	From the State University of New York Health Sciences Center, Stony Brook

	Atrial fibrillation is the most common sustained arrhythmia encountered in clinical practice, affecting approximately 2 million people in the United States alone.1 The risk of developing atrial fibrillation increases with age. Although its incidence in the fifth decade of life is only 0.5%, it increases to 4% by the seventh decade and to almost 9% by the eighth decade.2 In industrialized nations, the most common predisposing factor to atrial fibrillation is hypertension, with factors such as atherosclerotic heart disease, myocardial infarction, and cardiomyopathy playing lesser roles. In the developing world, rheumatic valvular disease outweighs other predisposing causes.

	Atrial fibrillation is typically characterized by an irregularly irregular R-R interval in the absence of P waves on electrocardiogram. The arrhythmia is recognized clinically by irregularly irregular heart sounds, often with variability in the intensity of S1, and a pulse deficit may be present. Disorganized atrial electrical activity may be evident, with atrial rates approaching 400 to 600 per minute.

	Depending on the atrioventricular nodal conduction, the ventricular rate in atrial fibrillation can be quite rapid. Gaining control of the ventricular rate is requisite for optimizing hemodynamics and avoiding tachycardia-related cardiomyopathy; however, ventricular rate control does not confer protection from the most feared complication of atrial fibrillation, namely, embolic stroke.

	Atrial fibrillation is a leading cause of stroke among Americans, accounting for an estimated 75,000 strokes annually.1 Cardioembolic strokes carry greater morbidity and mortality compared with nonembolic strokes.3

	Because of the economic impact and the severe long-term morbidity associated with stroke, there has been much investigation into stroke prevention in the population with atrial fibrillation. The primary approach to prevention has been warfarin therapy for chronic thromboprophylaxis in most patients, and unfractionated heparin for acute or interim therapy. The current American College of Cardiology/American Heart Association guidelines do show a role for aspirin therapy (table)4; however, only a small minority of patients with atrial fibrillation are eligible to be treated with aspirin alone.

	Until recently, restoration of sinus rhythm has been a major goal of atrial fibrillation therapy. Recent clinical trials, however, have shown rate control to be at least as effective, and, in some cases, superior to restoration of sinus rhythm. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) investigators’ data surprised many clinicians.5 This study showed that restoration of sinus rhythm does not reduce the rate of embolic events, and, with the exception of younger patients and those with congestive heart failure, rate control and concomitant warfarin therapy were superior to rhythm control.

	The effectiveness of warfarin therapy for thromboprophylaxis has been validated.6 Only about one half of the patients eligible for warfarin therapy actually receive it, however, because of its narrow therapeutic window, the need for close monitoring, and the agent’s many food and drug interactions. For these reasons, elderly patients, who are at the highest risk for embolic strokes, usually do not get warfarin therapy, whereas younger lower-risk patients with less to gain often do receive it.

	A report by Sudlow and colleagues underscores this problem.7 Their group looked at almost 5,000 patients selected at random from

	patients, 4.7% were found to have atrial fibrillation. Further investigation revealed that 43% of the patients with atrial fibrillation had a tem-porary contraindication to warfa-

	rin therapy, and 26% had a permanent contraindication as defined by the criteria set forth in the Stroke

	Prevention in Atrial Fibrillation (SPAF) trial.6

	Clearly, many patients need protection from cardioembolism but cannot take warfarin. This has led to the development of anticoagulants that act directly on thrombin rather than through the antagonism of vi-tamin K-dependent factor synthesis.

	Ximelagatran is an oral direct thrombin inhibitor. It is a competitive and reversible inhibitor of thrombin, and thus prevents the conversion of fibrinogen to fibrin. Ximelagatran is a prodrug that is hydrolyzed to form melagatran,

	the active compound. Melagatran, however, has poor bioavailability when taken orally, a problem overcome by substituting a hydroxyamidine group and an ethyl ester in place of an amidine and carboxylic acid moiety, respectively, to form ximelagatran. When taken orally, peak plasma levels are achieved in roughly 2 hours, with a half-life of 3.5 hours. The drug is excreted by the renal system and can be taken with or without food. Because of its reliable pharmacokinetics, ximelagatran does not require the extensive titration and monitoring needed with warfarin therapy.8

	The efficacy and safety of ximelagatran in the prevention of venous thromboembolism after orthopedic surgery have been validated.9 Recent studies have shown that ximelagatran is well tolerated and safe when taken by patients with atrial fibrillation for the prevention of stroke.10 In the Stroke Prevention by Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF II) trial, ximelagatran was given in three different dose schemes, each of which were compared with a control group on warfarin therapy.10 Based on the results, ximelagatran appears to be as effective as warfarin at preventing embolic stroke and is well tolerated at doses of up to 60 mg twice daily.10 Although there was a trend toward more minor bleeding in the ximelagatran group, the major bleeding episodes were similar between

	the two groups. The ximelagatran group also had a higher incidence

	of asymptomatic transaminase elevation (4.3% versus 0%). The transaminase elevations appeared 4 to 8 weeks into the study, and in all cases returned to baseline. Five of the patients with elevated liver function tests had a normalization of their values without stopping therapy. The mechanism and significance of these laboratory abnormalities remain under investigation. The ongoing SPORTIF III and IV trials continue to assess the efficacy and safety of ximelagatran in atrial fibrillation.

	Only 34% of the patients in the warfarin arm of SPORTIF II had an ideal international normalized ratio ([INR], 2—3) at the start of the study. This value increased to 57% by the completion of the 12-week study. This finding underscores the dif-ficult and cumbersome nature of warfarin therapy and its requir-

	ed monitoring. Rather than being an anomaly, these values likely reflect how well physicians are able to maintain warfarin therapy within its narrow therapeutic window, even under the best of circumstances.

	Some of the problems with warfarin therapy include this narrow therapeutic window and the drug’s contraindication in many patients. Finding an optimal therapy for patients at high risk for embolic stroke but with a contraindication to warfarin therapy has led physicians to explore new frontiers in treatment.

	It has been shown that in patients with nonrheumatic atrial fibrillation, most thrombi originate in the left atrial appendage. This finding has led to the hypothesis that occlusion, obliteration, or removal of the left atrial appendage may reduce cardioembolic events in atrial fibrillation patients. This is relatively easy to accomplish as an additional procedure for those undergoing aortocoronary bypass surgery or valvular surgery; however, most atrial fibrillation patients do not need these operations.

	It is feasible to perform surgical obliteration of the left atrial appendage with ligation or stapling using a thoracoscopic procedure.11 Sievert and colleagues demonstrated a technique called percutaneous left atrial appendage transcatheter occlusion, in which they achieved total occlusion of the left atrial appendage in 15 patients at risk of embolic stroke but with a contraindication to warfarin therapy.12 In a feasibility study, their group implanted a self-expanding poly-tetrafluoroethylene-coated nitinol cage into the left atrial appendage. Follow-up of these patients using transesophageal echocardiography showed the device to be well positioned and free of thrombus. Large-scale trials need to be done before further evaluation of this promising therapy can be made.

	Strokes that arise from cardio-emboli in the setting of atrial fibrillation are a major health concern for

	of oral direct thrombin inhibitors show promise as an effective and safe alternative to warfarin therapy. For those patients who cannot tolerate any degree of anticoagulation,

	percutaneous left atrial appendage transcatheter occlusion, like most catheter-based techniques, can be expected to evolve rapidly as a treatment for this population. Finally, patients who have the need for aortocoronary bypass or other open thoracotomy procedures may be treated with surgical ligation of the left atrial appendage.

Articles

Cardiology Review Online

Preventing strokes in atrial fibrillation: New answers to old questions

	In the fall of 1984, Cardiology Review first appeared and was known as Cardiology Board Review. We are celebrating the 20th anniversary of our journal with this special issue. Now is a good time to take stock of changes in the field because the past two decades have seen impressive strides in the diagnosis and treatment of cardiovascular disease.

	Several new drugs have been approved for hypertension treatment since Cardiology Review was founded. Twenty years ago, our antihypertensive armamentarium did not include angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers. Today, these are some of our most popular agents. At the same time, there are still conflicting views on which drugs to use as first-line agents and which combinations to employ. Many

	of the drugs in use have been shown to cause regression of left ventricular hypertrophy. Ironi-

	cally, diuretics are the exception; however, because of the recommendations of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7), this class of drugs is once again considered a first-line agent. Many of my colleagues are not so sure of the wisdom of this recommendation, nor am I.

	Momentous changes are apparent in the treatment of heart failure. The ramifications of these changes are discussed by Drs. Gretchen Wells and William C. Little and commented on in depth by Dr. Michael W. Rich.

	It also seems there is always a new drug to treat arrhythmias (atrial or ventricular), and the past two decades have seen a slew of such agents. None has had the impact of amiodarone for both types of arrhythmias, yet the greatest advance in this field has been nonpharmacologic. Despite drug therapy, we are now clearly in the era of automatic implantable cardioverter-defibrillators, which are extremely important life-saving devices. Dr. Stephen C. Vlay discusses the impact of device therapy in the past 20 years. Dr. William J. Mandel comments on his review and adds some thoughts of his own.

	The major advance in coronary artery disease (CAD) treatment has been the widespread use of interventional therapy, especially drug-eluting stents. Drs. Sailajah Janarthanan and Joseph S. Alpert nicely sum up where we stand today in the management of chronic angina, and Dr. Kanu Chatterjee provides additional insightful comments. Therapy of acute myocardial infarction (MI) has also been

	revolutionized, first with thrombolytic agents, then with per-cutaneous transluminal coron-ary angioplasty, and finally with stents.

	In lipid therapy we have had a fantastic breakthrough as well. The class of drugs commonly referred to as statins (HMG-CoA reductase inhibitors) have been shown to dramatically lower low-density lipoprotein cholesterol levels and to markedly improve the endothelial function of two of the most important arterial systems in the body—those supplying the heart and the brain. Thereduction in morbidity and mortality associated with these drugs in patients with known CAD (secondary prevention) is obviously of clinical importance, but I think in the long run the primary prevention of cardiovascular events in apparently healthy subjects will have an even greater public health impact.

	Just as statins have revolutionized lipid management, ACE inhibitors have done the same for diabetes, in many cases blunting the deleterious effect of this disease on the kidney and the vasculature (statins here are helpful as well). The controversy over whether tight blood glucose control can slow the development of vascular events now appears to be resolved—tight control helps. The major impact of the thrombolytic agents is just now being felt in stroke patients,

	a good decade after the breakthrough in the acute MI field. Treating a “brain attack” is now becoming more like treating a “heart attack.”

	This issue also features a bonus overview article. It appears in the combined stroke and arrhythmias section. Dr. Ethan Levine provides updates of current concepts in the relationship between atrial fibrillation and stroke, especially pathophysiology and treatment.

	I hope you enjoy this issue. Cardiology Review is 20 years old and still going strong. Happy Birthday!

Celebrating 20 years of advances in cardiology

	In this issue of Cardiology Review, Dr. Stephen Vlay (page 21) discusses a wide range of issues related to device therapy for cardiac arrhythmias, including evaluation and treatment aspects. The first device he reviews is the implantable loop recorder. This unit clearly helps clinicians who have evaluated patients with recurrent but previously undocumented symptoms, such as palpitations, tachycardia, or syncope. The loop recorder allows clinicians to use a long-term, automated device to document bradycardia or tachycardia in patients who have sporadic but seriously symptomatic episodes. Implantation and interrogation are simple, offering clinicians a major step forward in evaluating these difficult clinical problems.

	The second device Dr. Vlay reviews is the pacemaker. Since being introduced in the early 1960s, the dramatic improvements in the reliability of these devices have been superseded by their markedly enhanced pacing and recording capacities. Many data are available to assess the type, frequency, and duration of the arrhythmia. Telemetry data allow clinicians to differentiate between atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, and other arrhythmias. Interrogation of simple modes, such as mode switching, allows episodes of silent atrial fibrillation to be detected. Pacemakers help clinicians assess changes in therapy, such as anticoagulation, primary antifibrillation therapy, and others.

	The third section of Dr. Vlay’s review deals with implantable cardioverter defibrillators (ICDs). Since being introduced by Mirowski and Mower in 1973, there has been a

	devices.1 The indications for their use have expanded as these devices have become more complex. Significant controversy exists, however, with regard to the indications for their implantation. Questions still exist as to which patients will benefit from prophylactic (primary prevention implantation) versus therapeutic (secondary prevention implantation) use. Data from the secondary prevention trials (AVID, CIDS, and CASH [trial acronyms are defined on the next page]) have been reviewed in detail, but the criteria for identifying the ideal candidate for ICD implantation has not been resolved.2-4

	Even more controversy exists as to ICD use in primary prevention. A detailed analysis of trials such as the CABG Patch trial, MUSTT, MADIT, and MADIT II have undergone extensive scrutiny.5-8 Guidelines from both the United States and Europe have been published and should be reviewed by all clinicians who implant these devices.9,10

	The use of ICD therapy is further complicated by evaluation of the patient population. The use of prophylactic ICD implantation in those with nonischemic cardiomyopathy has been the subject of intense scru-tiny. Studies reviewing such trials

	as GESICA, CHF-STAT, and now AMIOVIRT have been done.11-13 These studies generally present a negative review with regard to the use of prophylactic ICD implantation in patients with nonischemic cardiomyopathy.

	Other controversies exist, including the need for a “shock box” with limited capabilities. The advantages of a more complex device, such as dual-chamber ICDs versus single-chamber ICDs, have not fully been evaluated. The latter controversy has been addressed in the DAVID study.14

	Another important area reviewed by Dr. Vlay concerns resynchronization therapy—a novel approach to the treatment of congestive heart failure. This form of pacing has gained rapid acceptance among cardiologists. Again, however, significant controversy exists with regard to what parameters should be used as indicators for using this device, from the simplistic use of QRS

	duration (with left bundle branch block) to the use of tissue Doppler studies and tagged magnetic res-onance imaging. Several clinical trials (COMPANION, MIRACLE ICD, Contak CD, and CARE HF) have focused on the evolution of this therapy.14-17 One interesting observation from the DAVID study has substantial implications for the entire pop-ulation of pacemaker patients; it

	questions whether right ventricular pacing itself promotes desynchronization, thereby causing ventricular function to worsen.

	Unique applications may be developed for pacing, including therapy for sleep apnea.18 Ultimately the development of a truly biologic pacemaker may be on the horizon.

Device therapy: Whats new  and different? William J. Mandel, MD

	From the Cardiology Division, State University of New York, Stony Brook

	Advances in technology have greatly enhanced the ability to diagnose and treat cardiac arrhythmias. This review focuses on the major device innovations achieved in the past decade and highlights their importance for the clinician. Implantable loop recorder Without a confirmed diagnosis, physicians cannot prescribe appropriate treatment for cardiac arrhythmias. Dizziness or syncope may be related to another cause. The Holter monitor was a significant diagnostic advance because it documented the cardiac rhythm for a 24-hour period, and its results could then be compared with the diary of symptoms that the patient recorded. In many cases, however, symptoms recurred after the patient had returned the Holter monitor for analysis. With an external loop recorder, the patient has a 30-day period to record symptoms. Although electrophysiology study documents conduction disturbances (atrial and ventricular arrhythmias), it may on occasion be nondiagnostic if the abnormalities are intermittent of if the arrhythmia is noninducible at the time of study. If the cause for a patient’s symptoms is elusive, an implantable loop recorder can be helpful. Inserted under the skin, it can record five auto-

	matic events as well as three patient-triggered events. The automatic events are programmed: for example, asystole greater than 3 seconds, and specified rates of tachycardia and of bradycardia.

	If symptoms (dizziness, syncope, and palpitations) are reported by the patient, the implantable loop recorder is interrogated. If sinus rhythm is documented, then the cause is not arrhythmia. The implantable loop recorder accurately documents every known rhythm disturbance, including heart block, supraventricular and ventricular tachycardia, asystole, and even myocardial ischemia.1 This device has a battery life of 14 months.

	Pacemaker technology has resulted in dramatic improvements in programmability and diagnostic features. Physicians know that available programmable features include rate, amplitude, time intervals, and rate response (the ability of the pacemaker to increase rate based on skeletal muscle activity). Today, however, pacemakers have many additional features that may be underutilized.

	One such important feature is stored telemetry. The ability to record the heart rate from both the

	atrial and ventricular electrodes allows documentation of cardiac arrhythmias. The rate histogram in-dicates the time that the patient spends at a particular heart rate, allowing the clinician to determine whether the heart rate is appropriate for the patient. If a high rate of atrial or ventricular activity is observed, the patient has an arrhythmia that requires attention. This is especially true for patients with silent atrial

	It is well known that atrial fibrillation is common after the age of 65 years. If a patient does not have symptoms, the arrhythmia may go unnoticed, and thrombus may occur and result in stroke. Anticoagulation can then be recommended (if otherwise appropriate) for pacemaker patients in whom atrial fibrillation is documented.2

	Automatic threshold measurement is available on many contemporary pacemakers, allowing the pacemaker to perform a test during which it measures the minimal amplitude necessary to evoke a potential. If loss of capture is noted, the pacemaker will automatically increase the output, ensuring a safety margin.

	In addition to documenting atrial arrhythmias, certain pacemakers can respond by attempting to pace the rhythm to normal.3 Antitachycardia pacing algorithms are used to interrupt a reentrant tachycardia that may lead to patient symptoms. This application may be useful for patients in whom radiofrequency catheter ablation has failed to eliminate the atrial arrhythmia. Antitachycardia pacing may also be used as the first therapy for ventricular tachycardia in patients who have implantable cardioverter defibrillators (ICDs).

	The superiority of ICD therapy over antiarrhythmic drug therapy is well established. For patients with life-threatening ventricular arrhythmias, the ICD is able to recognize the problem and deliver therapy within seconds. Physicians are able to program either antitachycardia pacing algorithms or shock therapy depending on the arrhythmia and the known response of the patient to pacing. Ventricular tachycardia is recognized in 3 to 4 seconds; the device charges in 3 to 4 seconds; and the arrhythmia is over in 6 to 8 seconds, which is faster than one can telephone for help.

	The Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) study showed an improved outcome using ICD therapy for postinfarction patients with an ejection fraction of 0.30 or less and a QRS duration of 130 milliseconds or more.4 Insurance reimbursement for this indication is controversial. Although Medicare has recommended payment, reimbursement is not in effect in all areas of the country.

	Innovations in ICD therapy include increased energy delivery and smaller battery and pulse generator size. The pectoral implant is easy to accomplish and is tolerated well by most patients. ICD pulse generators last approximately 5 to 6 years. ICDs also have enhanced telemetry data storage, enabling documentation of the arrhythmia. In a dual-chamber device, the stored electrograms from both the atrial and ventricular electrodes permit distinction between tachycardias from each chamber. Advances in electrode technology are designed to provide better sensing, energy delivery, and longevity.

	It is relatively straightforward to replace the pulse generator. The electrode is more problematic because it is an indwelling structure that can adhere to veins and the myocardium and thus may be difficult to extract.

	Health care providers should know that all ICDs have the ability to pace. Whether this function is enabled or is used as backup depends on the individual needs of the patient. Some patients require pacing because of conduction disturbances or to suppress arrhythmias. In other patients, constant ventricular pacing from the right ventricular apex may alter the geometry of contraction and thus be detrimental. In these patients, pacing may be programmed only for backup.5 For those who have heart failure related to pacing-induced bundle branch block, an upgrade to cardiac resynchronization therapy may be an option.

	Remote monitoring has recently become available with some ICDs. This ability benefits patients who require monitoring of the device but live far away. Presently, remote programming is not possible and is a limitation of this method of follow-up.

	Biventricular pacing for pacemaker and defibrillator patients has provided a major benefit for patients with congestive heart failure.6-8 Dyssynchrony between the right and left ventricles resulted in a reduction in cardiac output and a change in the geometry of ventricular contraction. As a result, the left ventricle dilates, the left ventricular ejection fraction decreases, in some cases the mitral annulus may enlarge, and mitral regurgitation occurs or increases.

	the left and right ventricle has been demonstrated to improve both morbidity and mortality. Most patients show an improvement in the following: New York Heart Associa-tion (NYHA) functional class, the ability to participate in a 6-minute walk test, myocardial oxygen consumption (decreases), left ventricular ejection fraction, and the amount of mitral regurgitation (decreases).

	Current indications for cardiac resynchronization therapy include heart failure patients with bundle branch block, QRS duration greater than 130 milliseconds, NYHA functional class III or IV heart failure on maximal tolerated medical therapy, and a left ventricular ejection fraction of 0.35 or more. Resynchronization is accomplished with an additional electrode to pace the left ventricle simultaneously with the right ventricle. To accomplish this, an electrode is inserted into a coronary sinus and advanced to a position in a branch vein, optimally a posterolateral branch. Alternate approaches are being studied.

	As more patients receive implanted devices, management of electrodes becomes an issue. Electrodes usually have longevity of more than 10 to 15 years before they deteriorate and cannot be used. Insulation and conduction failures, sometimes from a subclavian crush injury, result in the premature need for a new electrode.

	Every intravascular electrode limits the space and alters the anatomy for subsequent leads. In short, it gets “crowded” in the intravascular space and sometimes the vein becomes thrombosed. Removal of indwelling electrodes is difficult, particularly after the first 6 to 12 months, because they adhere to tissue. Pulling can tear the lining of the vein or remove a piece of myocardium, both of which can result in catastrophic bleeding or tamponade. Sometimes it is difficult to completely remove the electrode from the vein.

	An extraction system was developed in which a sheath was placed over the electrode and advanced down to the tip, breaking adhesions along the way. When the sheath reached the tip, it was braced against the myocardial wall, providing countertraction as the electrode was pulled back, avoiding eventration. The most recent innovation uses a laser extraction sheath that lyses the adhesions as the sheath is advanced and results in easier removal.9

	Some physicians favor the removal of all old hardware. The procedure has risks, however, and is currently reserved for those situations in which removal of the electrode is absolutely necessary, such as in cases of infection. Another situation in which extraction is helpful is when the vein is thrombosed. The old electrode can be removed through the laser-guided sheath and the new electrode introduced through the same sheath.

	Sudden cardiac arrest is treated most successfully the faster the arrhythmia is terminated. The recent development and widespread availability of automatic external defibrillators is expected to improve outcome. The devices are small, lightweight, and easy to use. Although they were once limited to paramedics and fire and police departments, they are becoming readily available in public facilities, including schools, offices, shopping malls, and theaters. Health care providers have a responsibility to educate the public about their benefit.

	Clinical electrophysiology continues to evolve with better understanding of arrhythmias and novel ways to prevent or eliminate them. Health care providers should be aware of the indications for pacing and ICD therapy. These recommendations are available from the NASPE-Heart Rhythm Society, the American College of Cardiology, and the American Heart Association.10  n

Advances in device therapy for cardiac arrhythmias

	Chronic stable angina is a fairly common clinical syndrome. In the United States, it has been reported that the annual incidence of angina in patients older than 30 years is 213 per 100,000.1 It has also been estimated that currently 16.5 million Americans have stable angina.2 The incidence of stable angina from chronic ischemic heart disease is likely to increase in the future because of an aging population and improved survival of patients with acute coronary syndromes. The World Health Organization projects that in the year 2020 coronary artery disease will still remain a major disease burden, accounting for 5.9% of the total global disease burden and 11.2% of that in developed countries.3

	In approximately 50% of patients with ischemic heart disease, chronic stable angina is the initial manifestation.2 Chronic stable angina is not a benign clinical entity. It is associated with considerable morbidity and mortality. The rate of myocardial infarction (MI) is about 3% to 3.5% in patients with angina, affecting approximately 1 million patients per year in the United States.

	The economic burden is also considerable. The annual Medicare payments for the evaluation and management of stable angina are approximately $7.5 billion, with total hospitalization costs including non-Medicare patients being almost twice this amount. Thus, future studies should address how to reduce the morbidity, mortality, and economic burden associated with treating patients with chronic stable angina. Drs. Janarthanan and Alpert lucidly describe the pathophysiologic mechanisms of stable angina that result from myocardial ischemia, which is caused by an imbalance between myocardial oxygen demand and oxygen supply. Myocardial ischemia may occur from an excessive increase in myocardial oxygen demand or from a primary decrease in oxygen supply because of decreased coronary blood flow. The principal abnormality inducing myocardial ischemia, however, may not be the same in all the clinical subsets of stable angina (table).4 In patients with classic angina (angina of effort), an excessive increase in myocardial oxygen demand is the principal mechanism (demand ischemia). In patients with vasospastic angina, a focal spasm of an epicardial coronary artery decreases coronary blood flow and induces myocardial ischemia (supply ischemia). In those with linked angina, walk-through angina, postprandial angina, and syndrome X, increased coronary vascular resistance decreasing coronary blood flow is the principal mechanism of myocardial ischemia. In some clinical subsets, such as mixed angina, increased myocardial oxygen demand and increased coronary vascular resistance contribute to myocardial ischemia. An understanding of the mechanisms of myocardial ischemia in the various clinical subsets of angina is necessary for appropriate management. Future studies that delineate the precise mechanisms of dynamic changes in myocardial oxygen demand and coronary vascular tone will improve treatment of patients with chronic stable angina.

	Drs. Janarthanan and Alpert’s detailed review of the management of stable angina shows two major objectives of treatment. The first is to decrease the risks of death and MI, and the second is to relieve myocardial ischemia and its major symptom, angina. Antiplatelet drugs, such as aspirin and clopidogrel,

	and angiotensin-converting enzyme inhibitors, beta-adrenergic antagonists, and lipid-lowering agents (HMG-CoA reductase inhibitors [statins]), have been proved to decrease morbidity and mortality. All patients with ischemic heart disease should receive these therapies.

	Concomitant therapies to modify risk factors (diabetes, hypertension, obesity, and smoking) should be implemented. Clinicians should understand that the treatments presently available are only partially successful in reducing risks of death and MI. Research must continue to develop newer treatments to further reduce morbidity and mortality. A promising treatment, infusion of apolipoprotein MILANO, has been reported to cause rapid regression of atherosclerotic plaque.

	The conventional pharmacotherapy for relief of angina and myocardial ischemia, as outlined by Drs. Janarthanan and Alpert, consists of beta-adrenergic antagonists, nitrates, and calcium channel blocking agents. Nonpharmacotherapy is catheter-based or surgical revascularization. Because the incidence of refractory angina is increasing, research must continue to discover newer treatments for angina. Enhanced external counterpulsation is already an approved therapy for refractory angina.

	Several pharmacologic agents are undergoing clinical trials and a few appear promising. Nicorandil, a potassium channel activator, not only decreases myocardial oxygen demand and improves myocardial perfusion, but also possesses cardioprotective effects. Ranolazine, a partial inhibitor of free fatty acid oxidation, reduces myocardial ischemia by increasing myocardial oxygen supply without increasing coronary blood flow or changing myocardial oxygen demand. Angiogenic gene therapy with adenovirus 5 fibroblast growth factor-4 also shows potential for treating angina.5 These promising new therapies indicate it is reasonable to be optimistic about the future management of myocardial ischemia and angina.

Chronic stable angina: Looking into the future

	From the Department of Medicine, University of Arizona Health Sciences Center, Tucson, Arizona

	Coronary artery disease (CAD) is the leading cause of death in adults in the United States, accounting for about one third of all deaths in subjects older than 35 years.1 The prevalence of this disease is approximately one third to one half that of all cardiovascular disease. The lifetime risk of CAD for individuals at age 40 years is 49% for men and 32% for women; the lifetime risk is also appreciable in those free of this disease at age 70 years, at 35% for men and 24% for women. The death rate from CAD is higher in men than in women, declining from three times higher at ages 25 to 34 years to 1.6 times higher at ages 75 to 84 years, and in blacks than in whites, an excess that disappears by age 75 years. Among the Hispanic population, mortality from CAD is not as high as it is among blacks or whites.1

	Mortality rates for cardiovascular disease and CAD in men and women and in blacks and whites have fallen in most countries by 24% to 28% since 1975, although the decline has slowed since 1990.1 Approximately 45% of this reduction is attributable to improvement in medical therapy for coronary disease; the remaining 55% is the result of risk-factor reduction, particularly to a decline in smoking and from treatment of hypertension.

	Data from 44 years of follow-up of the original Framingham Heart

	Study1 cohort and 20 years of surveillance of their offspring have allowed the incidence of initial coronary events to be ascertained, including both

	recognized and clinically unrecognized myocardial infarction (MI), angina pectoris, unstable angina, and sudden and nonsudden coronary deaths. For 40-year-olds, the lifetime risk of developing CAD is 49% in men and 32%

	in women. For those reaching age 70 years, it is 35% for men and 24% for women. For the more serious manifestations of CAD, such as MI and sudden death, women lag behind men in incidence by 20 years, but the sex ratio for incidence narrows progressively with advancing age. The incidence at ages 65 to 94 years compared with ages 35 to 64 years more than doubles

	in men and triples in women. In premenopausal women, serious man-

	ifestations of CAD, such as MI and sudden death, are relatively rare. Be-

	yond menopause, the incidence and severity of coronary disease increases abruptly. The male predominance of CAD is least striking for angina pectoris. Before age 75 years, the initial presentation of coronary disease in women is more likely to be angina pectoris than MI. Furthermore, angina in women is more likely to be uncomplicated (80% of cases), whereas angina in men often occurs after an MI (66%).1 Infarction predominates at virtually all ages in men, in whom only 20% of infarctions are preceded by long-standing angina, with the percentage being even lower if the MI is silent or unrecognized.

	Angina is caused by myocardial ischemia that occurs whenever myocardial oxygen demand exceeds oxygen supply. An understanding of the pathophysiology of angina first requires a brief review of the determinants of oxygen demand and supply.

	Myocardial oxygen demand. Four major factors determine myocardial work and therefore myocardial oxygen demand: (1) heart rate; (2) systolic blood pressure (the clinical marker of afterload); (3) myocardial wall tension or stress (the product of ventricular end-diastolic volume or preload and myocardial muscle mass); and (4) myocardial contractility.

	Clinical conditions associated with an increase in oxygen demand affect one or more of these parameters. Examples include increased catecholamine levels, as with vigorous exertion or mental-stress tachycardia of any etiology; hypertension; and left ventricular hypertrophy. Individuals consistently experience angina during exercise testing when asked to exceed a defined angina threshold or absolute double-product value.

	Myocardial oxygen supply. The major determinants of oxygen supply are the oxygen-carrying capacity of the blood. This is determined by oxygen tension and hemoglobin level; the degree of oxygen unloading from hemoglobin to the tissues, which is related to red blood cell 2,3-diphosphoglycerate levels; and coronary artery blood flow, which is influenced by: (1) coronary artery diameter and vessel tone (resistance); (2) collateral flow; (3) perfusion pressure, which is determined by the pressure gradient from the aorta to the coronary end-arterial vessels and by the left ventricular end-diastolic pressure (because the direction of blood flow is from epicardium to endocardium); and (4) heart rate and diastolic period (because coronary artery blood flow occurs primarily during diastole).

	The most frequent cause of myocardial ischemia is coronary arterial atherosclerosis. Other causes include coronary artery vasospasm, fibrosis, and embolism. In addition, stimulation of the esophagus by acid can cause coronary artery vasoconstriction and a reduction in coronary blood flow via a neural cardio-esophageal reflex.

	A clinical diagnosis of angina pectoris has a 90% predictive accuracy for the presence of CAD2; however, based on Bayesian principles, this depends upon the prevalence of CAD in population subgroups, such as men versus women and young versus old persons.

	Atherosclerotic obstruction is the fundamental mechanism underlying exertional angina. Although a plaque causing a tight stenosis is more prone to cause complete obstruction and to result in unstable angina or MI, most MIs are characterized by rupture of plaque with less than 50% stenosis. This is true because nonobstructive plaques are so abundant. Why smaller lesions are more likely to cause acute ischemic events is incompletely understood. One possibility is that activation of foam cells (macrophages that contain lipids) at the margins of small plaques contributes to plaque rupture through these cells’ secretion of metalloproteinases that penetrate the thin fibrous cap of the plaque. In contrast, larger lesions are more likely to be calcified, with less inflammation and a thicker cap. Another possible explanation is that less obstructive plaques are subject to greater circumferential tensile stress on the fibrous cap. According to Laplace’s law, vascular wall tension is related to luminal pressure and the radius of the vessel, and less obstructive lesions therefore result in larger luminal diameters and greater wall stress. Also, individuals with tight stenoses are more likely to develop collateral circulation that can protect them from MIs in the face of a complete arterial occlusion.

	Endothelial dysfunction is one of the earliest signs of atherosclerosis. The endothelium consists of cells that line the walls of the vasculature and actively secrete substances that determine vascular tone as well as local balance of coagulation, anticoagulation, and cellular activity. These cells secrete substances such as ni-tric oxide, endothelin, prostacyclin, thromboxane, tissue plasminogen activator, heparin, platelet-derived growth factor, and macrophage colony-stimulating factor. Endothelial-dependent vasorelaxation depends upon the generation and preservation of nitric oxide—also known as endothelium-derived relaxing factor&mdash;a most potent endogenous vasodilator. Endothelial-independent vasorelaxation refers to dilatory capacity when a nitric-oxide precursor is given.

	Endothelial function may be assessed invasively by measuring vasodilatory response to an infusion of acetylcholine. A normal response is dilation, whereas an abnormal response is constriction or no change. Noninvasive measurement of brachial artery dilation in response to

	postocclusive hyperemia is the most common way to assess endothelial function in vivo.

	The composition of atheroscle-rotic plaques is an important deter-minant of their susceptibility to instability and fissure, rupture, or dissection, with resulting thrombosis. In an angioscopic study of human coronary arteries, yellowish plaques with an increased lipid core and a thin fibrous cap were associ-ated with a high incidence of acute ischemic events, such as unstable angina or infarction. In comparison, white plaques, which have thicker fibrous caps overlying the lipid core, were primarily associated with stable angina. Ruptured yellow plaques and red or pink thrombi also were more common in patients with acute coronary syndromes.

	Yellow plaques at angioscopy are also associated with higher serum concentrations of total cholesterol, low-density lipoprotein (LDL) cholesterol, and apolipoprotein (apo) B than is the case with white plaques. Among men with coronary disease who die suddenly, hypercholesterolemia appears to predispose vul-

	nerable plaques to rupture, with subsequent sudden death. Why atherosclerotic plaques become disrupted is not fully understood. Two major factors thought to contribute to weakening of the fibrous cap of a plaque are inflammation and accelerated degradation of collagen and other matrix components.

	The immediate site of plaque rupture or erosion is marked by an active inflammatory process consisting of activated monocytes and macrophages and, to a lesser degree, T cells. In addition, an inverse relationship has been noted between the extent of macrophage and T-cell

	inflammation in culprit lesions and the clinical stability of the ischemic syndrome. Current data therefore support the concept that endothelial dysfunction and accelerated atherosclerosis are tightly intertwined and must be addressed together when developing therapeutic regimens

	Both well-established traditional risk factors and poorly proven, nontraditional risk factors are associated with CAD and atherosclerosis.1,3-9

	Sex and age. Male sex and older age put individuals at higher risk for atherosclerotic CAD.

	tor for CAD, particularly among younger individuals with a family history of premature disease. A paternal MI in those younger than

	60 years is associated with a greater risk than is infarction at a later age; in comparison, any maternal history of infarction is associated with greater risk.3,4

	Lipids. The serum total cholesterol and the LDL and high-density lipoprotein (HDL) cholesterol concentrations are clear risk factors for CAD, with the risk increasing progressively with higher values. The following lipid abnormalities are associated with increased CAD risk: elevated LDL, low HDL, increased ratio of total cholesterol to HDL, hypertriglyceridemia, increased lipoprotein a (Lp[a]), increased non-HDL, increased apo B, and decreased apo A-I.

	is increased in patients with premature CAD, ranging as high as 75% to 85% as compared with approximately 40% to 48% in age-matched controls without CAD. The disturbance in lipoprotein metabolism is often familial.

	Proof of the pathogenic importance of serum cholesterol in CAD has come from randomized trials in which reductions in levels of total and LDL cholesterol led to a reduced frequency of coronary events and reduced mortality.

	Hypertension. Hypertension is a well-established risk factor for adverse cardiovascular outcomes, including CAD-related mortality and stroke. Systolic blood pressure is at least as powerful a coronary risk factor as diastolic blood pressure. Isolated systolic hypertension is now established as a major hazard for CAD and stroke. There is also evidence that pulse pressure (the difference between the systolic and diastolic blood pressures) is determined primarily by large-artery stiffness and is a predictor of risk.

	Diabetes mellitus. Insulin resistance, hyperinsulinemia, and glucose intolerance are associated with atherosclerotic cardiovascular disease. In the Framingham Heart Study, for example, diabetes was an independent predictor of cardiovascular disease, especially in women. In addition to the importance of diabetes as a risk factor for CAD, diabetics have a greater burden of other atherogenic risk factors than nondiabetics, including hypertension, obesity, increased ratios of total to HDL cholesterol, hypertriglyceridemia, and an elevated plasma fibrinogen level.5

	Obesity. Obesity is associated with hypertension, insulin resistance, glucose intolerance, hypertriglyceridemia, reduced HDL cholesterol, and an elevated fibrinogen level. Obesity is also associated with an increased risk of cardiovascular disease and mortality.6

	Metabolic syndrome. Patients with the constellation of abdominal obesity, hypertension, diabetes, and dyslipidemia are considered to have the metabolic syndrome. These individuals have a much higher risk of CAD than the general population.

	C-reactive protein. Among apparently healthy men and women, the baseline level of systemic inflammation, as assessed from the plasma concentration of C-reactive protein (CRP), predicts the long-term risk of a first MI, ischemic stroke, or peripheral vascular disease. Measurement of CRP levels, along with an analysis of the lipid profile, improves risk stratification of patients.

	Lifestyle factors. A diet high in calories, saturated fat, and cholesterol contributes to other risk factors that predispose to CAD. Epidemiologic data indicate that moderate alcohol intake has a protective effect against this disease.

	Diet. In addition to the role of dietary lipids in the development

	of CAD, there is growing evidence that fruit and vegetable consumption and a diet with a high-fiber content are inversely related to the risk of developing this condition. High-fiber intake is associated with a 40% to 50% lower risk of CAD and stroke than a low-fiber intake.

	Exercise. Even a moderate amount of exercise has a protective effect against CAD and all-cause mortality. In addition to the amount of ex-ercise, the degree of cardiovascular fitness (a measure of physical activ-ity), as determined by duration of exercise and maximal oxygen uptake during exercise on a treadmill, is associated with a reduction in CAD risk and overall cardiovascular mortality.

	Cigarette smoking. Cigarette smoking is an important and reversible risk factor for CAD. The incidence of MI is 6-fold greater in women and 3-fold greater in men who smoke at least 20 cigarettes per day than in respective subjects who never smoke.10 CAD risk increases with greater levels of tobacco consumption in both men and women, and is higher in inhalers than in noninhalers. Similarly, the risk of recurrent infarction in a study of smokers who had had an MI decreased by 50% within 1 year of smoking cessation, and normalized to that of nonsmokers within 2 years. The benefits of smoking cessation are seen regardless of how long or how much the patient has previously smoked.

	Vitamins and homocysteine. Moderately high levels of plasma homocysteine are associated with subsequent risk of MI independently of other coronary risk factors. Because high levels can often be easily treated with vitamin supplements, homocysteine may be an independent, modifiable risk factor for CAD.8

	Microalbuminuria. Microalbuminuria reflects renal vascular damage and may be a marker of early systemic arterial disease. Its presence can be regarded as an index of increased vulnerability to cardiovascular disease and a signal for vigorous efforts at correcting known risk factors.9

	Left ventricular hypertrophy. Left ventricular hypertrophy is one of the less common but ominous risk

	factors for CAD, stroke, and heart failure. The chief determinants of this condition, aside from age, are elevated blood pressure, obesity, height, and glucose intolerance. Downward trends in the prevalence of left ventricular hypertrophy over four decades indicate that it is preventable, and this has coincided with improved control of hyper-

	tension. When evidence of this condition disappears, the risk of mor-tality from all-causes, cardiovascular disease, and CAD is substantially reduced.

	Evaluation of patients with suspected CAD

	General principles. Patients with stable chest-pain syndromes should undergo a thorough clinical evaluation, including classification of chest-pain type into definite or probable angina or nonspecific chest pain. Evaluation should also include identification of risk factors, such as age, tobacco use, dyslipidemia, hypertension, family history of premature CAD, activity profile, obesity, postmenopausal status, and diabetes.2-9,11 The physical examination usually detects evidence of other types of heart disease that can cause angina (aortic stenosis, hypertrophic cardiomyopathy, severe pulmonary

	hypertension, and others). An assessment of contraindications to coronary angiography should be part

	of this clinical assessment. Severe symptoms suggest severe CAD and are an indication for cardiac catheterization. The American College of Cardiology/American Heart Association (ACC/AHA) 2002 guidelines recommend evaluating hemoglobin and doing a fasting glucose determination and fasting lipid panel for new patients presenting with angina. Comorbid conditions that may precipitate functional angina should be considered. These include anemia, hyperthyroidism, tachyarrhythmias, cocaine abuse, or uncontrolled hypertension.

	Disease prevalence affects the positive predictive value of a test; low disease prevalence results in a higher false-negative rate. Thus, a 50-year-old man with atypical chest pain has a 30% likelihood of disease, whereas a 65-year-old woman with typical angina has a 90% likelihood. The greatest increase in predictive value with the addition of a diagnostic test comes from the evaluation of a population with an in-

	termediate prevalence of disease (commonly defined as 10%—90%). A diagnostic test in a population with low prevalence of a disease provides little added benefit because the test will have a high false-positive rate and a low positive predictive value. The ACC/AHA 2002 guidelines rely heavily on initial clinical assessment and data regarding disease prevalence in different populations to guide testing in individual patients.

	Exercise stress testing. Exercise electrocardiographic testing has become increasingly important in evaluating patients with known or suspected CAD and in assessing the therapeutic effects of cardiac drugs. Exercise electrocardiography also provides significant prognostic information for patients with known CAD. Despite this, a great deal of controversy surrounds the use of exercise electrocardiographic testing in screening for “silent” coronary ischemia in asymptomatic individuals without known coronary disease.

	Radionuclide imaging. Once the decision is made to perform a stress test to obtain diagnostic or prognostic information, or both, the use

	of myocardial perfusion imaging may be of critical importance. The ACC/AHA 2002 guidelines for exercise testing and for the clinical use of radionuclide imaging strongly recommend an imaging study as part of the evaluation in the following groups of patients: (1) those who are unable to exercise to a level high enough to produce meaningful results on exercise electrocardiographic testing; and (2) those with baseline electrocardiographic abnormalities that interfere with interpretation

	of the exercise electrocardiogram (ECG). These abnormalities include pre-excitation, a paced ventricular rhythm, more than 1 mm of resting ST-segment depression, and complete left bundle branch block. The use of digoxin and the presence of left ventricular hypertrophy also reduce the specificity of exercise electrocardiographic testing, although its sensitivity may remain unaffected.

	Several other subsets of patients benefit incrementally from the use of radionuclide imaging. These include patients with previous MI or coronary revascularization procedures (percutaneous coronary intervention or coronary artery bypass graft [CABG] surgery), known significant CAD (for identification of the culprit lesion causing ischemia), diabetes, or a previous positive radionuclide imaging study.

	For many years, planar imaging and single-photon emission computed tomography (SPECT) with thallium 201 constituted the only scintigraphic techniques available for detecting CAD and assessing prognosis. A major limitation of imaging with this method is the

	high false-positive rate attributed to image-attenuation artifacts, such as breast tissue in women and diaphragmatic attenuation in obese patients, and occasionally to variants of normal. These limitations prompted the development of new radionuclides for cardiac imaging.

	Technetium-99m—labeled imaging agents and gated SPECT. Currently, two technetium-99m–labeled perfusion agents are primarily used for clinical purposes: technetium-99m–

	tetrofosmin. These agents have improved imaging characteristics over those of thallium 201 because of

	shorter half-life of technetium-99m. Perhaps most importantly, they allow easy ECG-gated acquisition (gated SPECT imaging), permitting the simultaneous evaluation of left ventricular systolic function and myocardial perfusion. The current consensus is that SPECT imaging has superior sensitivity, partly because of its ability to detect an individual stenosis on the basis of localization of stress-induced perfusion defects.

	Pharmacologic stress testing. Stress testing through the intravenous use of pharmacologic agents has become the most widely accepted method of nonexercise-based cardiovascular stress testing. This is because such tests are quick and easy to perform.

	Agents used for pharmacologic stress-testing are classified as either vasodilator or inotropic and chronotropic drugs. Vasodilators, which include adenosine, dipyridamole, and adenosine triphosphate ([ATP] a derivative of adenosine), produce primary coronary vasodilatation. Adenosine and dipyridamole are equally effective, but adenosine has the advantages of a very short half-life, rapid reversal of side effects after the test is completed, and possibly more predictable vasodilatation. Inotropic and chronotropic agents include dobutamine and arbutamine.

	Combined exercise electrocardiography and pharmacologic stress testing. In many laboratories, submaximal treadmill exercise electrocardiographic testing is performed in conjunction with vasodilator stress imaging. This may be particularly helpful in preventing a test from being nondiagnostic as the result of a patient’s limited exercise capacity.

	Coronary angiography. Coronary angiography is used to detect or exclude atherosclerotic disease in coronary arteries. This technique helps to assess the severity of an obstructive lesion. When combined with left ventricular angiocardiography, it also enables the investigator to evaluate global and regional function of the left ventricle.

	Coronary arteriography is indi-cated in: (1) severely symptomatic patients with chronic stable angina pectoris who are being considered for revascularization; (2) patients with troublesome symptoms that present diagnostic difficulties and in whom there is need to confirm or rule out the diagnosis of ischemic heart disease; (3) patients with known or possible angina pectoris who have survived sudden cardiac death; and (4) patients judged to be at high risk for sustaining coronary events on the basis of having signs of severe ischemia on noninvasive testing, regardless of the presence or severity of symptoms.

	Positron emission tomography. Positron emission tomography (PET) is a noninvasive alternative method to radionuclide imaging and pharmacologic stress testing for evaluating myocardial perfusion and viability. A potential major advantage of PET over SPECT as an imaging tech-

	nique is its ability to identify and quantify specific metabolic cellular events. PET requires the use of positron-emitting isotopes (such as oxygen 15, carbon 11, nitrogen 13, and fluorine 18) that can be incorporated into physiologically active molecules.

	Electron-beam computed tomography. Electron-beam computed to-mography (EBCT) can detect and quantify coronary calcification noninvasively, using serial and contig-uous electrocardiogram-triggered, 100-millisecond, thin-section (3 mm) tomograms from the aorta through the apex of the heart.12,13 Direct relationships have been established between coronary calcification as measured by EBCT and histological, ultrasonic, and angiographic measures of CAD on a heart-by-heart, vessel-by-vessel, and segment-by-segment basis.

	Coronary calcification detected by EBCT is found in individuals who have significant angiographic CAD, with a sensitivity ranging from 90% to 100%, a specificity of 45% to 76%, a positive predictive accuracy of 55% to 84%, and a negative predictive accuracy of 84% to 100%.12,13 The finding of coronary calcification on EBCT can identify asymptomatic patients at high risk for CAD, but it is not certain whether this translates into the identification of patients with silent ischemia, which is important because silent ischemia is predictive of cardiac events.

	The short-term goal of therapy for chronic angina is improved symptoms. The long-term goal is reduced mortality and prevention of adverse cardiac events. The mainstay of management, however, is still risk-factor modification and patient education.

	Therapy of ischemic heart disease can be classified as traditional or emerging and nontraditional. The traditional therapies are listed in the table. Nontraditional therapies include spinal cord stimulation, potassium channel blockers, external counterpulsation, transmyocardial laser revascularization, gene therapy, and heart transplantation.10,14-20

	Spinal cord stimulation. Spinal cord stimulation is probably the most promising neurostimulatory mode of therapy for managing angina pectoris. In this technique, electrodes are used to stimulate thoracic nerve fibers. This therapy results in increased sympathetic nerve outflow, with consequent redistribution of myocardial blood flow to ischemic areas and a decrease in the sensation of pain (angina). Patients with refractory angina pectoris experience no adverse clinical rebound phenomenon when neuro-

	stimulation is withheld.15,16 Spinal cord stimulation is effective in preventing hospital admissions of patients with refractory angina, without masking serious ischemic symptoms or lead-ing to silent infarction.

	Potassium channel blockers. Potassium channel blockers are potent arterial and venous vasodilators. They also activate ATP-driven transmembrane potassium channels, leading to myocardial preconditioning that protects myocardial cells from ischemic injury. Relief of anginal symptoms is similar to that observed with nitrates.14 Nicorandil is the most commonly used potassium channel blocker. It has been used successfully in antianginal therapy outside the United States.

	External counterpulsation. Enhanced external counterpulsation increases coronary perfusion pressure and thereby decreases anginal symptoms. External counterpulsation uses a timed sequential inflation of pressure cuffs placed on the legs. Inflation occurs during cardiac diastole, thereby increasing venous return, decreasing left ventricular afterload, and increasing diastolic filling pressures. Cuff pressure is abruptly discontinued just before the beginning of systole. Therapy with external counterpulsation in patients with refractory angina has been reported to improve coronary collateral circulation.

	Enhanced external counterpulsation reduces angina and extends the time to exercise-induced ischemia in patients with symptomatic CAD. In most patients such treatment is relatively well tolerated and free of limiting side effects.17

	Transmyocardial laser revascularization. Transmyocardial laser revascularization is a technique that uses laser ablation to create transmural channels in ischemic myocardium in areas where revascularization is not possible. Initially, these channels were thought to carry arterialized blood from the left ventricular cavity into the ischemic myocardium; however, it now appears that transmyocardial laser revascularization increases angiogenesis, thereby providing new collateral channels into the ischemic myocardial zone. This revascularization technique appears to be an excellent adjunct to CABG surgery for achieving improved myocardial revascularization in patients with vessels that can and cannot be grafted. Surgical experience has shown this procedure to

	be safe. Postoperative follow-up studies of patients who underwent CABG surgery and transmyocardial laser revascularization showed significant improvement in myocardial function and perfusion in zones treated with the laser.18-20 Transmyocardial laser revascularization has also been used in patients with refractory angina who were receiving maximal medical therapy. In this setting, this therapy reduced angina and decreased the number of cardiac events during follow-up as compared with medical therapy alone given to similar patients.

	Transmyocardial laser revascularization can be performed during open-heart surgery with a hand-held device, or can be done with a specially designed catheter during cardiac catheterization.

	Gene therapy. The use of recombinant genes or growth factors to enhance myocardial collateral blood vessel function represents a new approach to the treatment of cardiovascular disease.10 Proof of concept for this approach has been demonstrated in animal models of myocardial ischemia, and it is currently undergoing clinical trials. A number of angiogenic growth factors have been shown to stimulate blood vessel growth under different circumstances. These include the following: members of the fibroblast growth factor, vascular endothelial growth factor, and platelet-derived growth families; angiopoietins; cytokines, such as interleukin-6 and interleukin-8; “master switch” genes, such as hypoxia-inducible factor-1a; and platelet-activating factor. Currently, it is unknown which of these methods offers the safest and most effective delivery strategy for inducing clinically important, therapeutic angiogenic responses in ischemic myocardium. Most strategies for transcatheter delivery of angiogenic factors have used an intracoronary route, a technique that may have limitations because of imprecise localization of genes or proteins as well as their systemic delivery to noncardiac tissue.

	The effect of direct intraoperative, intramyocardial injection of angiogenic factors on collateral function has been reported in experimental models, and angiogenesis is being studied after direct intramyocardial injection of angiogenic peptides or plasmid vectors during human open-heart surgery. Catheter-based transendocardial injection of angiogenic factors may provide equivalent benefit without the need for surgery. Intrapericardial delivery of angiogenic factors is another potential route of delivery for these new therapeutic agents. This latter route offers the theoretical advantage of prolonged exposure of either coronary or myocardial tissue to the administered drug as a result of the reservoir function of the pericardium.15

	Angina pectoris is one of the most common serious medical conditions seen in medical practice today. The evaluation and treatment of these patients has improved markedly over recent years. Newer treatments will soon find their way into daily practice.

Chronic stable angina

	In the past 30 years, heart failure has emerged as a major public health problem in the United States and many other countries. This is in large part due to the progressive aging of the population and to improved survival among persons with hypertension and coronary artery disease, the two leading causes of heart failure in North America and Europe.

	Nearly 5 million Americans have clinical heart failure, and more than 500,000 new cases are diagnosed each year.1 As a result, heart failure is the leading cause of hospitalization in the Medicare age group and is the most costly diagnosis-related group by a factor of 2. Women account for approximately 55% of all heart failure hospitalizations, and more than 50% of heart failure admissions occur in persons age 75 years or older.2

	As concisely articulated by Drs. Wells and Little (page 14), the rise in the incidence of heart failure has been appropriately accompanied by intensified research, and major advances in the diagnosis and treatment of acute and chronic heart failure have occurred during the past two decades. Without question, these advances have led to substantial improvements in the prognosis and quality of life for many such patients, particularly those younger than 75 years whose heart failure is a result of impaired left ventricular systolic function. Unfortunately, such patients comprise less than one half of the total heart failure population. Thus, it is germane to ask: to what extent has recent progress in heart failure affected the epidemiology and clinical outcomes on a population-wide basis?

	From 1979 to 2000, hospitalizations for heart failure in the United States increased by a factor of 2.65, from 377,000 to 999,000.1-3 In addition, several studies indicate that heart failure incidence has decreased slightly or remained unchanged during the past several decades,4,5 despite the emergence of new drug classes, such as angiotensin-converting enzyme (ACE) inhibitors and HMG-CoA reductase inhibitors (statins), which have been shown to reduce the incidence of heart failure in high-risk populations.6,7 Even more telling are a se-ries of studies reported during the past 20 years indicating that improvements in heart failure care have had virtually no impact on rehospitalization rates among elderly heart failure patients (table).8-14 Furthermore, although both age- and gender-adjusted mortality rates have declined modestly, the absolute number of deaths attributable to heart failure continues to rise.5,15

	Why is it that the dramatic reductions in mortality and hospitalization rates reported in clinical trials (typically between 25% to 40%16) are not being realized in the broader heart failure population, despite the fact that authoritative, evidence-based guidelines for heart failure care have been widely promulgated? First, for reasons that remain obscure, a significant portion of heart failure patients who are candidates for proven therapies, including ACE inhibitors and beta blocking agents, are not receiving them.17,18 Even among those treated with these agents, dosing is often suboptimal or well below the doses proved efficacious in clinical trials. Second, patient compliance with prescribed medications and dietary and physical activity modifications is frequently poor. This partly reflects inadequate patient evaluation and follow-up as well as the confounding effects of psychosocial factors, such as depression, social isolation, and the inability to afford the high cost of multiple medications. Although many of these issues have been successfully addressed by various heart failure disease management strategies,19 access to such programs remains limited, largely because there is no established method of reimbursement for these services.

	A third major element contributing to the relative lack of impact of new heart failure therapies is the fact that almost all of the major heart failure trials have targeted middle-aged patients with impaired left ventricular systolic function. Women, ethnic minorities, and elderly patients, who comprise most of the heart failure cases in the United States, have been markedly underrepresented in these trials. The applicability of the study findings to these major demographic subgroups remains uncertain.20 In fact, a recent meta-analysis of the ACE inhibitor trials failed to show a significant benefit of these drugs among 1,066 patients age 75 years or older.21 Furthermore, as Wells and Little point out, scant data are available to guide therapy in the 40% or more of patients (predominantly elderly women) with heart failure and preserved left ventricular systolic function, a condition associated with substantial disability.22

	In discussing the future of heart failure, it is important to recognize that patients with symptomatic heart failure represent the proverbial tip

	be termed “pre-heart failure,” or asymptomatic left ventricular systolic or diastolic dysfunction (stage B heart failure).16 There are even more who have prevalent risk factors, such as hypertension, diabetes, or obesity (stage A heart failure).16 For these patients, the importance

	of preventive strategies, including optimal control of blood pressure, blood glucose, and serum lipid levels, and a healthy lifestyle, including exercise and weight control, cannot be overemphasized. Recent innovations notwithstanding, the prognosis for established heart failure remains dismal.

Progress in heart failure: Some good news, some bad Michael W. Rich, MD

	There have been remarkable advances in the diagnosis and treatment of heart failure during the past 20 years. The diagnosis of this condition has been impacted by the wide-scale adoption of 2-dimensional echocardiography and the recognition of B-type natriuretic peptide as a

	biomarker. Heart failure treatment has also been revolutionized, from the mere management of congestive symptoms to the alteration of adverse neurohormonal activation and, more recently, to the development of biventricular pacing, implantable cardioverter-defibrillators, and left ventricular assist devices.

	In the past, the diagnosis of heart failure was made in patients with characteristic signs and symptoms predominantly resulting from fluid overload. A chest radiograph showing cardiomegaly and pulmonary congestion confirmed this clinical diagnosis. In the 1980s, the widespread availability of 2-dimensional echocardiography allowed for the evaluation of left ventricular size and systolic function, quantitated as the left ventricular ejection fraction. In patients with clinical heart failure, a reduced ejection fraction confirms the presence of a cardiac abnormality. This has become an important criterion for the diagnosis of heart failure. A reduced ejection fraction has served as an entry requirement for almost all of the pivotal clinical trials that provide the evidence that guides heart failure therapy. In the past decade, however, it has become clear that many patients with the typical syndrome of heart failure (40% or more) have a normal ejection fraction above 50%.1 These patients are often elderly and predominantly women. Understanding the pathophysiology and cause of heart failure in these patients and determining the optimal management technique is one of the current challenges.

	Plasma B-type natriuretic peptide and its inactive cleavage product,

	NT-B-type natriuretic peptide, recently have emerged as useful biomarkers.2 B-type natriuretic peptide and NT-B-type natriuretic peptide are elevated in most patients with decompensated heart failure. These biomarkers decrease in response to effective therapy and provide important prognostic information; thus, they appear to play an important role in the diagnosis and treatment of patients with heart failure. The full value and role of these and other potential biomarkers continue to be an important area of investigation.

	Twenty years ago, heart failure management focused on relieving symptoms of congestion with diuretics and improving cardiac output with digitalis and inotropic agents. Since then, there has been tremendous progress that has completely changed the way this condition is managed. The adverse consequences of neurohormonal activation in heart failure were first shown in animal studies and subsequently proved in many large randomized clinical trials. The neurohormonal pathways include the renin-angiotensin-aldosterone system and the beta-adrenergic system. Angiotensin-converting enzyme (ACE) inhibitors are now a mainstay for the treatment of heart failure. These drugs reduce mortality and hospitalizations, improve the quality of life, and delay the development of heart failure in patients with asymptomatic left ventricular dysfunction evidenced by a reduced ejection fraction.3 Treatment with ACE inhibitors is now indicated for patients with heart failure of all New York Heart Association (NYHA) functional classes and for those who are asymptomatic and have reduced ejection fractions.4

	During treatment with an ACE inhibitor, angiotensin II may be produced by alternate pathways. The cardiovascular effects of angiotensin II—however it is produced&mdash;can be blocked with angiotensin II receptor blockers (ARBs). Despite the potential theoretical advantages of ARBs compared with ACE inhibitors, initial studies have not shown ARBs to be superior in patients with symptomatic heart failure or in those who have had a myocardial infarction (MI). Thus, ACE inhibitors remain the cornerstone of treatment for heart failure and for those who have had a large MI. ARBs are, however, an attractive alternative in those who cannot tolerate ACE inhibitors.5 Adding an ARB to an adequate dose of an ACE inhibitor may provide an additional benefit.6,7 Angiotensin stimulates the production of aldo-sterone, which stimulates sodium retention and potassium wasting, and is a powerful mediator of cardiac fibrosis. A substantial portion of aldosterone production occurs independent of angiotensin II and is not blocked by ACE inhibitors or ARBs.8 Adding aldosterone antagonists to ACE inhibitors has been found to be beneficial in patients with NYHA functional class III or IV heart failure and in those with heart failure after a large MI.9,10

	One of the greatest advances in heart failure treatment during the past 20 years has been the use of beta blocking agents. Initially, it was thought that beta blockers were

	In fact, the infusion of beta-adrenergic agents was used to treat this condition. The beta1-specific beta blocker (sustained-release metoprolol)11 and the beta1, beta2, and alpha1 blocker (carvedilol), however, have been shown to improve survival

	tion and reduce hospitalizations.12-15 Thus, these beta-adrenergic blocking agents are indicated in all patients with NYHA functional class II to IV heart failure.4 The recently published Carvedilol Or Metoprolol European Trial (COMET) showed improved survival with carvedilol compared with short-acting metoprolol.16 Whether this observation applies to higher doses of long-acting metoprolol is not known.

	Many patients with the typical syndrome of heart failure have a preserved left ventricular ejection fraction (> 50%).1 It has been assumed that heart failure is caused by a problem with filling, or diastolic heart failure, in these patients. The pathophysiology and mechanism of heart failure in these patients remain an area of active investigation. The recently completed Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM)-Preserved study is the only large, randomized, multicenter study of patients with diastolic heart failure.17 The results of this study suggest that treatment with the ARB candesartan may reduce hospitalizations, but not mortality, in these patients. Several other studies are currently evaluating ARBs, ACE inhibitors, and beta blockers in this population.

	Twenty years ago, cardiac transplantation was becoming established as a viable treatment alternative for patients with end-stage heart failure. The number of transplants performed in the United States has plateaued at about 2,500 per year and is limited by the number of donors. Therefore, most patients

	with end-stage heart disease cannot be treated with cardiac transplantation. As a result, attention has been focused on other mechanical and surgical interventions.

	Many patients with heart failure have conduction disturbances that lead to dyssynchronous activation of the left ventricle. This produces an uncoordinated and inefficient contraction pattern, contributing to impaired cardiac performance. Bi-ventricular pacing or pacing of the left ventricle alone improves the synchronicity of left ventricular contraction, resulting in improved ejection fraction, exercise time, and quality of life.18 The recently completed Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure (COMPANION) trial demonstrated that biventricular pacing with or without defibrillation reduces mortality and hospitalizations compared with medical therapy in patients with end-stage heart failure and conduction abnormalities.18

March 2004

Preventing strokes in atrial fibrillation: New answers to old questions

Celebrating 20 years of advances in cardiology

Device therapy: Whats new and different? William J. Mandel, MD

Advances in device therapy for cardiac arrhythmias

Chronic stable angina: Looking into the future

Chronic stable angina

Progress in heart failure: Some good news, some bad Michael W. Rich, MD

Heart failure: 20 years of progress

Stroke is the most common ischemic event after index stroke

Stroke is the most common ischemic event after index stroke

Antianginal under review has unique mechanism of action

Metabolic syndrome is important stroke risk factor

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