Ischemic heart disease

Oxygen demand of the heart dynamically changes, and the coronary artery can adjust its blood flow to fulfill the myocardial oxygen demand (coronary blood flow reserve). Normally, the oxygen supply and the oxygen demand are well balanced in healthy subjects. When the oxygen supply to the heart becomes inadequate for the needs of the heart, myocardial ischemia occurs. That is, ischemic heart disease (IHD) is caused by an imbalance between the oxygen supply (coronary blood flow) and the oxygen demand of the heart. Depending on myocardial damage caused by ischemia, IHD is categorized into two groups: angina pectoris and myocardial infarction. However, from the therapeutic point of view, IHD is divided into chronic coronary artery disease (CAD) and acute coronary syndrome (ACS).

Chronic CAD is characterized by atherosclerosis that results in reduction of blood supply to the heart. Stable atherosclerotic plaques cause narrowing of coronary arteries in most chronic CAD (stable angina), while functional spasm narrows coronary arteries in some cases (variant angina). When mechanical coronary stenosis is present, the downstream coronary artery maximally dilates by metabolic responses. Therefore, drugs that dilate coronary arteries aiming at increasing blood supply are not effective for stable angina. In that case, oxygen demand should be decreased. In contrast, if coronary artery spasm is the underlying cause of CAD, coronary vasodilators are effective.

ACS is characterized by unstable atherosclerotic plaques that are prone to rupture. Atherosclerotic plaque rupture is followed by dysregulated platelet aggregation and thrombus formation, which causes coronary artery narrowing and occlusion. There are three subtypes of ACS: unstable angina, non-ST elevated myocardial infarction, and ST elevated myocardial infarction. Drugs that affect arterial thrombosis are used to treat ACS.

1. Chronic CAD

Chronic CAD is treated with nitrates, β-adrenergic blockers and calcium channel blockers depending on the pathologies: anti-ischemic therapy.

(1) Nitrates

Organic nitrates are metabolized in the body to release nitric oxide (NO). NO activates soluble guanylyl cyclase to produce cyclic guanosine 3', 5'-monophosphate (cGMP) that relaxes vascular smooth muscle. Nitrates decrease preload to the heart by dilating capacitance veins, which is their primary therapeutic effect. Decrease of the preload reduces myocardial oxygen demand. Nitrates also decrease afterload of the heart by dilating resistance arterioles, which also reduces myocardial oxygen demand. In addition, nitrates increase myocardial blood flow by dilating large coronary arteries. Adverse effects include headache, postural hypotension, and tachycardia. Nitrates cannot be used in combination with phosphodiesterase 5 (PDE5) inhibitors such as sildenafil, because it may cause severe hypotension. Tolerance to nitrates can easily develop, which should be considered in clinical settings.

(2) β-blockers

β-blockers reduce myocardial oxygen demand by decreasing myocardial contractility and heart rate via acting on cardiac β₁-adrenoceptors. It is their primary therapeutic effect for CAD. β-adrenergic blockers are used to treat stable angina. Blocking of vascular β₂-adrenoceptor inhibits vascular relaxation, which may worsen myocardial ischemia. Therefore, β-blockers cannot be used to treat CAD when coronary artery spasm is the underlying mechanism.

(3) Calcium channel blockers (CCBs)

CCBs block Ca2+ entry into cells via L-type Ca2+ channels that play an important role in cardiac muscle and vascular smooth muscle. Each CCB has a different profile in terms of tissue selectivity: dihydropyridines (DHPs) such as nifedipine have a high selectivity to vascular L-type Ca2+ channels, whereas verapamil and diltiazem have a relatively high selectivity to cardiac L-type Ca2+ channels. CCBs can increase oxygen supply by dilating coronary arteries. CCBs can also reduce myocardial oxygen demand by dilating resistance arterioles to decrease afterload. In addition, CCBs that act on the heart at therapeutic concentrations, such as verapamil and diltiazem, reduce myocardial oxygen demand by decreasing cardiac contractility and heart rate. Although increase of oxygen supply and decrease of oxygen demand are therapeutic effects of CCBs, each CCB has differential effect on the supply and demand. For example, nifedipine (a short acting DHP) strongly dilates arterioles to cause hypotension that leads to reflex tachycardia. Therefore, nifedipine rather increases myocardial oxygen demand, which may worsen CAD. Adverse effects include flushing, dizziness, pedal edema, constipation, and gingival hyperplasia. Unlike β-blockers, CCBs are the first-line drug for vasospastic angina.

2. ACS

In addition to anti-ischemic therapy, antithrombotic therapy is indicated for the treatment of ACS, since ACS is caused by dysregulated platelet aggregation and thrombus formation.

(1) Antiplatelet drugs

As antiplatelet drugs, aspirin, a nonsteroidal-antiinflammatory drug (NSAID), is most frequently prescribed to treat ACS. Aspirin inhibits cyclooxygenase (COX), reducing the synthesis of thromboxane A₂ (TXA2) that potently stimulates platelet aggregation. Since aspirin irreversibly inhibits COX and de novo protein synthesis does not occur in platelets, antiplatelet effects of aspirin continue until new platelets are produced. Other antiplatelets used include ADP receptor inhibitors, such as clopidogrel and ticlopidine, and inhibitors of phosphodiesterase 3 (PDE3), such as cilostazol and dipyridamole.

(2) Anticoagulants

Heparin is indicated in most ACS patients. Heparin acts on the endogenous anticoagulant antithrombin III (AT III) that inhibits coagulation factor proteases including thrombin and factor X. Heparin shows its anticoagulation activity via accelerating binding of AT III to the coagulation factors by 1,000-fold. Besides heparin, direct and indirect inhibitors of Factor Xa are used. Fondaparinux, an indirect inhibitor of factor Xa, also binds to AT III and selectively inhibits factor Xa.

(3) Thrombolytics

Cross-linked fibrin that is digested by plasmin is a major component of a thrombus. Therefore, tissue plasminogen activator (t-PA) and pro-urokinase that activates plasminogen, the plasmin precursor, are used to lyse thrombus. They are administered intravenously or intra-coronary.