XASIM_Issue_4_10Bp794_802.pdf

S794 Vol. 4 (10B) n November 2004

ABSTRACT

Coronary artery disease (CAD) is a principalcause of morbidity and mortality around theglobe. An important indicator of CAD is anginapectoris, defined as a syndrome of substernalchest discomfort, with a characteristic quality andduration that is provoked by exertion or emotion-al stress, and is relieved by rest or the adminis-tration of nitroglycerin. The main pathologicabnormality in stable angina is the presence ofan intimal plaque within the coronary arterylumen that limits flow to a portion of the left ven-tricle. Inflammatory processes are a major dri-ving force of atherosclerosis and are involved inthe disruption of plaques and the resulting throm-bosis. Anginal pain is most likely mediated byadenosine released from the ischemic myocardi-um that activates sensory nerves in the heart. Theexact location of ischemia in the myocardium(subendocardial vs transmural) is related towhether or not patients with CAD experienceangina. Asymptomatic patients do not have thetraditional endpoints of disease and the develop-ment of a cardiac event is often the initial mani-festation of CAD. Unstable angina presents as achange in the usual pattern of stable angina andusually occurs at rest. Treatment options availablefor the management of chronic stable angina areplentiful and include pharmacologic, nonphar-macologic, and alternative therapies.Unfortunately, there are many patients with angi-na refractory to current medical treatment strate-

gies or who are not candidates for surgical orcatheter-based revascularization. There is a needfor new effective therapies for these patients withangina who are not receiving full benefit fromcurrent therapies.(Adv Stud Med. 2004;4(10B):S794-S802)

Afull review of ischemic heart disease can bea daunting task. There is much that can bewritten about atherogenesis, plaque biolo-gy, risk factors for atherosclerogenesis, and

the natural history of coronary atherosclerosis. Indeed,entire books and reviews can and have been writtenabout each of these areas. The focus of this monographis to develop a conceptual framework for understand-ing angina pectoris, the most common symptom ofmyocardial ischemia experienced by individuals withcoronary atherosclerosis. This paper will brieflydescribe the magnitude of the problem of atheroscle-rotic cardiovascular disease (CVD) in general andcoronary artery disease (CAD) in particular, and thenmove quickly to a focus on angina pectoris.

MAGNITUDE OF THE PROBLEM

CAD remains a major healthcare problem in theUnited States and around the globe, despite dramaticadvances in medicine. The reasons for this are multifac-torial and are largely due to the advancing age of our pop-ulation.1 It has been estimated that CVD and stroke willcost the United States $368.4 billion in 2004. Coronaryheart disease (CHD) is expected to consume more thanone third of this expenditure at $133.2 billion.

CHD affects 6.4% of the US population, or morethan 13 million Americans.1 The prevalence of CHD

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ISCHEMIC HEART DISEASE: AN OVERVIEW

Marc D. Thames, MD, FACC*; David R. Sease, MD, FACC; Andrei Damian, MD, FACC

*Cardiovascular Consultants, Ltd, Phoenix, Arizona;Cardiovascular Consultants, Ltd, Phoenix, Arizona;Cardiovascular Consultants, Ltd, Phoenix, Arizona.

Address correspondence to: Marc D. Thames, MD,FACC, Cardiovascular Consultants, Ltd, 16601 N 40thStreet, Suite 204, Phoenix, AZ 85032. E-mail: [email protected].

Advanced Studies in Medicine n S795

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increases with age for both males and females and ismore prevalent in men at each age group, except fromage 25 to 44 years. Atherosclerotic CVD is the leadingcause of death in men and women in the United Stateswith CAD accounting for more than half (54%) ofthose deaths.1 CVD is also a major cause of morbidityand can result in myocardial infarction (MI) withresulting impairment in cardiac function and conges-tive heart failure, loss of limbs with reduction inmobility, and stroke with its devastating effects onmobility, communication, and other cognitive func-tions. These diseases have taken on increasingly globalimportance as the epidemic of obesity and type 2 dia-betes mellitus spreads to large countries such as Indiaand China. Patients with type 2 diabetes seem todevelop an especially aggressive form of CVD andCAD. The World Health Organization projects that in2020, CAD will account for 6% of the total global dis-ease burden, of which only 11% will be in developedregions, the rest being in developing nations.2

SUBSTRATE FOR ANGINA

Atherosclerosis is a systemic disease. Indeed,patients with this disease may experience problemsdue to CAD, atherosclerotic peripheral arterial dis-ease, and atherosclerotic cerebrovascular disease. Ineach instance, it is the reduction in flow to the specif-ic vascular bed that results in symptoms such as angi-na pectoris, intermittent claudication, and variouscentral nervous system symptoms (such as transientischemic attacks or strokes).

WHAT IS ANGINA PECTORIS?

Angina pectoris is a discomfort that individualsexperience when the supply of blood flow to themyocardium is inadequate to meet the metabolicneeds of the myocardium. Although most patientsexperience discomfort in the chest, others may experi-ence symptoms exclusively in the back, throat, neck,jaw, shoulders, elbows, forearms, wrists, or gums.Some patients experience discomfort that is limited toonly one of these areas. It is a visceral discomfort thatassorted patients say is hard to describe. Manypatients, when asked if they have chest pain, willdeny pain. It is for this reason that the physicianshould ask the patient if he or she has discomfort (notpain) in the chest or in the other locations where angi-

na may be felt. Women often have very atypical symp-toms, which can be especially difficult to interpret.

Table 1 lists the conditions that may provoke orexacerbate angina pectoris.3 There are 2 important pointsto be made from this table. First, conditions exist inwhich angina occurs in the presence of anatomically nor-mal coronary arteries. Perhaps the best example of this isaortic stenosis, where large increases in cardiac work (thestenotic valve plus exercise) with inadequate supply (rel-atively low coronary perfusion pressure plus limitation ofcoronary vasodilation) lead to myocardial ischemia andangina pectoris.

Second, the most common cause of angina pec-toris, not shown on Table 1, is coronary atherosclero-sis. Angina in CAD also results from an imbalancebetween supply and demand. It is the supply that isaffected by CAD. The supply of oxygen to themyocardium and removal of metabolites are depen-dent on coronary blood flow. Normally, incrementalincreases in myocardial oxygen demand are met almost

Table 1. Conditions That May Provoke or Exacerbate Ischemia

Increased Oxygen Demand Decreased Oxygen Supply

Noncardiac NoncardiacHyperthermia AnemiaHyperthyroidism HypoxemiaSympathomimetic toxicity Pneumonia(eg, cocaine use) Asthma

Hypertension COPDAnxiety Pulmonary hypertensionArteriovenous fistulas Interstitial pulmonary fibrosis

Obstructive sleep apneaCardiac Sickle cell disease

Hypertrophic cardiomyopathy Sympathomimetic toxicityAortic stenosis (eg, cocaine use)Dilated cardiomyopathy HyperviscosityTachycardia Polycythemia

Ventricular LeukemiaSupraventricular Thrombocytosis

Hypergammaglobulinemia

CardiacAortic stenosisHypertrophic cardiomyopathy

COPD = chronic obstructive pulmonary disease.Reprinted with permission from Bales. Medical management of chronic ischemicheart disease. Selecting specific drug therapies, modifying risk factors. PostgradMed. 2004;115(2):39-46.3


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entirely by a balanced increase in coronary blood flow;not so in CAD.

WHAT IS THE SUBSTRATE FOR ANGINA PECTORIS?

Angina pectoris in CAD is due to impingement ofthe lumen by atherosclerotic plaque in the coronaryartery, thereby restricting coronary blood flow. Thedevelopment of this plaque may begin early in life.Indeed, many young soldiers who died in the KoreanWar who were autopsied were shown to have surprising-ly advanced CAD. The atherosclerotic plaque is com-posed of a fibrous cap that covers the surface. Beneaththe cap is the soft portion of the plaque, filled with lipid-laden macrophages, oxidized low-density lipoprotein(LDL) cholesterol, and other cellular waste products.Often there is bone-like calcification in the plaque.

Based on studies with intracoronary ultrasound,angina tends to be mainly stable and reproducibly pro-voked by exertion when the plaque is hard and com-posed mainly of fibrous plaque and calcification withrelatively low lipid content. Soft plaques, which havea thin fibrous cap and high lipid content, are prone torupture. Features associated with plaque rupture arelisted in Table 2.4 Rupture exposes the contents of theplaque, which are highly thrombogenic, to the bloodin the vicinity of the rupture. The thrombus thatdevelops at the site of plaque rupture can be fullyocclusive resulting in a transmural infarction. Thethrombus may also be partially occlusive resulting inacute coronary syndromes such as unstable angina ornonST-segment elevation nontransmural MI. Onthe contrary, the plaque and related thrombus maynot be sufficiently occlusive to cause immediate symp-toms but may heal in such a way as to increase thedegree of structural occlusion, only to repeat thisprocess at a later date leading to any of the sequelaeoutlined here.

There are many anginal syndromes. Stable anginais the most common and is reproducibly provoked byexertion and oftentimes by emotion. In contrast,unstable angina may occur at rest, thereby indicatingrestriction in coronary blood flow so severe as to pre-vent sufficient coronary blood flow to meet metabolicneeds of the myocardium when the patient is inactive.Angina may occur after meals, especially when walk-ing, and is termed postprandial angina. In these cir-cumstances, the cardiac work of supplying theexercising muscle plus the gut that is in the absorp-

tive/digestive state may require more coronary blood flowthan the diseased coronaries can deliver. Other episodesof angina may awaken the individual from sleep (noctur-nal angina), or occur when the patient becomes recum-bent (angina decubitis). These and other anginalsyndromes have unique factors that contribute to theprovocation of angina, but share the common character-istic of inadequate coronary blood flow in relationship tometabolic demands. The chest discomfort associated withthe full range of ischemic insults from acute MI to stableexertional angina tends to differ, not in character, but in

Table 2. Features Associated with Plaque Rupture

1. Large eccentric soft lipid core

2. Thin fibrous cap

3. Inflammation in the cap and adventitia

4. Increased plaque neovascularity

5. Outward or positive vessel remodeling

Reprinted with permission from Shah. Pathophysiology of coronary throm-bosis: Role of plaque rupture and plaque erosion. Prog Cardiovasc Dis.2002;44(5):357-368.4

Figure 1. Regulation of Coronary Flow

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severity. As the amount of myocardium that is ischemicincreases, there is more likely to be radiation of the dis-comfort to other areas like the arms, as well as associatedsymptoms of dyspnea, diaphoresis, and nausea.

WHAT CAUSES THE SENSATION OF ANGINA?

The discomfort of angina is transmitted to the centralnervous system by nerve fibers that travel with the sym-pathetic nerves. Bilateral stellate block eliminates angina.Although it is difficult to study basic mechanisms of angi-na in humans, experimental data suggest that the nerveendings responsible for angina are activated by adenosine,probably by stimulation of adenosine A1 receptors.5-8

Consistent with this concept is the finding that adminis-tration of aminophylline, a non-selective adenosinereceptor antagonist that blocks A1 receptors, prolongs thetime to exercise-induced angina without reducingmyocardial ischemia. Based on ambulatory electrocardio-gram monitoring, two thirds of all episodes of myocardialischemia that occur during activities of daily life aresymptomless (ie, silent ischemia). Although the precisemechanism for this is not clear, myocardial ischemia dur-ing activities of daily life is mainly subendocardial, thusinvolving the inner portions of the left ventricular (LV)myocardium. Experimental data suggest that the nerveendings responsible for the sensation of angina may bepreferentially distributed to the outer portions of the LVmyocardium. Thus, during activities of daily life, thestimulus (probably adenosine) is remote from the fibersthat are activated by myocardial ischemia.

WHAT IS THE RELATIONSHIP BETWEEN THESEVERITY OF CORONARY ARTERY STENOSIS ANDTHE DEVELOPMENT OF MYOCARDIAL ISCHEMIA?

In a normal coronary circulation, coronary bloodflow can be increased 3- to 4-fold, but only by phar-macologic means. Agents such as adenosine (or itsanalogues) and persantine (which blocks the uptake ofadenosine) have been used to induce maximal coro-nary vasodilation. Adenosine is the most potent natu-rally occurring vasodilator. Many patients who receiveintravenous or intracoronary adenosine describesymptoms of chest discomfort that sound like angina,thus, providing further support for the concept thatthis substance, released from the ischemic myocardi-um in large amounts, is the main stimulus for nerveendings that detect myocardial ischemia.

The difference between normal resting coronaryblood flow and the maximally dilated flow is called max-imal or pharmacologic coronary flow reserve. Figure 1illustrates the effect of increasing degrees of coronarystenosis on maximal coronary flow reserve. There is gen-erally no reduction in maximal flow reserve in a coronaryartery containing plaque until the cross-sectional area isreduced by 70% (50% diameter reduction). A highlytrained athlete uses about half of his or her maximalcoronary flow reserve during peak effort (maximal func-tional reserve). Activities of daily life generally occur atlevels of coronary blood flow less than half of the maxi-mal functional reserve (functional reserve). In Figure 1,the curve for functional reserve intersects the pharmaco-logic flow reserve curve far to the right on the stenosisaxis. What this means is that in order to induce ischemiaand thus angina, the stenosis must be severe (ie, general-ly >70% cross-sectional area reduction).

There are some qualifiers for what has just beenoutlined above. Less severe stenosis can cause myocar-dial ischemia when the stenosis is long. In addition,changes in vasomotor tone, the degree of constrictionof vascular smooth muscle in the wall of the artery inthe stenotic segment, can alter the degree of stenosis(Figure 2), thereby adding a dynamic component tothe degree of stenosis that is superimposed on thestructural component (ie, the plaque). Coronarystenoses that are not severe when vasomotor tone islow may become severely narrowed by constriction of

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Figure 2. Effect of Vasomotor Tone on Percentage Stenosis

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smooth muscle in the wall of the coronary arteries.In addition, a tight stenosis creates areas of highshear that activate platelets. Platelet adhesion andaggregation at the site of stenosis can contribute tothe reduction in cross-sectional area. Vasoactivesubstances released from platelets, such as throm-boxane A2 and serotonin, can induce vasoconstric-tion and reversibly worsen the severity of thestenosis. Finally, LV hypertrophy (LVH) alonereduces coronary flow reserve in the absence ofcoronary disease. Thus, patients with LVH may beeven more susceptible to the flow-limiting effects ofcoronary stenoses than those without LVH, andthey may develop myocardial ischemia with lesssevere degrees of stenosis.

The key concept to understanding coronary flowin CHD is the following: during activity, when theexisting degree of vasodilator reserve is insufficient tomeet the demand of the myocardium for flow and,thus for oxygen delivery, ischemia results. Theischemia in turn provokes the symptom of angina pec-toris. When the subject is inactive, then discomfort(angina) may occur at rest (Figure 2).

The initial manifestation in more than half ofpatients with CAD is chronic stable angina. TheAmerican Heart Association (AHA) and the AmericanCollege of Cardiology (ACC) have estimated that 16.5million Americans have stable angina.9 Such patientscan often identify specific activities or situations thatprovoke angina pectoris. For those with myocardialischemia that is symptomless (or silent), the initialevidence of underlying CAD may be an acute coro-nary syndrome, sudden death, or the conversion tosymptomatic angina.

TREATMENT OPTIONS

The primary goals for the treatment of chronicstable angina are to reduce the risk of mortality andmorbidity and to reduce or eliminate anginal pain.9

The objective of therapy is to enable patients toreturn to normal activities. Ideally, management ofischemic heart disease should have as few side effectsas is possible. The ACC and the AHA have devel-oped guidelines for the management of patientswith chronic stable angina.10 These guidelines focuson risk assessment and treatment of asymptomaticas well as symptomatic patients with known or sus-pected CAD.

PHARMACOLOGICA wide array of pharmacologic agents is available

for the treatment of ischemic heart disease. Whenselecting the most appropriate pharmacologic treat-ment for an individual patient, specific considerationshould be given to agents that have been proven toimprove prognosis. An in-depth discussion of theseagents is beyond the scope of this paper; rather, a briefoverview of agents used to treat ischemic heart diseaseis provided.

Beta blockers. Blockade of beta-adrenergic receptorscauses cardiac slowing and decreased myocardial con-tractility and may lower arterial pressure. These effectsserve to reduce the myocardiums demand for oxygen,and thus flow, especially during exercise. Patients onbeta blockers thus require a smaller portion of theircoronary flow reserve to do a given amount of physi-cal activity, and are, thus, less likely to have myocardialischemia when coronary flow reserve is limited. Putanother way, patients with flow-limiting coronarystenoses can do more physical activity with their avail-able coronary flow reserve following beta blockade.Figure 3 illustrates the portion of the functional coro-nary flow reserve used before and after beta blockade.Note that the beta blocker curve intersects the func-tional flow reserve curve further to the right. Thus,after beta blockade, ischemia will occur at a higherdegree of stenosis than before blockade. Not only can

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Figure 3. Effect of Beta Blockers on Coronary Blood Flow

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beta blockers provide symptomatic relief from angina,several trials have demonstrated that these agents canalso improve survival in patients with recent or priorMI.10 Beta blockers should be considered as initialtherapy for chronic stable angina, secondary preven-tion post-MI, and for the reduction of mortality andmorbidity in hypertensive patients. Concurrent asth-ma or bronchospasm and atrioventricular (AV) con-duction abnormalities are relative contraindications tobeta blocker therapy; however, diabetes mellitus is notgrounds for avoiding these antianginal agents.

Calcium channel blockers. Long-acting or slow-release calcium channel antagonists are able to relievethe symptoms of chronic stable angina. The nondihy-dropyridine calcium channel blockers, such as vera-pamil and diltiazem, reduce heart rate and should beadministered with caution in patients receiving con-current beta blocker therapy or with evidence of sinusnode or LV dysfunction or AV block. Calcium chan-nel blockers may exert antianginal effects by decreas-ing heart rate at exercise and rest. These agents workby lowering arterial pressure at rest and with exercise,thereby decreasing oxygen demand. Finally, calciumchannel blockers relax vascular smooth muscle in thecoronaries thereby minimizing the dynamic compo-nent of angina (Figure 4).

Nitroglycerin. This agent is efficacious in relievingangina by decreasing myocardial oxygen requirements(reduced preload via systemic venodilation) and byimproving myocardial perfusion (by relaxing thesmooth muscle in diseased and stenotic coronaryarteries) (Figure 4). When combined with beta block-ers or calcium channel blockers, nitrates can improvethe antianginal efficacy of these agents.10 Diseasedcoronaries produce less nitric oxide (NO) than normalcoronaries. NO is the key naturally occurring epicar-dial coronary vasodilator. Nitroglycerin and relatedlong-acting nitrates are NO donors and cause relax-ation of vascular smooth muscle.

Antiplatelet therapy. Aspirin, the most commonantiplatelet therapy, has been shown to decrease therisk of nonfatal MI in chronic stable angina patientsby 33% and to reduce the risk of serious vascularevents by about 25%.11 The antithrombotic effect ofaspirin is induced by the inhibition of cyclooxyge-nase and the subsequent production of thromboxaneA2 and prostacyclin.3 Patients intolerant of aspirinmay be treated with clopidogrel, an antiplateletmedication that prevents adenosine diphosphate-

mediated activation of platelets. Clopidogrel is asso-ciated with a reduction in the combined risk of MI,vascular death, or stroke in high-risk patients withestablished vascular disease.12 There is little evidencethat either aspirin or clopidogrel have any antiangi-nal effect.

Lipid-lowering therapy. The importance of anaggressive approach to the control of lipids in patientswith CAD is paramount. The use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, orstatins, has been associated with a decrease in mortali-ty of up to 30% and a reduction in major coronaryevents in patients with known CAD of up to 35%.13-15

These impressive results included some patients withbaseline levels of LDL cholesterol levels under 100mg/dL.15 Reducing LDL may limit progression or eveninduce regression of CAD, thereby having an indirectanti-ischemic effect. As discussed below, it also stabi-lizes plaques and thereby reduces the risk of acutecoronary syndromes.

Angiotensin-converting enzyme inhibitors. Tworecent multicenter, randomized trialsthe HeartOutcomes Prevention Evaluation (HOPE) study,and the European Trial on Reduction of CardiacEvents with Perindopril in Stable Coronary ArteryDisease (EUROPA)demonstrated the efficacy ofangiotensin- converting enzyme (ACE) inhibitors inpatients with CAD or those at risk of CAD.16,17 The


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Figure 4. Effect of Nitrates and Calcium ChannelBlockers on Coronary Blood Flow

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significant effect on the incidence of cardiovasculardeath, MI, or stroke was reported to be independentof the blood pressure- lowering effects of ACE inhi-bition. The results of HOPE have lead to the rec-ommendation that ACE- inhibitor therapy isappropriate for all patients with CAD and forasymptomatic patients with CAD who have concur-rent diabetes or LV dysfunction. Some controversyexists regarding the true nature of the vascular protec-tive effects observed with ACE-inhibitor therapy inHOPE. It is possible that these cardioprotective bene-fits may have been due to an antihypertensive effectthat is more evident when the effects of ramipril onblood pressure are examined over 24 hours rather thanat a single endpoint.

Novel agents. Novel drug therapies for the treat-ment of CAD decrease anginal symptoms via opti-mization of myocardial energy metabolism. Thesetherapies include carnitine derivatives, antioxidants,and fatty acid oxidation inhibitors (reviewed byStanley in 2002).18 Perhaps the most clinically excitingof these novel agents are the fatty acid oxidationinhibitors, trimetazidine (available outside the UnitedStates) and ranolazine (currently under US Food andDrug Administration review). These agents havedemonstrated an improvement in symptomswhen used as monotherapy or when combinedwith traditional pharmacologic agents.

NONPHARMACOLOGIC THERAPIESLifestyle modifications are important in the

management of patients with ischemic heart dis-ease. Such modifications include maintenance ofideal body weight, diet, exercise, and smoking ces-sation.1 In general, lifestyle modifications shouldbe instituted prior to or along with pharma-cotherapy and should serve to complement phar-macotherapy in the control of blood pressure anddyslipidemia.

ALTERNATIVE THERAPIESSome patients with ischemic heart disease

require surgical intervention in addition tolifestyle modification and pharmacotherapy. In aneffort to improve the prognosis of patients withCHD, the incidence of revascularization proce-dures has grown dramatically over the past 2decades.1 Percutaneous coronary intervention andcoronary artery bypass graft surgery are the pri-

mary treatment options for those CAD patients withhigh-risk features or who are refractory to maximalmedical management. However, many patients withCAD are not good candidates for conventional revas-cularization and their management remains a clinicalchallenge. This is especially true of diabetics in whomCAD is often both severe and diffuse. Alternative ther-apies for chronic stable angina in these difficult-to-treat patients include surgical laser transmyocardialrevascularization (TMR), enhanced external counter-pulsation (EECP), and spinal cord stimulation.10,19

The mechanisms for improvement in symptomsin patients with chronic stable angina associatedwith surgical TMR are currently unclear and mayinclude increased myocardial perfusion, denervationof the myocardium, or stimulation of angiogenesis.EECP is a nonpharmacologic technique that hasbeen found to be associated with a decrease in angi-na frequency and improved time to exercise-inducedischemia. Further study of this treatment is warrant-ed; however, widespread use of EECP is limited bysignificant exclusion criteria, limited availability ofthe device, the occurrence of adverse events, and thelack of long-term effect.

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Figure 5. Plaque Stabilization as a Means of Reduction inClinical Events

Plaque Instability

Plaque PhenotypeLarge lipid coreReduced SMC and collagenInflammationIncreased neovascularityEnhanced thrombogenicityEndothelial dysfunction

Plaque stability

Plaque PhenotypeReduced lipid coreIncreased SMC and collagenReduced InflammationReduced neovascularityReduced thrombogenicityImproved endothelial function

Atherosclerotic plaque

Reduced clinical events

Increased clinical events

Systemic factors

Reduced thrombogenicityIncreased lytic activity

Increased thrombogenicityReduced lytic activity

SMC = smooth muscle cells.Reprinted with permission from Shah. Pathophysiology of plaque rupture and the con-cept of plaque stabilization. Cardiol Clin. 2003;21(3):303-314.20

Spinal cord stimulation has been used since the late1980s as a means of providing analgesia in patientswith chronic angina refractory to medical, catheter-based, or surgical treatment. Although there are sever-al studies evaluating the efficacy of this technique,there is a general lack of data on the intermediate- andlong-term benefits of spinal cord stimulation. Thistechnique is used more widely in Europe than in theUnited States.

STABILIZATION OF PLAQUE

It is well established that luminal narrowing by anatherosclerotic plaque contributes to the clinical man-ifestations of occlusive vascular disease.4 However, thedevelopment of an arterial thrombus superimposed onan underlying disrupted plaque is responsible for themost acute and potentially lethal manifestations ofCAD. The majority of coronary thrombi occur at siteswhere the fibrous cap of an atherosclerotic plaque hasfissured eroded, or ruptured. Although the exactmechanisms responsible for plaque rupture are notfully defined, several features present prior to rupturehave been identified (Table 2).

Studies have demonstrated that risk factor modifi-cation leads to a decrease in the formation of newlesions, less lesion progression, and in some cases,actual regression of disease.4,20 The magnitude of clini-cal event reduction observed is much greater thanwhat can be accounted for with small changes in theseverity of stenosis. Therefore, it has been postulatedthat risk factor modification may not change plaquemass and stenosis severity, but may change the com-position of the plaque thereby reducing the propensi-ty for plaque rupture. This plaque stabilizationbrought on by lipid modification may be due tochanges in the composition of plaque and therefore areduction in the frequency of acute vaso-occlusiveevents (Figure 5). Some scientists have postulated thatthe depletion of lipids and decreased inflammationfrom atherosclerotic plaques may help reduce the riskof plaque rupture and subsequent thrombosis viaplaque stabilization with resultant clinical benefits.

CONCLUSIONS

Ischemic heart disease is a prevalent disease world-wide and is associated with significant morbidity andmortality. Treatment of CHD may include lifestyle

changes, pharmacological, and/or catheter-based orsurgical therapy. Traditionally, pharmacologicapproaches for treating ischemic heart disease haveeither increased the oxygen supply to the heart muscleor decreased the oxygen demand of the muscle. Noveltherapies utilizing a different mechanism of action todecrease anginal symptoms via optimization ofmyocardial energy metabolism are an exciting option.Current drug treatments of ischemic heart disease aredirected toward symptom control and prevention ofdisease progression and sequelae. However, manyagents are associated with side effects that affect quali-ty of life (events such as impotence, fatigue, edema,and headache).8 In addition, many patients need totake more than 1 antianginal agent for appropriatemanagement,21 thereby increasing the risk of sideeffects. Regardless of the condition being treated, mul-tidrug regimens are generally associated with lowercompliance than are simple regimens.

Many patients with CAD suffer from persistentsymptoms despite administration of standard therapy.Up to one fourth (26%) of CAD patients 1-year post-revascularization still experience anginal attacks,including patients who receive antianginal pharma-cotherapy.22,23 Refractory patients face persistent symp-toms and the risk of a cardiac event or death. There isa need for interventions that can induce plaque regres-sion and eventually reverse ischemic heart diseaseitself. Until such interventions become widely avail-able, there will continue to be a major demand fortherapies that reduce angina pectoris.

We have reviewed the causation of angina as well astherapeutic options. Despite numerous choices oftreatment for these patients, there are millions ofpatients who continue to experience angina. Manypatients are not suitable for revascularization due tothe extent and severity of their disease. There is a needfor new effective therapies for the many patients whosuffer from chronic angina and are not receiving fullbenefit from traditional treatment.

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