize the metabolic syndrome are abdominal obesity, dyslipidemia (elevated triglycerides, small dense LDL particles, low HDL-C), raised blood pressure, insulin resistance, and prothrombotic and proinflammatory states. ATP III recognizes this syndrome as a secondary target of risk reduction therapy after the primary target, LDL-C.
Ballantyne CM, Herd A, Ferlic LL et al: Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy. Circulation 1999;99:736.
Erbel R, Haude M, Hopp HW et al: Coronary artery stenting compared with balloon angioplasty for restenosis after initial balloon angioplasty. N Engl J Med 1998;339:1672.
Pitt B, Waters D, Brown WV et al: Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999;341:70.
The Post Coronary Artery Bypass Graft Trial Investigators: The effect of aggressive lowering of low density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous vein coronary artery bypass grafts. N Engl J Med 1997;336:153.
Stenestrand U, Wallentin L: Early statin treatment following acute myocardial infarction and 1-year survival. JAMA 2001;285: 430.
Syvanne M, Nieminen MS, Frick H et al: Association between lipoproteins and the progression of coronary and vein graft atherosclerosis in a controlled trial with gemfibrozil in men with low baseline levels of HDL cholesterol. Circulation 1998;98:1993.
Walter DH, Schachinger V, Elsner M et al: Effect of statin therapy on restenosis after coronary stent implantation. Am J Cardiol 2000;85:962.
C. NONPHARMACOLOGIC APPROACHES

1. Dietary modification—The NCEP recommends dietary modification as the first-line treatment for hyperlipidemia (see Table 2–7). It advises a diet that limits cholesterol intake to no more than 200 mg daily and fat intake of less than 30% of total calories, saturated fat constituting less than 7% of daily caloric intake. High intakes of saturated fat, cholesterol, and calories (in excess of body requirements) are implicated as causes for elevated plasma cholesterol. Current recommendations for dietary modification are founded largely on both population-based observational studies and smaller, controlled dietary trials.
Saturated, polyunsaturated, and monounsaturated fats are thought to raise, lower, and have no effect on serum cholesterol, respectively. It has been postulated that monounsaturated fats (eg, olive oil, rapeseed oil), which consist mainly of oleic acid, lower serum cholesterol as much as do polyunsaturated fats, which consist mainly of linoleic acid. The monounsaturated fats offer the added benefit of maintaining heart-protective HDL-C levels. One randomized trial involving postmyocardial infarction patients suggested that intake of n-3 polyunsaturated fatty acids reduced nonfatal myocardial infarction, cerebrovascular accidents, and mortality rates as compared with vitamin E and placebo. However, the study was limited by relatively high drug discontinuation rates. The favorable effects of polyunsaturated fat on serum cholesterol have been counterbalanced by evidence that high intake not only tends to lower HDL levels but may promote gallstone formation.
Trans-fatty acids are formed by commercial hydrogenation processes, which harden polyunsaturate-rich marine and vegetable oils. In the United States, consumption of dietary trans-fatty acids averages about 8–10 g/d, or approximately 6–8% of total daily fat intake, much of it in the form of margarine. Lipid profiles are known to be adversely affected by a high trans-fatty-acid diet, which depresses mean HDL-C levels and elevates mean LDL-C levels. Patients at increased risk of atherosclerosis should therefore limit their intake of this type of fat.
Stearic acid, which contributes substantially to the fatty acid composition in beef and other animal products, has been found to be as effective as oleic acid (monounsaturated fat) in lowering plasma cholesterol, when either one replaced palmitic acid (saturated fat). These findings have implications for the use of lean beef as a meat choice in a lipid-lowering diet.
The ATP III also emphasizes the use of plant stanols and sterols and viscous (soluble) fiber as therapeutic dietary options to enhance the lowering of LDL-C.
Clearly, research remains equivocal on certain key issues: the most effective macronutrient composition of a lipid-lowering diet and the relationship of exogenous cholesterol to serum lipid levels.
DeLorgeril M, Salen P, Martin J-L et al: Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction. Circulation 1999;99:779.
Denke MA: Dietary prescriptions to control dyslipidemias. Circulation 2002;105:132.
GISSI-Prevenzione Investigators: Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: Results of the GISSI-Prevenzione trial. Lancet 1999;354:447.
Von Schacky C, Angerer P, Kothny W et al: The effect of dietary w-3 fatty acids on coronary atherosclerosis: A randomized, double blind, placebo controlled trial. Ann Intern Med 1999;130:554.
2. Exercise—Daily physical activity is recommended as an adjunct to dietary modification for the initial treatment of hyperlipidemia. Cross-sectional and prospective studies have provided evidence suggesting that increased physical activity reduces the risk of morbidity and mortality from CAD. An independent relationship between exercise and fitness, and the level of total-C, HDL, LDL, and triglycerides has yet to be established definitively, however. The effects of exercise on plasma lipids and lipoproteins may be a consequence of changes in body weight, diet, or medication use.
It thus appears that individuals with high total cholesterol, LDL, and triglyceride levels and those with low HDL levels can show favorable changes in these parameters with physical training (both endurance and resistance). A randomized, controlled trial examined dietary modification and aerobic exercise with controls and concluded that the combination of diet and exercise reduced LDL levels but not HDL levels. Moreover, diet or exercise alone did not significantly alter LDL levels. What still needs to be defined, however, is the intensity, duration, and frequency of exercise necessary to benefit patients.
Stampfer MJ, Hu FB, Manson JE et al: Primary prevention of coronary heart disease through diet and lifestyle. N Engl J Med 2000;343:16.
Stefanik ML, Mackey S, Sheehan M et al: Effects of diet and exercise in men and postmenopausal women with low levels of HDL cholesterol and high levels of LDL cholesterol. N Engl J Med 1998;339:12.

Lipid Disorders

Lipid Disorders
CURRENT Diagnosis & Treatment in Cardiology

Peter C. Chien, MD & William H. Frishman, MD

General Considerations
Clinical Findings

ESSENTIALS OF DIAGNOSIS

Total serum cholesterol greater than 200 mg/dL on two samples at least 2 weeks apart

LDL cholesterol greater than 100 mg/dL

HDL cholesterol less than 40 mg/dL

Triglycerides greater than 200 mg/dL


General Considerations
In recent years, a great deal of emphasis has been placed on the relationship between elevated serum cholesterol levels—especially low-density lipoprotein cholesterol (LDL-C)—and the incidence of coronary artery disease (CAD). Hyperlipidemia represents a public health epidemic that continues to parallel the increased prevalence of obesity and is intimately implicated in the development of CAD. It is estimated that approximately 100 million American adults have total serum cholesterol levels in excess of 200 mg/dL and more than 12 million adults would qualify for lipid-lowering therapy by current national standards. Lowering LDL levels through diet and medication has been shown to reduce the progression of CAD and CAD mortality. According to the Framingham study, a 10% decrease in cholesterol level is associated with a 2% decrease in incidence of CAD morbidity and mortality.
A. LIPOPROTEINS

The major circulatory forms of cholesterol, cholesterol ester and triglyceride, are both insoluble in water; to circulate in an aqueous environment they combine with phospholipids and proteins in complexes known as lipoproteins. The protein components of these complexes, apoproteins, play an important role in the interaction between cell surface lipases and the lipoprotein receptors necessary for lipid catabolism. The six major classes of lipoproteins are listed in Table 2–1.

Table 2–1. Lipoprotein classes and composition.

1. Lipoprotein metabolism—Lipoprotein metabolism can be divided into exogenous and endogenous pathways, as shown in Figure 2–1.

Figure 2–1. Exogenous and endogenous pathways of lipoprotein metabolism. C = cholesterol; TG = triglyceride; MG = monoglyceride; DG = diglyceride; FFA = free fatty acid; LPL = lipoprotein lipase; APO = apolipoprotein; PL = phospholipids. Reproduced, with permission, from Mitchel Y: Evaluation and treatment of lipid disorders. Prac Diabetol 1987;6:6.


a. Exogenous pathway—The exogenous pathway is mainly responsible for absorption of dietary fat in the postprandial state and its subsequent distribution to the tissues. It begins with the absorption of dietary cholesterol and free fatty acids in intestinal microvilli, where they are converted to cholesterol esters and triglycerides, respectively, and packaged into chylomicrons that are secreted into the lymphatic system and enter the systemic circulation. In the capillaries of adipose tissue and muscle, the chylomicrons interact with an enzyme, lipoprotein lipase, which cleaves core triglycerides into mono- and diglycerides and free fatty acids that are taken up by surrounding tissue. Triglyceride hydrolysis reduces the core size of the chylomicron, resulting in an excess of surface components that are transferred to high-density lipoprotein (HDL). The remaining particle, a chylomicron remnant, is greatly reduced in size; it contains approximately equal amounts of cholesterol and triglycerides, and it acquires atherogenic potential.
The chylomicrons are rapidly removed from the circulation by the liver in a receptor-mediated process. The cholesterol can also be secreted, as bile acids, into the bile.
b. Endogenous pathway—The endogenous pathway delivers cholesterol and triglyceride to the tissues in the fasting state. It begins with the synthesis and secretion of very-low-density lipoprotein (VLDL) by the liver. This triglyceride-rich lipoprotein, which is smaller than the chylomicron, also interacts with lipoprotein lipase in the capillaries, adipose tissue, and muscle. Triglycerides within the core of the particle are cleaved and taken up by the surrounding fat and muscle; the redundant surface components are transferred to the HDL fractions. The remaining particle (VLDL remnant, or intermediate-density lipoprotein [IDL]), is a smaller lipoprotein, similar to the chylomicron remnant in its lipid composition and atherogenic potential. Approximately 50% of VLDL remnants are removed by the liver through the LDL receptor, which recognizes apoprotein E or the VLDL remnant. The highly atherogenic LDL contains mostly cholesterol ester and only one apoprotein, B-100. Its function is the delivery of cholesterol to tissues that require it (gonads, adrenals, rapidly dividing cells). The liver also plays a role in removing LDL from the blood via the LDL receptor. Two thirds of LDL is removed in this fashion; the remainder is removed by a non-LDL-receptor-mediated pathway in Kupffer cells, smooth muscle cells, and macrophages. It is believed that this mode of LDL uptake contributes to the development of foam cells and atherosclerosis. HDL, which seems to exert a protective effect against the development of atherosclerosis, is synthesized in both the liver and intestine and receives components during the lipoprotein lipase reaction. HDL is composed of approximately 50% protein (apoprotein A-I, A-II) and 20% cholesterol and comprises two major subfractions in the blood: HDL2 and HDL3. The latter is a small, dense particle that is believed to be the precursor of the larger cholesterol-enriched HDL2. The transfer of surface components during the lipoprotein lipase reaction is felt to be important in the formation of HDL2 and HDL3. HDL2 is believed to exert its protective effect through its participation in reverse cholesterol transport (picking up cholesterol from the cells involved in the atherosclerotic process and delivering them to the liver for excretion). HDL levels are higher in premenopausal women than in men, contributing to the lower incidence of CAD in women. There has been recent interest in cholesterol ester transfer protein, which is involved with the enzyme lecithin cholesterol acyl transferase in driving the reverse cholesterol transport process in moving cholesterol from peripheral tissues into plasma and then back into the liver.
B. LIPOPROTEIN(A)

Lipoprotein(a), a variation of LDL, is formed by two components: an LDL-like particle with apoprotein B-100 and a hydrophilic protein moiety known as apoprotein(a), which has a close structural homology with plasminogen. It may cause a perturbation in the thrombolytic system by binding to and displacing plasminogen from binding sites on fibrin, fibrinogen, and cell surfaces. It inhibits plasminogen activation by tPA through stearic hindrance of tPA-binding sites.
Accumulation of lipoprotein(a) has been found in atherosclerotic lesions, and it is now believed to be an atherogenic lipoprotein. Elevated plasma levels greater than 30 mg/dL in humans appear to be associated with an increased risk for the development of CAD, with a rate of occurrence estimated to be two to five times greater than in normal controls. Lipoprotein(a) is thought to be inherited by autosomal codominance. Some studies restrict identification of lipoprotein(a) as a risk factor for CAD only in the setting of elevated plasma LDL levels. Others have found the condition to be an independent risk factor. Diet, age, sex, smoking, body mass index, and apoprotein E polymorphism have not been found to correlate with plasma levels of lipoprotein(a). Increased lipoprotein(a) levels have been noted in patients with diabetes mellitus or nephrotic syndrome and immediately following myocardial infarction. In other studies, no changes have been observed in lipoprotein(a) levels in patients with acute myocardial infarction or unstable angina. Of the hypolipidemic interventions, niacin, neomycin, and extracorporeal removal of cholesterol have been shown to affect elevated lipoprotein(a) levels. Estrogen and fenofibrate may also reduce lipoprotein(a) levels.
C. LIPOPROTEINS AND ATHEROSCLEROSIS

Current concepts in atherosclerosis suggest that oxidation of LDL is involved in its pathogenesis. It is hypothesized that the critical role of oxidized LDL in atherogenesis is due to its rapid uptake by the foam cells lining the arterial intima, which are thought to have macrophage-like properties. The LDL is then oxidized, exerting a chemotactic effect on monocytes, leading to more uptake of LDL and thus to the formation of the atherosclerotic plaque. The endothelial cells and smooth muscles can also oxidize LDL.
Support for this lipid oxidation hypothesis comes from evidence that antioxidants such as vitamin E inhibit formation of lesions in hypercholesterolemic rabbits. Observations in some population studies also show an association between low plasma vitamin E levels and CAD incidence. However, clinical trials have not substantiated a reduction in the rates of fatal or nonfatal myocardial infarction with daily vitamin E use.
Clinical Findings
A. HISTORY

A history of lipid disorders should be sought in all routine evaluations and in patients with suspected or overt cardiovascular disease. Many individuals already know they have high cholesterol levels from screening tests performed at shopping malls, in other physicians' offices, or during prior hospitalization. A family history of premature cardiovascular disease is also useful. A history compatible with overt cardiovascular disease, especially in a young man or a premenopausal woman is highly suggestive of a lipoprotein disorder. In addition, a history or symptoms of other diseases associated with lipoprotein abnormalities (eg, diabetes mellitus, hypothyroidism, end-stage renal disease) should be sought (Table 2–2). Other risk factors for CAD should also be identified because they multiply the risk caused by lipid disorders (Table 2–3).

Table 2–2. Some acquired causes of hyperlipidemia.

Table 2–3. Risk factors that modify LDL-cholesterol goalsa

B. PHYSICAL EXAMINATION

Most individuals with lipid disorders have no specific physical findings. Depending on the duration and severity of the lipid disorder, they may have overt evidence of lipid deposition in the integument that follows certain phenotypes (I–V), as originally proposed by Frederickson and Lees. Eruptive xanthomas occur when triglyceride levels are high; they are seen in types I (increased chylomicrons caused by lipoprotein lipase deficiency), IV (familial combined hyperlipidemia), and V (familial hypertriglyceridemia). Tendon xanthomas are characteristic of type II (familial hypercholesterolemia) patients, who can also have tuberous xanthomas and xanthelasma; the latter, however, is nonspecific and can be found in individuals with normal lipid levels. Palmar and tuberoeruptive xanthomas are characteristic of type III (familial dysbetalipoproteinemia).
C. LABORATORY ASSESSMENT

The Expert Panel Report of the National Cholesterol Education Program on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP) suggests that a fasting lipid profile should be obtained in all adults 20 years of age or older at least once every 5 years. Without a family history of premature CAD or a history of familial hyperlipidemia, cholesterol screening should not be done routinely in children. Cholesterol values in the general pediatric population may not always predict the future development of hypercholesterolemia in adults.
For many years clinicians depended on total cholesterol and triglyceride measurements to determine specific patient treatment regimens. More sophisticated lipoprotein measurements were available only in research facilities. Recent advances have made lipoprotein subclass and apoprotein determinations available from many clinical laboratories.
LDL-C has been shown to be a more accurate predictor of CAD risk than is total-C. Low levels of HDL-C and the subfractions HDL2 and HDL3 have also been shown to be more powerful than total-C in predicting CAD. Levels of plasma apoproteins are also accurate predictors of CAD risk. It is controversial whether increases in plasma apoprotein B levels (the major apoprotein of LDL) and decreases in levels of apoproteins A-I and A-II (the major apoproteins of HDL) are better predictors of increased coronary risk than are total-C, HDL-C, LDL-C, or the ratio of total-C to HDL-C.
Nonetheless, a patient's risk of CAD can be adequately estimated by an accurate total-C measurement and a calculated LDL-C determination. (Mean serum cholesterol and calculated LDL-C values for various population groups have been reported on by the National Center for Health Statistics.)
Serum total-C levels can be measured at any time of day in the nonfasting state because total-C concentrations do not vary appreciably after eating. Patients who are acutely ill, losing weight, or pregnant or who recently had a myocardial infarction or stroke should be studied at a later time because cholesterol levels may be suppressed. Venipuncture should be carried out in patients who have been in the sitting position for at least 5 min, with the tourniquet applied for the briefest time possible. The blood may be collected as either serum or plasma. The National Cholesterol Education Program has established guidelines for standardization of lipid and lipoprotein measurements because of the great variations in accuracy at different laboratories that have been reported. The recommendation is that intralaboratory precision and accuracy for cholesterol determinations be no more than 3%. In a recent study assessing compact chemical analyzers for routine office determinations, some of the machines tested were shown to have accuracy and precision above the older (l988) target of 5% variance. A rapid capillary blood (fingerstick) methodology for cholesterol measurement is currently under development and evaluation.

LDL-C measurements are usually indirectly derived from the following formula:

LDL–C (mg/dL) = Total–C (mg/dL) – HDL–C (mg/dL) – triglyceride (mg/dL) ÷ 5

When using this formula with mm/L units, divide the triglyceride value by 2.3.

A reliable direct method for measuring LDL-C is needed because the accuracy of indirect estimates of LDL-C reflects measurements of total-C, HDL-C, and triglycerides, each of which contributes some degree of imprecision. Because triglyceride values are influenced by food, the patient should fast for at least 12 h before blood is taken for the LDL-C determination. If the triglyceride values are higher than 4.52 mm/L (> 400 mg/dL), the LDL-C value will be even less accurate. Direct measurement of LDL in a specialized laboratory, using ultracentrifugation, may be necessary when significant hypertriglyceridemia persists despite fasting.
Tests are now available for specific apolipoproteins. These tests have proven to be accurate predictors of cardiovascular risk in various research studies. Unfortunately, until more is known about their utility in clinical practice, they should not be used in routine clinical management.

Davis CE, Rifkind BM, Brenner H, et al: A single cholesterol measurement underestimates the risk of coronary heart disease. An empirical example from the Lipid Research Clinics Mortality Follow-Up Study. JAMA 1990;264:3044.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486.
Frishman WH, Zimetbaum P: Lipid-lowering drugs. In: Frishman WH, Sonnenblick EH, eds. Cardiovascular Pharmacotherapeutics. New York: McGraw Hill, 1997:399.
Frishman WH: Medical Management of Lipid Disorders: Focus on Prevention of Coronary Artery Disease. Mt. Kisco: Futura Publishing, 1992.
Lauer RM, Clarke WR: Use of cholesterol measurements in childhood for the prediction of adult hypercholesterolemia. The Muscatine Study. JAMA 1990;264:3034.
Virtamo J, Rapola JM, Ripatti S et al: Effect of vitamin E and beta-carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease. Arch Intern Med 1998;158:668.

Approach to Cardiac Disease Diagnosis-4

Approach to Cardiac Disease Diagnosis
CURRENT Diagnosis & Treatment in Cardiology

Approach to Cardiac Disease Diagnosis

Michael H. Crawford, MD

Physical Findings (cont'd)

B. DIAGNOSTIC STUDIES

1. Electrocardiography—Electrocardiography (ECG) is perhaps the least expensive of all cardiac diagnostic tests, providing considerable value for the money. Modern electrocardiogram-reading computers do an excellent job of measuring the various intervals between waveforms and calculating the heart rate and the left ventricular axis. These programs fall considerably short, however, when it comes to diagnosing complex ECG patterns and rhythm disturbances, and the test results must be read by a physician skilled at ECG interpretation.
Analysis of cardiac rhythm is perhaps the ECG's most widely used feature; it is used to clarify the mechanism of an irregular heart rhythm detected on physical examination or that of an extremely rapid or slow rhythm. The ECG is also used to monitor cardiac rate and rhythm; Holter monitoring and other continuous-ECG monitoring devices allow assessment of cardiac rate and rhythm on an ambulatory basis. ECG radio telemetry is also often used on hospital wards and between ambulances and emergency rooms to assess and monitor rhythm disturbances. There are two types of ambulatory ECG recorders: continuous recorders that record all heart beats over 24 or more hours and intermittent recorders that can be attached to the patient for weeks for months and then activated to provide brief recordings of infrequent events. In addition to analysis of cardiac rhythm, ambulatory ECG recordings can be used to detect ST-wave transients indicative of myocardial ischemia and certain electrophysiologic parameters of diagnostic and prognostic value. The most common use of ambulatory ECG monitoring is the evaluation of symptoms such as syncope, near-syncope, or palpitation for which there is no obvious cause and cardiac rhythm disturbances are suspected.
The ECG is an important tool for rapidly assessing metabolic and toxic disorders of the heart. Characteristic changes in the ST-T waves indicate imbalances of potassium and calcium. Drugs such as procainamide and the tricyclic antidepressants have characteristic effects on the QT and QRS intervals at toxic levels. Such observations on the ECG can be life-saving in emergency situations with comatose patients or cardiac arrest victims.
Chamber enlargement can be assessed through the characteristic changes of left or right ventricular and atrial enlargement. Occasionally, isolated signs of left atrial enlargement on the ECG may be the only diagnostic clue to mitral stenosis. Evidence of chamber enlargement on the ECG usually signifies an advanced stage of disease with a poorer prognosis than that of patients with the same disease but no discernible enlargement.
The ECG is an important tool in managing acute myocardial infarction. In patients with chest pain that is compatible with myocardial ischemia, the characteristic ST-T-wave elevations that do not resolve with nitroglycerin (and are unlikely to be the result of an old infarction) become the basis for thrombolytic therapy or primary angioplasty. Rapid resolution of the ECG changes of myocardial infarction after reperfusion therapy has prognostic value and identifies patients with reperfused coronary arteries.
Evidence of conduction abnormalities may help explain the mechanism of bradyarrhythmias and the likelihood of the need for a pacemaker. Conduction abnormalities may also aid in determining the cause of heart disease. For example, right bundle branch block and left anterior fascicular block are often seen in Chagas' cardiomyopathy, and left-axis deviation occurs in patients with a primum atrial septal defect.
A newer form of electrocardiography is the signal-averaged, or high-resolution, electrocardiogram. This device markedly accentuates the QRS complex so that low-amplitude afterpotentials, which correlate with a propensity toward ventricular arrhythmias and sudden death, can be detected. The signal-averaged ECG permits a more accurate measurement of QRS duration, which also has prognostic significance of established value in the stratification of risk of developing sustained ventricular arrhythmias in postmyocardial infarction patients, patients with coronary artery disease and unexplained syncope, and patients with nonischemic cardiomyopathy.
2. Echocardiography—Another frequently ordered cardiac diagnostic test, echocardiography is based on the use of ultrasound directed at the heart to create images of cardiac anatomy and display them in real time on a television screen or oscilloscope. Two-dimensional echocardiography is usually accomplished by placing an ultrasound transducer in various positions on the anterior chest and obtaining cross-sectional images of the heart and great vessels in a variety of standard planes. In general, two-dimensional echocardiography is excellent for detecting any anatomic abnormality of the heart and great vessels. In addition, because the heart is seen in real time, this modality can assess the function of cardiac chambers and valves throughout the cardiac cycle.
Transesophageal echocardiography (TEE) involves the placement of smaller ultrasound probes on a gastroscopic device for placement in the esophagus behind the heart; it produces much higher resolution images of posterior cardiac structures. TEE has made it possible to detect left atrial thrombi, small mitral valve vegetations, and thoracic aortic dissection with a high degree of accuracy.
The older analog echocardiographic display referred to as M-mode, motion-mode, or time-motion mode, is currently used for its high axial and temporal resolution. It is superior to two-dimensional echocardiography for measuring the size of structures in its axial direction, and its 1/1000-s sampling rate allows for the resolution of complex cardiac motion patterns. Its many disadvantages, including poor lateral resolution and the inability to distinguish whole heart motion from the motion of individual cardiac structures, have relegated it to a supporting role.
Doppler ultrasound can be combined with two-dimensional imaging to investigate blood flow in the heart and great vessels. It is based on determining the change in frequency (caused by the movement of blood in the given structure) of the reflected ultrasound compared with the transmitted ultrasound, and converting this difference into flow velocity. Color-flow Doppler echocardiography is most frequently used. In this technique, frequency shifts in each pixel of a selected area of the two-dimensional image are measured and converted into a color, depending on the direction of flow, the velocity, and the presence or absence of turbulent flow. When these color images are superimposed on the two-dimensional echocardiographic image, a moving color image of blood flow in the heart is created in real time. This is extremely useful for detecting regurgitant blood flow across cardiac valves and any abnormal communications in the heart.
Because color-flow imaging cannot resolve very high velocities, another Doppler mode must be used to quantitate the exact velocity and estimate the pressure gradient of the flow when high velocities are suspected. Continuous-wave Doppler, which almost continuously sends and receives ultrasound along a beam that can be aligned through the heart, is extremely accurate at resolving very high velocities such as those encountered with valvular aortic stenosis. The disadvantage of this technique is that the source of the high velocity within the beam cannot always be determined but must be assumed, based on the anatomy through which the beam passes. When there is ambiguity about the source of the high velocity, pulsed-wave Doppler is more useful. This technique is range-gated such that specific areas along the beam (sample volumes) can be investigated. One or more sample volumes can be examined and determinations made concerning the exact location of areas of high-velocity flow.
Two-dimensional echocardiographic imaging of dynamic left ventricular cross-sectional anatomy and the superimposition of a Doppler color-flow map provide more information than the traditional left ventricular cine-angiogram can. Ventricular wall motion can be interrogated in multiple planes, and left ventricular wall thickening during systole (an important measure of myocardial viability) can be assessed. In addition to demonstrating segmental wall motion abnormalities, echocardiography can estimate left ventricular volumes and ejection fraction. In addition, valvular regurgitation can be assessed at all four valves with the accuracy of the estimated severity equivalent to contrast angiography.
Doppler echocardiography has now largely replaced cardiac catheterization for deriving hemodynamics to estimate the severity of valve stenosis. Recorded Doppler velocities across a valve can be converted to pressure gradients by use of the simplified Bernoulli equation (pressure gradient = 4 × velocity2). Cardiac output can be measured by Doppler from the velocity recorded at cardiac anatomic sites of known size visualized on the two-dimensional echocardiographic image. Cardiac output and pressure gradient data can be used to calculate the stenotic valve area with remarkable accuracy. A complete echocardiographic examination including two-dimensional and M-mode anatomic and functional visualization, and color-, pulsed-, and continuous-wave Doppler examination of blood flow provides a considerable amount of information about cardiac structure and function. A full discussion of the usefulness of this technique is beyond the scope of this chapter, but individual uses of echocardiography will be discussed in later chapters.
Unfortunately, echocardiography is not without its technical difficulties and pitfalls. Like any noninvasive technique, it is not 100% accurate. Furthermore, it is impossible to obtain high-quality images or Doppler signals in as many as 5% of patients—especially those with emphysema, chest wall deformities, and obesity. Although TEE has made the examination of such patients easier, it does not solve all the problems of echocardiography. Despite these limitations, the technique is so powerful that it has moved out of the noninvasive laboratory and is now frequently being used in the operating room, the emergency room, and even the cardiac catheterization laboratory, to help guide procedures without the use of fluoroscopy.
3. Nuclear cardiac imaging—Nuclear cardiac imaging involves the injection of tracer amounts of radioactive elements attached to larger molecules or to the patient's own blood cells. The tracer-labeled blood is concentrated in certain areas of the heart, and a gamma ray detection camera is used to detect the radioactive emissions and form an image of the deployment of the tracer in the particular area. The single-crystal gamma camera produces planar images of the heart, depending on the relationship of the camera to the body. Multiple-head gamma cameras, which rotate around the patient, can produce single-photon emission computed tomography, displaying the cardiac anatomy in slices, each about 1-cm thick.
a. Myocardial perfusion imaging—The most common tracers used for imaging regional myocardial blood-flow distribution are thallium-201 and the technetium-99m-based agents, sestamibi and teboroxime. Thallium-201, a potassium analog that is efficiently extracted from the bloodstream by viable myocardial cells, is concentrated in the myocardium in areas of adequate blood flow and living myocardial cells. Thallium perfusion images show defects (a lower tracer concentration) in areas where blood flow is relatively reduced and in areas of damaged myocardial cells. If the damage is from frank necrosis or scar tissue formation, very little thallium will be taken up; ischemic cells may take up thallium more slowly or incompletely, producing relative defects in the image.
Myocardial perfusion problems are separated from nonviable myocardium by the fact that thallium eventually washes out of the myocardial cells and back into the circulation. If a defect detected on initial thallium imaging disappears over a period of 3–24 h, the area is presumably viable. A persistent defect suggests a myocardial scar. In addition to detecting viable myocardium and assessing the extent of new and old myocardial infarctions, thallium-201 imaging can also be used to detect myocardial ischemia during stress testing (see item 5. Stress Testing) as well as marked enlargement of the heart or dysfunction. The major problem with thallium imaging is photon attenuation because of chest wall structures, which can give an artifactual appearance of defects in the myocardium.
The technetium-99m-based agents take advantage of the shorter half-life of technetium (6 h; thallium 201's is 73 h); this allows for use of a larger dose, which results in higher energy emissions and higher quality images. Technetium-99m's higher energy emissions scatter less and are attenuated less by chest wall structures, reducing the number of artifacts. Because sestamibi undergoes considerably less washout after the initial myocardial uptake than thallium does, the evaluation of perfusion versus tissue damage requires two separate injections. Teboroxime, on the other hand, undergoes rapid washout after its initial accumulation in the myocardium, and imaging must be completed within 8 min after injection. It is used to detect rapid changes in the patient's status caused by dynamic changes in coronary patency that are produced by progression of the disease or the effects of treatment.
In addition to detecting perfusion deficits, myocardial imaging with the single-photon emission computed tomography (SPECT) system allows for a three-dimensional reconstruction of the heart, which can be displayed in any projection on a monitor screen. Such images can be formed at intervals during the cardiac cycle to create an image of the beating heart, which can be used to detect wall motion abnormalities and derive left ventricular volumes and ejection fraction. Matching wall motion abnormalities with perfusion defects provides additional confirmation that the perfusion defects visualized are true and not artifacts of photon attenuation. Also, extensive perfusion defects and wall motion abnormalities should be accompanied by decreases in ejection fraction.
b. Radionuclide angiography—Radionuclide angiography is based on visualizing radioactive tracers in the cavities of the heart over time. Radionuclide angiography is usually done with a single gamma camera in a single plane, and only one view of the heart is obtained. The most common technique is to record the amount of radioactivity received by the gamma camera over time and plot it. Although volume estimates by radionuclide angiography are not as accurate as those obtained by other methods, the ejection fraction is quite accurate. Wall motion can be assessed in the one plane imaged, but the technique is not as sensitive as other imaging modalities for detecting wall motion abnormalities.
Of the two basic techniques for performing radionuclide angiography, the oldest is the first-transit technique. This requires injecting a bolus of technetium-99m and observing its movement through the venous system into the right heart, pulmonary circulation, and finally to the left heart and the aorta. Because the sampling rate is relatively short in relation to the ECG R-R interval, it is possible to sample at least one cardiac cycle in each chamber of the heart. By determining the change in radioactivity over time, it is possible to measure the stroke volume or ejection fraction for each ventricle or chamber. The more popular radionuclide angiographic technique is multiple-gated acquisition (MUGA), or equilibrium-gated blood pool, radionuclide angiography. In this approach, technetium-99m is used to label the patient's own red blood cells, which remain within the vascular space, allowing imaging studies to be acquired for several hours. Imaging acquisition is synchronized with the R wave of the ECG, so that the lower amounts of radioactivity generated from this equilibrium technique can be accumulated from beat to beat. Once enough counts are collected in each phase of the cardiac cycle, the camera computer generates a composite cardiac cycle, with the final time/activity curve and imaging representing a composite of approximately 200 heart beats. MUGA is well suited for exercise stress testing because one injection of isotope can be used for both the resting and the exercise studies. Because many heart beats must be collected, imaging during exercise must be done during steady-state periods, when no marked fluctuations are present in heart rate. One limitation of the technique is that sudden beat-to-beat changes in left ventricular performance are obscured by the averaging technique. Because ischemic heart disease often results in such changes, the exercise MUGA has lost favor as a technique for detecting ischemic heart disease, since its sensitivity is not as high as other techniques. Currently, the major use of MUGA is to assess left ventricular performance (ejection fraction), especially in patients with technically inadequate echocardiograms.
4. Other cardiac imaging
a. Plain-film chest radiography—Plain-film chest radiography is used infrequently now for evaluating cardiac structural abnormalities because of the superiority of echocardiography in this regard. The chest x-ray film, however, has no equal for assessing pulmonary anatomy and is very useful for evaluating pulmonary venous congestion and hypoperfusion or hyperperfusion. In addition, abnormalities of the thoracic skeleton are found in certain cardiac disorders and radiographic corroboration may help with the diagnosis. Detection of intracardiac calcium deposits by the x-ray film or fluoroscopy is of some value in finding coronary artery, valvular, or pericardial disease.
b. Computed tomographic scanning—Computed tomography (CT) has been applied to cardiac imaging, but the image suffers because of the motion of the heart. Computed tomography has done a better job with evaluating the thoracic aorta and the pericardium, which are less mobile than the heart. Both these structures are more accurately evaluated with magnetic resonance imaging (MRI), however. Electron beam computed tomography (EB-CT) solves some of the motion problems and can be used more successfully for cardiac imaging. The major application of this newer technology to date has been the detection of small amounts of coronary artery calcium as an indicator of atherosclerosis in the coronary arterial tree. Although this technique has tremendous potential, its actual clinical utility, compared with other standard approaches is controversial.
c. Magnetic resonance imaging—Magnetic resonance imaging (MRI) probably has the most potential as a technique for evaluating cardiovascular disease. It is excellent for detecting aortic dissection and pericardial thickening and assessing left ventricular mass. Newer computer analysis techniques have solved the problem of myocardial motion and can be used to detect flow in the heart, much as color-flow Doppler is used. In addition, regional molecular disturbances can be created that place stripes of a different density in either the myocardium or the blood; these can then be followed through the cardiac cycle to determine structural deformation (eg, of the left ventricular wall) or the movement of the blood. When its full potential is reached, MRI might well compete successfully, in terms of image quality and information obtained, with Doppler echocardiography. Unfortunately, MRI studies take a long time to perform and are not readily done in sick patients who need a bedside evaluation; it is not likely to replace echocardiography in the near future.
d. Positron emission tomography—Positron emission tomography (PET) is a technique using tracers that simultaneously emit two high-energy photons. A circular array of detectors around the patient can detect these simultaneous events and accurately identify their origin in the heart. This results in improved spatial resolution, compared with single-photon emission computed tomography. It also allows for correction of tissue photon attenuation, resulting in the ability to accurately quantify radioactivity in the heart. PET scanning can be used to assess myocardial perfusion and myocardial metabolic activity separately by using different tracers coupled to different molecules. Most of the tracers developed for clinical use require a cyclotron for their generation; the cyclotron must be in close proximity to the PET imager because of the short half-life of the agents. Agents in clinical use include oxygen-15 (half-life 2 min), nitrogen-13 (half-life 10 min), carbon-11 (half-life 20 min) and fluorene-18 (half-life 110 min). These tracers can be coupled to many physiologically active molecules for assessing various functions of the myocardium. Because rubidium-82, with a half-life of 75 s, does not require a cyclotron and can be generated on-site, it is frequently used with PET scanning, especially for perfusion images. Ammonia containing nitrogen-13 and water containing oxygen-15 are also used as perfusion agents. C-11-labeled fatty acids and 18F fluorodeoxyglucose are common metabolic tracers used to assess myocardial viability, and acetate containing carbon-11 is often used to assess oxidative metabolism.
The main clinical uses of PET scanning involve the evaluation of coronary artery disease. It is used in perfusion studies at rest and during pharmacologic stress (exercise studies are less feasible). In addition to a qualitative assessment of perfusion defects, PET allows for a calculation of absolute regional myocardial blood flow or blood flow reserve. PET also assesses myocardial viability, using the metabolic tracers to detect metabolically active myocardium in areas of reduced perfusion. The presence of viability imply that returning perfusion to these areas would result in improved function of the ischemic myocardium. Although many authorities consider PET scanning the gold standard for determining myocardial viability, it has not been found to be 100% accurate. Thallium reuptake techniques and echocardiographic and MR imaging of wall-thickening characteristics have proved equally valuable for detecting myocardial viability in clinical studies.
5. Stress testing—Stress testing in various forms is most frequently applied in cases of suspected or overt ischemic heart disease (Table 1–3). Because ischemia represents an imbalance between myocardial oxygen supply and demand, exercise or pharmacologic stress increases myocardial oxygen demand and reveals an inadequate oxygen supply (hypoperfusion) in diseased coronary arteries. Stress testing can thus induce detectable ischemia in patients with no evidence of ischemia at rest. It is also used to determine cardiac reserve in patients with valvular and myocardial disease. Deterioration of left ventricular performance during exercise or other stresses suggests a diminution in cardiac reserve that would have therapeutic and prognostic implications. Although most stress test studies use some technique (Table 1–4) for directly assessing the myocardium, it is important not to forget the symptoms of angina pectoris or extreme dyspnea: light-headedness or syncope can be equally important in evaluating patients. Physical findings such as the development of pulmonary rales, ventricular gallops, murmurs, peripheral cyanosis, hypotension, excessive increases in heart rate, or inappropriate decreases in heart rate also have diagnostic and prognostic value. It is therefore important that a symptom assessment and physical examination always be done before, during, and after stress testing.

Table 1–3. Indications for stress testing.

Table 1–4. Methods of detecting myocardial ischemia during stress testing.

Electrocardiographic monitoring is the most common cardiac evaluation technique used during stress testing; it should be part of every stress test in order to assess heart rate and detect any arrhythmias. In patients with normal resting ECGs, diagnostic ST depression of myocardial ischemia has a fairly high sensitivity and specificity for detecting coronary artery disease in symptomatic patients if adequate stress is achieved (peak heart rate at least 85% of the patient's maximum predicted rate, based on age and gender). Exercise ECG testing is an excellent low-cost screening procedure for patients with chest pain consistent with coronary artery disease, normal resting ECGs, and the ability to exercise to maximal age- and gender-related levels.
A myocardial imaging technique is usually added to the exercise evaluation in patients whose ECGs are abnormal or, for some reason, less accurate. It is also used for determining the location and extent of myocardial ischemia in patients with known coronary artery disease. Imaging techniques, in general, enhance the sensitivity and specificity of the tests but are still not perfect, with false-positives and -negatives occurring 5–10% of the time.
Which adjunctive myocardial imaging technology to choose depends on the quality of the tests, their availability and cost, and the services provided by the laboratory. If these are all equal, the decision should be based on patient characteristics. For example, echocardiography might be appropriate for a patient suspected of developing ischemia during exercise profound enough to depress segmental left ventricular performance and worsen mitral regurgitation. On the other hand, in a patient with known three-vessel coronary artery disease and recurrent angina after revascularization, perfusion scanning might be the best test to determine which coronary artery is producing the symptoms.
Choosing the appropriate form of stress is also important (Table 1–5). Exercise, the preferred stress for increasing myocardial oxygen demand, also simulates the patient's normal daily activities and is therefore highly relevant clinically. There are essentially only two reasons for not choosing exercise stress, however: the patient's inability to exercise adequately because of physical or psychologic limitations; or the chosen test cannot be performed readily with exercise (eg, PET scanning). In these situations, pharmacologic stress is appropriate.

Table 1–5. Types of stress tests.

6. Cardiac catheterization—Cardiac catheterization is now mainly used for the assessment of coronary artery anatomy by coronary angiography. In fact, the cardiac catheterization laboratory has become more of a therapeutic than a diagnostic arena. Once significant coronary artery disease is identified, a variety of catheter-based interventions can be used to alleviate the obstruction to blood flow in the coronary arteries. At one time, hemodynamic measurements (pressure, flow, oxygen consumption) were necessary to accurately diagnose and quantitate the severity of valvular heart disease and intracardiac shunts. Currently, Doppler echocardiography has taken over this role almost completely, except in the few instances when Doppler studies are inadequate or believed to be inaccurate. Catheter-based hemodynamic assessments are still useful for differentiating cardiac constriction from restriction, despite advances in Doppler echocardiography. Currently, the catheterization laboratory is also more often used as a treatment arena for valvular and congenital heart disease. Certain stenotic valvular and arterial lesions can be treated successfully with catheter-delivered balloon expansion.
Myocardial biopsy is necessary to treat patients with heart transplants and is occasionally used to diagnose selected cases of suspected acute myocarditis. For this purpose, a biotome is usually placed in the right heart and several small pieces of myocardium are removed. Although this technique is relatively safe, myocardial perforation occasionally results.
7. Electrophysiologic testing—Electrophysiologic testing uses catheter-delivered electrodes in the heart to induce rhythm disorders and detect their structural basis. Certain arrhythmia foci and structural abnormalities that facilitate rhythm disturbances can be treated by catheter-delivered radiofrequency energy (ablation) or by the placement of various electronic devices that monitor rhythm disturbances and treat them accordingly through either pacing or internally delivered defibrillation shocks. Electrophysiologic testing and treatment now dominate the management of arrhythmias; the test is more accurate than the surface ECG for diagnosing many arrhythmias and detecting their substrate, and catheter ablation and electronic devices have been more successful than pharmacologic approaches at treating arrhythmias.
8. Test selection—In the current era of escalating health-care costs, ordering multiple tests is rarely justifiable, and the physician must pick the one test that will best define the patient's problem. Unfortunately, cardiology offers multiple competing technologies that often address the same issues, but only in a different way. The following five principles should be followed when considering which test to order:



What information is desired? If the test is not reasonably likely to provide the type of information needed to help the patient's problem, it should not be done, no matter how inexpensive and easy it is to obtain. At one time, for example, routine preoperative ECGs were done prior to major noncardiac surgery to detect which patients might be at risk for cardiac events in the perioperative period. Once it was determined that the resting ECG was not good at this, the practice was discontinued, despite its low cost and ready availability.



What is the cost of the test? If two tests can provide the same information and one is much more expensive than the other, the less expensive test should be ordered. For example, to determine whether a patient's remote history of prolonged chest pain was a myocardial infarction, the physician has a choice of an ECG or one of several imaging tests, such as echocardiography, resting thallium-201 scintigraphy, and the like. Because the ECG is the least expensive test, it should be performed for this purpose in most situations.



Is the test available? Sometimes the best test for the patient is not available in the given facility. If it is available at a nearby facility and the patient can go there without undue cost, the test should be obtained. If expensive travel is required, the costs and benefits of that test versus local alternatives need to be carefully considered.



What is the level of expertise of the laboratory and the physicians who interpret the tests? For many of the high-technology imaging tests, the level of expertise considerably affects the value of the test. Myocardial perfusion imaging is a classic example of this. Some laboratories are superlative in producing tests of diagnostic accuracy. In others, the numbers of false-positives and -negatives is so high as to render the tests almost worthless. Therefore, even though a given test may be available and inexpensive and could theoretically provide essential information, if the quality of the laboratory is not good, an alternative test should be sought.



What quality of service is provided by the laboratory? Patients are customers, and they need to be satisfied. If a laboratory makes the patients wait a long time, if it is tardy in getting the results to the physicians, or if great delays occur in accomplishing the test, choose an alternative lab (assuming, of course, that alternatives are available). Poor service cannot be tolerated.
Many other situations and considerations affect the choice of tests. For example, a young patient with incapacitating angina might have a high likelihood of having single-vessel disease that would be amenable to catheter-based revascularization. It might be prudent to take this patient directly to coronary arteriography with an eye toward diagnosing and treating the patient's disease in one setting for maximum cost-effectiveness. This approach, however, presents the risk of ordering an expensive catheterization rather than a less-expensive noninvasive test if the patient does not have significant coronary disease. If an assessment of left ventricular global performance is desirable in a patient known to need coronary arteriography, the assessment could be done by left ventricular cine-angiography at the time of cardiac catheterization. This would avoid the extra expense of echocardiography if it was not otherwise indicated. Physicians are frequently solicited to use the latest emerging technologies, which often have not been proved better than the standard techniques. It is generally unwise to begin using these usually more expensive methods until clinical trials have established their efficacy and cost-effectiveness.
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