Epidemiology,Pathophysiology,and Therapeutic Targets in Stable Ischemic Heart Disease

C.Richard Conti,MD,MACC

1 University of Florida Medical School,Gainesville,FL,USA

Abstract

Keywords:stable angina ;epidemiology ;pathophysiology

Introduction

Angina is caused by myocardial ischemia,which occurs whenever myocardial oxygen demand exceeds oxygen supply.Myocardial ischemia is associated with increases in the late sodium current and intracellular sodium and calcium concentrations,calcium overload,and impairment of contractile relaxation(i.e.,increased diastolic wall tension).Intracellular sodium overload and calcium overload play a key role in both electrical and mechanical dysfunction in ischemia.It is hypothesized that sodium-related calcium overload mediates a vicious cycle of ischemia begetting more ischemia.

Management of stable angina includes relief of symptoms and reduction of the risk of future

adverse cardiovascular events.Traditional antianginal agents include nitrates,beta-blockers,and calcium channel blockers.Despite use of traditional drug therapy,there may be persistence of angina,and this underscores the need for newer agents with different mechanisms that may interfere with the ischemic process at another level.

Chronic Stable Angina:Epidemiology

Angina occurs in approximately 10 million Americans,with more than 500,000 new cases per year[1].This results in a high socioeconomic burden that signif cantly limits functional capacity and impairs quality of life as well as contributing to the high cost of care.This increasing cost of care is probably related to the growing prevalence of recurring ischemia due to residual coronary artery disease after percutaneous coronary intervention(PCI)or coronary artery bypass grafting(CABG).

Persons of Advanced Age

On the basis of data in the Framingham Heart Study database,there is an age-related increase in the incidence of angina among men and women.

Of the 10 million Americans with angina,half are older than 65 years and at the present time account for more than 50% of PCI and CABG operations in the United States each year[1,2].In addition,older patients tend to have more severe disease and a higher risk of hemodynamic adverse events with traditional antianginal agents.

The Magnitude and Impact of Ischemic Heart Disease in Women

Cardiovascular disease is a well-recognized cause of morbidity and death among women.The leading causes of death are ischemic heart disease and stroke.Chronic stable angina is a more common manifestation of coronary heart disease in women than in men.The presence of common comorbidities,including diabetes,is associated with poorer outcomes.The growing prevalence of recurring ischemia due to residual coronary artery disease after PCI or CABG is a manifestation of coronary heart disease in women[3-7].

On the basis of information generated by the WISE study,persistent chest pain is predictive of future cardiovascular events.

During the WISE study,Johnson et al.[7]found that the 6-year incidence of all combined cardiovascular events was twice as high in women with persistent chest pain than in women without persistent chest pain in the nonobstructive coronary artery disease subgroup(20.5 vs.10.1%,P=0.03)but not in the obstructive coronary artery disease subgroup(38.2 vs.36.8%,P=0.72).For prediction of composite cardiovascular events,the hazard ratio for persistent chest pain was 1.89(P=0.03)in women without obstructive coronary artery disease and 1.17(P=0.49)in women with obstructive coronary artery disease.

These f ndings suggest that,contrary to popular belief,women without obstructive coronary artery disease but with persistent chest pain had more than twice the number of cardiovascular events(including myocardial infarctions,strokes,congestive heart failure,and cardiovascular deaths)compared with those without persistent chest pain.Women with no obstructive coronary artery disease but with persistent chest pain should have aggressive risk factor reduction therapy designed to reduce adverse cardiovascular events as well as follow-up monitoring.

Common Comorbid Conditions in Patients with Stable Angina

The following are common comorbid conditions in patients with stable angina[8-10]:

· Hypertension(59-82%)

· Diabetes(26-37%)

· Chronic obstructive pulmonary disease(13-21%)

· Peripheral vascular disease(27-28%)

· Congestive heart failure(20-26%)

The presence of these comorbidities often complicates medical or revascularization treatment of chronic stable angina.

Persistence of Angina Despite Use of Traditional Drug Therapy

Patients report an average of two angina attacks per week despite taking traditional antianginal therapies(i.e.,beta-blockers,calcium channel blockers,nitrates).A signif cant proportion develop intoler-ance to these agents on follow-up.

Patients who experienced infarction or required repeated catheter-based intervention after the initial PCI hospitalization tended to report more angina 1 year after PCI,whereas patients who underwent bypass surgery after the index PCI reported signif-cantly less angina[11].

ARTS:Persistent Angina following Optimal Revascularization

ARTS was a prospective randomized study in patients with multivessel disease(n=1205)who underwent PCI/stent placement(600 patients)or CABG(605 patients)[12].Patients were followed up for 1-year after optimal revascularization,and 59-79% still require antianginal agents and 11-21% still have angina.

Overlapping Pharmacodynamic Effects

Beta-blockers and many calcium channel blockers have similar depressive ef fects on blood pressure,heart rate,and/or atrioventricular(A V)nodal conduction;thus newer agents with dif ferent pharmacodynamic mechanisms are needed.

Pathophysiology of Stable Angina

Symptoms tend to occur at the end of the ischemic cascade.Myocardial ischemia begins with relaxation,and angina is usually the last event.

Approximately half of patients with angina also experience episodes of asymptomatic(silent)ischemia;thus many episodes of ischemia never become painful.Why this is the case is not known but could be related to the short duration of myocardial ischemia.

Cardiac Ischemia:General Pathophysiologic Considerations

A sudden reduction in coronary f ow/myocardial oxygen supply is usually the mechanism of acute coronary syndromes[13].Recent plaque injury often superimposed on thrombosis and/or microembolism,endothelial dysfunction,and heightened smooth muscle reactivity causes the acute coronary syndromes.These ischemic episodes result in myocyte injury or micronecrosis(e.g.,troponin release or regional wall motion abnormality on left ventricular echocardiography).

Increase in myocardial oxygen demand,in the setting of limited ability to increase myocardial oxygen supply,is usually the mechanism of chronic stable angina.An episode of ischemia in chronic stable angina patients is transient and without evidence of myocyte injury(e.g.,troponin release).

Clas sic Clinical Presentation of Angin a

Most patients describe a sensation of chest discomfort over or near the sternum.It is usually described as heaviness,pressure,squeezing,smothering,or choking,and only rarely as frank pain.The discomfort is often crescendo-decrescendo in nature,and typically lasts 2-5 minutes.

The discomfort can radiate to either shoulder and to both arms,and occasionally also arises in or radiates to the back,interscapular region,root of the neck,jaw,teeth,and epigastrium.Rarely is the discomfort localized below the umbilicus or above the mandible.

Usual Precipitating Factors for SIHD

Chronic stable angina is usually precipitated by exercise,a cold environment,walking after a meal,emotional upset,fright,anger,or coitus.

Conditions Provoking or Exacerbating Ischemia in the Stable Angina Patient

There are several causes of increased oxygen demand and decreased oxygen supply[14].The following are causes of increased oxygen demand:hyperthermia,hyperthyroidism,sympathomimetic toxicity,hypertension,anxiety,arteriovenous f stulae,hypertrophic cardiomyopathy,aortic stenosis,dilated cardiomyopathy,and tachycardia(ventricular or supraventricular,e.g.,atrial f brillation).

The following are causes of decreased oxygen supply:anemia,hypoxemia of any pulmonary cause,obstructive sleep apnea,sickle cell disease,sympathomimetic toxicity,and cardiomyopathy.

Usual Relief of SIHD

Rest and/or glycerol trinitrate provides the stable angina patient with relief of the discomfort caused by myocardial ischemia.

Atypical Angina

In many instances,angina pectoris may be atypical in location and not strictly related to provoking factors(i.e.,it may occur at rest).These episodes of ischemia are considered angina equivalents.Symptoms of myocardial ischemia other than chest discomfort include dyspnea,nausea,fatigue,and faintness.

Pathophysiologic Effects of Traditional Antianginal Drugs

The effects are mostly hemodynamic that decrease oxygen demand(e.g.,heart rate,arterial pressure,venous return and myocardial contractility)or increase coronary blood f ow[14].

Beta-blockers decrease heart rate,blood pressure,and myocardial contractility.

Calcium channel blockers decrease heart rate,blood pressure,and myocardial contractility and increase coronary blood f ow.

Nitrates have a variable ef fect on heart rate,decrease blood pressure and contractility,and increase coronary blood f ow.

Traditional Antianginal Drugs and Conditions That May Limit Their Use

Beta-blockers should be used only if the patient is hospitalized and under observation if the following conditions are apparent:asthma,severe bradycar-dia,AV block,severe depression,Raynaud syndrome,or sick sinus syndrome.

In severe aortic stenosis,nitrates can be used if angina is refractory to other agents.In hypertrophic obstructive cardiomyopathy,theoretically the use of nitrates will increase the left ventricular pressure difference.Nitrates must not be used in a patient with erectile dysfunction if the patient is taking sildenaf l.

I would not use calcium channel blockers in any of the following conditions:AV block,bradycardia,heart failure,left ventricular dysfunction,and sinus node dysfunction.

What Is Happening during Myocardial Ischemia?

During myocardial ischemia the late sodium channel is impaired.Impaired sodium channel function contributes to:

· Pathologic increase of the late sodium current[15]

· Sodium overload

· Sodium-induced calcium overload by the sodium/calcium exchanger

Calcium overload causes impaired diastolic relaxation,which:

· Increases diastolic wall tension

· Increases myocardial oxygen demand

· Reduces myocardial blood f ow and oxygen supply(microvascular hypoperfusion)

· Worsens ischemia and angina

Ranolazine blunts the adverse consequences of myocardial ischemia by its inhibition of the late Na + current[16].

Metabolic Modulation:Partial Fatty Acid Oxidation Inhibition

The myocyte oxygen requirement of the glucose pathways is lower than that of the free fatty acid pathway.During ischemia,oxidized free fatty acid levels rise in myocytes,blunting the glucose pathway.Trimetazidine(not available in the United States)partially inhibits fatty acid oxidation,thereby shifting energy metabolism toward glucose utilization.

Preconditioning

Nicorandil(not available in the United States)is an ATP-sensitive K+ channel opener that may be responsible for ischemic preconditioning.It causes dilation of coronary resistance arterioles.It is also a nitric acid donor responsible for vasodilation of coronary epicardial arteries.

Blockade of Coronary Spasm Induced by Acetylcholine

Fasudil is a selective Rho-kinase inhibitor and vasodilator available only in Japan.It has been shown to effectively treat coronary spasm.

Funny Current

Ivabradine selectively targets the Na+/K + current(Ifcurrent)in pacemaker cells of the sinoatrial node.Channels that carry the Ifcurrent are unique to the sinoatrial node,although ion channels in the retina have a similar structure and are probably the source of mild,transient visual disturbances in some patients taking Ifblockers.

Ivabradine selectively inhibits the hyperpolarization-activated,mixed Na+/K + inward Ifcurrent and decreases rest and exercise heart rate responsiveness,thus decreasing myocardial oxygen consumption[17].

Classic Management Strategies for Chronic Stable Myocardial Ischemia

I use the following as a reminder as to what patients should be taking or doing to control angina symptoms:

A:Aspirin and ACE inhibitor,angiotensin receptor blocker,angioplasty/stent placement

B:Beta blockers,blood pressure

C:Cholesterol,cigarettes,clopidogrel,CABG

D:Diet(weight control),diabetes,drugs(new)

E:Education about nitrates,exercise,enhanced external counterpulsation and ranolazine

Confl ict of Interest

The author declares no conf icts of interest.