Cardiovascular disease

The normal heart beats regularly at 60–100 beats per min (bpm), which is controlled by the sinoatrial (SA) node located in the right atrium. Tachycardia describes a heart that beats more rapidly (>100 bpm). Bradycardia describes a situation where the heart beats more slowly (<60 bpm). Electrical signals generated in the SA node travel through a conduction pathway in the wall of the atria (causing atrial contraction) before reaching and depolarising the AV node. The electrical signal delays while passing through the AV node, which allows the ventricles to fill with blood from the atria. The signal then spreads rapidly through the ventricles via the His bundle–branches in specialised Purkinje fibres. These rapidly-conducting fibres mean that the ventricular muscle contracts simultaneously, raising the pressure that expels blood from the left and right ventricles to supply the systemic and pulmonary circulations. 

Arrhythmias are abnormalities of the heart rhythm, which occur when the electrical signals coordinating the regular heartbeats are disordered. Mechanisms of arrhythmias are abnormal automaticity, triggered activity and re-entry.

Antiarrhythmic drugs

Antiarrhythmic drugs suppress the causative mechanisms mainly by

1) increasing the threshold potential for depolarisation,

2) decreasing the conduction velocity, and

3) prolonging the refractory period.

Antiarrhythmic drugs are divided into four groups according to the Vaughan Williams classification.

Class I drugs inhibit Na⁺ channels to increase the threshold potential and decrease the conduction velocity in the atrial and ventricular tissues where Na⁺ entry generates the action potential upstroke phase.

Class IV drugs exert similar effects in the SA and AV node by inhibiting Ca²⁺ channels since Ca²⁺ entry generates the action potential upstroke phase in the nodal cells. The increase of the threshold potential suppresses the automaticity and the triggered activity. The decrease of the conduction velocity could block re-entry to terminate some arrhythmias.

Class III drugs prolong the refractory period by inhibiting K⁺ channels and some class I drugs prolong it by slowing recovery from the inactivation of Na⁺ channels. The prolongation of the refractory period could also block re-entry to terminate arrhythmias.

Class II drugs are beta-adrenoceptor antagonists (β-blockers) and slow firing of the SA and AV node, which causes slowing of the heart rate and AV conduction velocity. Class II drugs also suppress catecholamine-induced increase of Ca²⁺ currents, Na⁺ currents and K⁺ currents (I_Ks: slow component of the delayed rectifier K⁺ currents).

Arrhythmias

Arrhythmias can be divided into three types: premature contraction, tachyarrhythmia and bradyarrhythmia. Premature contraction and tachyarrhythmia are originated either from the atria or the ventricles, and bradyarrhythmia is caused by dysfunction of the SA node. The following are common arrhythmias and their treatments.

I.       Premature contractions
1. Supraventricular premature contractions (SVPCs). SVPCs do not usually require treatment unless they affect quality of life (QOL). Reduction of caffeine and alcohol intake is recommended. Symptomatic SVPCs are sometimes treated with β-blockers. Class I drugs can be used for patients with SVPCs without organic heart diseases.

2. Ventricular premature contractions (VPCs)

• Without organic heart diseases (Idiopathic VPCs). Asymptomatic or mildly symptomatic VPCs do not require treatment. Life style changes including reduction of caffeine intake are usually sufficient. Symptomatic VPCs that impair patients’ QOL are treated with β-blockers, class IV drugs and class I drugs depending on their pathophysiology.
• With organic heart diseases. Symptomatic or frequent VPCs are treated with β-blockers and amiodarone (a class III drug having multiple actions on ion channels and receptors), which improves cardiac function by reducing VPCs.

II.      Tachyarrhythmias
1. Paroxysmal supraventricular tachycardia (PSVT). AV nodal re-entry tachycardia (AVNRT) and AV reciprocating reentry tachycardia (AVRT) are major PSVT. If the episodes are not self-limited, these arrhythmias are acutely treated with drugs that slow AV nodal conduction - adenosine, β-blockers and verapamil (a class IV, non-dihydropiridine Ca²⁺ channel blocker). Adenosine is not approved in Japan and ATP is used instead. Adenosine (or ATP) is rapidly injected intravenously. For pharmacological prophylactic therapy, β-blockers and verapamil are used, but catheter ablation is the first-line therapy that could provide a permanent cure.  

2. Atrial fibrillation (AF). AF is the most commonly encountered arrhythmia in clinical practice. Abnormal automaticity and formation of re-entry circuits in the atrium and pulmonary vein play a pivotal role in onset and maintenance of AF. In general, the paroxysmal form of AF progresses to the persistent or permanent form of AF after repetitive occurrence. When AF occurs because the atria excite chaotically and irregularly, the ventricles cannot respond to every atrial beat. Therefore. the ventricular responses are irregular and heart rate may increase to ≥150–200 bpm, which impairs the pump function of the heart and can increase the chances of heart failure. In addition, the chaotic and ineffective contraction of the atria increases the potential for clot formation in the atria, which can increase the risk of stroke and systemic thromboembolism. Therefore, the heart rate needs to be reduced by rate control or rhythm control, and the clot formation needs to be prevented by anticoagulation therapy. AF patients can be treated with drugs or catheter ablation.

• Anticoagulation therapy. In AF patients, risk of thromboembolism needs to be assessed when starting anticoagulation therapy. For anticoagulation therapy, warfarin and novel direct oral anticoagulants (DOACs) are used. Warfarin is a vitamin K antagonist, which takes time to have a therapeutic effect, and has higher risk for bleeding than the novel DOACs. There are two kinds of DOACs, direct thrombin inhibitors (e.g. dabigatran) and factor Xa inhibitors (e.g. rivaroxaban, apixaban). Their onset of therapeutic effect is earlier (within a day) and they have less bleeding risk.
• Rate control therapy. Drugs used for rate control therapy are β-blockers, non-dihydropyridine Ca²⁺ blockers (e.g. verapamil, diltiazem) and digoxin. β-blockers are normally the first line drugs, because they can be used for AF patients with or without heart failure. Non-dihydropyridine Ca²⁺ blockers are used only for AF patients without heart failure. Digoxin is for AF patients with heart failure.
• Rhythm control (sinus rhythm maintenance) therapy. Drugs used for rhythm control therapy are class I drugs (except lidocaine and mexiletine) and multiple channel blockers, amiodarone and bepridil.

3. Atrial flutter. Atrial flutter is a macro-re-entrant tachyarrhythmia and, in contrast to AF, the atria beat regularly. The atrial beat is so rapid (240–440 bpm) that the ventricles usually cannot respond to every beat. If AV conduction ratio is 2:1, the heart rate is 150 bpm when the atrial rate is 300 bpm. Similar to AF, sinus rhythm restoration, rate control therapy and anticoagulation are considered.

• Anticoagulation therapy. Warfarin and novel DOACs are used. Anticoagulation therapy is recommended in atrial flutter patients because it is known that risks of thromboembolism are comparable to AF.
• Rate control therapy. Similar to AF, β-blockers, non-dihydropyridine Ca²⁺ blockers (e.g. verapamil, diltiazem) and digoxin are used to control heart rate. While non-dihydropyridine Ca²⁺ blockers are used for patients with hemodynamically stable atrial flutter, digoxin can be used for patients who are hemodynamically unstable.
• Rhythm control (sinus rhythm restoration) therapy. Class III drugs which prolong the refractory period and class I drugs which slow the conduction velocity are used to stop atrial flutter. When sinus rhythm restoration therapy is attempted, caution should be taken not to lead to a rapid 1:1 ventricular response: it is preferable to use β-blockers and non-dihydropyridine Ca²⁺ blockers to delay AV conduction.

4. Ventricular tachycardia (VT)

• Without organic heart diseases (idiopathic VT). Idiopathic VT can originate from various areas, most frequently from the outflow tract. In patients with idiopathic VT, a β-blocker and verapamil (class IV) are useful. Class I drugs can sometimes be effective.
• With organic heart diseases. If the patient is hemodynamically unstable with VT, direct-current cardioversion should be performed. For pharmacological treatment, amiodarone and sotalol are frequently used, and lidocaine may be considered.

5. Ventricular fibrillation (VF). Ventricular fibrillation (VF), chaotic and irregular excitement in the ventricles, is the main cause of sudden cardiac death. Electrical cardioversion is the only therapy to immediately stop VF.  

III.     Bradyarrhythmias
Bradyarrhythmias are rhythm disturbances including sinus node dysfunction and AV conduction disturbances. In general, pacemaker implantation is indicated for patients with symptomatic bradyarrhythmias. No treatment is necessary for asymptomatic bradycardia. Atropine and sympathomimetics can be used to treat bradycardia until pacemaker implantation.

Dr. Kuniaki Ishii

Heart failure (HF) is caused by the heart’s inability to pump enough blood to meet the body’s needs. In response, the body activates compensatory mechanisms, such as the sympathetic nervous system which leads to tachycardia, sodium and water retention, vasoconstriction, and over time, ventricular hypertrophy, all geared towards increasing cardiac output. Leading causes of HF are coronary artery disease and hypertension.

Neurohormonal signaling by angiotensin II, norepinephrine, aldosterone, and others drive cardiac remodeling. These hormones promote disease progression, making them ideal targets for pharmacologic therapy. On the other hand, some other medications may exacerbate HF through negative inotropic effects, direct cardiotoxicity, or increased sodium and water retention.

Heart failure with reduced ejection fraction (HFrEF) (Systolic heart failure) is characterized by a reduced (≤40%) left ventricular ejection fraction (LVEF). It is caused by the heart’s impaired ability to contract. Myocardial infarction, dilated cardiomyopathies, and ventricular hypertrophy can lead to HFrEF. Heart failure with reduced ejection fraction is amenable to the medical therapies described below.

Heart failure with preserved ejection fraction (HFpEF) (Diastolic heart failure) is characterized by impaired ventricular relaxation and increased diastolic stiffness. In HFpEF, the LVEF is preserved (≥50%). Ventricular stiffness, ventricular hypertrophy, myocardial ischemia and myocardial infarction, mitral or tricuspid valve stenosis, and pericardial disease can lead to HFpEF. There is no standard treatment regimen for patients with HFpEF. Management consists of optimal treatment of the underlying diseases, such as hypertension, diabetes, and obesity.

The following classes of drugs have been shown to reduce mortality in patients with HFrEF:

1) Angiotensin Converting Enzyme Inhibitors (ACEIs) decrease angiotensin II and aldosterone, reducing ventricular remodeling, vasoconstriction, and sodium and water retention. These drugs inhibited the conversion of angiotensin I to angiotensin II by inhibiting ACE. All patients with HFrEF should receive an ACEI unless contraindicated. Patients who do not yet have HF symptoms but already have structural heart disease should receive an ACEI to prevent HF development. Drugs in this class include captopril, lisinopril, enalapril and others. ACEIs also inhibit the inactivation of bradykinin which contributes to dry cough in patients taking an ACEI.

2) Angiotensin Receptor Blockers (ARBs) such as valsartan are similar to ACEIs in their blockade of the harmful effects of angiotensin II. Drugs in this class are highly selective, competitive receptor antagonists at the AT₁ receptor, which mediates the effects of angiotensin II. They are recommended for patients unable to tolerate ACEIs, usually due to dry cough. ARBs should not be initiated in patients with a history of angioedema, hypotension, hyperkalemia, or renal insufficiency with ACEIs.

Doses of ACEIs/ARBs should start low and be titrated to the target dose every 2 weeks as tolerated. Monitor renal function and potassium at baseline and 1 to 2 weeks after initiation.

3) Angiotensin Receptor/Neprilysin Inhibitors (ARNI) include the combination valsartan and sacubitril. Natriuretic peptides may produce beneficial effects in patients with heart failure including promotion of diuresis and natriuresis, vasodilation, and inhibition of sympathetic nervous system by reduced catecholamine secretion and inhibition of renin-angiotensin-aldosterone system. Natriuretic peptides are catabolized and inactivated by the enzyme neprilysin. Sacubitril inhibits neprilysin thereby maintaining levels of natriuretic peptides. Neprilysin also breaks down angiotensin II, necessitating the combination of the sacubitril with valsartan.

Patients with HFrEF that remain symptomatic while taking an ACEI or ARB can be transitioned to an ARNI. Patients taking an ARB can switch immediately; however, patients taking an ACEI require a 36-hour washout period due to the risk of angioedema.

4) Aldosterone Receptor Antagonists (ARAs) such as spironolactone block the aldosterone (mineralocorticoid) receptor, thereby inhibiting oxidative stress, sodium reabsorption, potassium excretion, and cardiac remodeling.

ARAs are recommended for patients with a LVEF <35%. HF patients with mild symptoms should only be considered for ARAs if they have a history of prior cardiovascular hospitalization or elevated BNP levels. ARAs are also recommended in patients who develop symptoms of HF or with a history of diabetes mellitus following an acute-MI and a LVEF <40%. ARAs are contraindicated in patients with an eGFR <30 mL/min/1.73 m² or a potassium level >5 mEq/L.

5) Beta-blockers reduce heart rate, cardiac oxygen consumption, remodeling due to cardiac hypertrophy, and stimulation of the renin-angiotensin-aldosterone system by antagonizing the sympathetic nervous system.

Only bisoprolol, carvedilol, and metoprolol succinate have shown mortality benefits and are recommended for all patients with HFrEF. Doses should start low and be titrated to the target dose every two weeks as tolerated. Beta-blockers can be initiated while optimizing the dose of ACEI/ARBs but should not be started in patients with volume overload.

The following classes of drugs decrease symptoms associated with HFrEF and improve quality of life. However, they have not been shown to reduce mortality.

6) Diuretics, in addition to dietary sodium restriction, are recommended for patients with clinical signs of volume overload. Loop diuretics such as furosemide are typically required. However, patients with mild fluid retention may benefit from a less potent thiazide class diuretic like hydrochlorothiazide.

7) Nitrates and hydralazine: The combination of hydralazine and nitrates (isosorbide dinitrate) decreases cardiac remodeling by promoting vasodilation. The combination is recommended to reduce morbidity and mortality in symptomatic patients self-described as African American already receiving ACEI/ARB, an ARA, and evidence-based beta blockers. They are also recommended in patients who cannot tolerate an ACEI or an ARB.

8) Ivabradine inhibits the “funny” current in the SA node, decreasing heart rate. The funny current is responsible for a steady increase in resting membrane potential through sodium and potassium ionic currents. Inhibition of this current prolongs diastolic depolarization, slowing firing in the SA node, and ultimately reducing heart rate. Ivabradine reduces hospitalizations in HF patients on a target dose of ACEI/ARB and beta-blocker. Patients must be in sinus rhythm and have a heart rate over 70 bpm.

9) Digoxin inhibits the Na/K ATPase pump, resulting in increased intracellular sodium. This promotes an influx of calcium via the Na/Ca exchange pump which increases contractility of the heart. Because the heart can pump with greater contractility, sympathetic tone is reduced and vagal tone predominates, suppressing AV node conduction and slowing the heart rate. It is recommended in patients experiencing symptoms despite taking the target doses of ACEI/ARBs and beta-blockers.

Abigail Elmes, Kelly Karpa

Elevated blood pressure (BP) is the product of increased cardiac output (CO) and peripheral vascular resistance (PVR). Increased CO may result from increased fluid volume from excess sodium intake or renal sodium retention, stimulation of the renin-angiotensin-aldosterone system (RAAS), or activation of the sympathetic nervous system (SNS). Functional constriction or structural hypertrophy of the vasculature increases PVR. Both result from excess stimulation of the RAAS, SNS overactivity, genetic alterations of cell membranes, or endothelial-derived factors.

Recommendations for treating hypertension are based on the 2017 American College of Cardiology /American Heart Association (ACC/AHA) Hypertension Guidelines. Hypertension is diagnosed from the average of two or more BP measurements. Normal BP is less than 120/80 mmHg. Elevated BP is 120-129/<80 mmHg. Stage 1 hypertension is classified as 130-139/80-89 mmHg. Stage 2 hypertension is considered at pressures greater than 140/90 mmHg. The BP goal for most patients with hypertension is less than 130/80 mmHg.

Patients with elevated and Stage 1 hypertension with an atherosclerotic cardiovascular disease (ASCVD) 10-year risk less than 10% should be managed through nonpharmacologic regulation of BP which includes weight loss with a heart-healthy diet, dietary sodium restriction and potassium supplementation, increased physical activity, and limited alcohol consumption. If these patients have an ASCVD 10-year risk greater than 10% or clinical CVD, antihypertensive drug therapy should also be initiated. Patients with Stage 2 hypertension will most likely require two or more medications to reach the target BP.

Angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and thiazides reduce mortality in patients with hypertension and are considered first-line therapies. As a group, African American patients show a smaller response in BP reduction to ACEIs or ARBs than Caucasian patients. Therefore, patients that self-identify as Black or African American should be preferentially placed on a CCB or thiazide. If microalbuminuria is present (urine albumin:creatinine ≥300 mg/g), an ACEI or ARB should be considered.

1. ACEIs (lisinopril, enalapril, captopril, etc.) decrease angiotensin II formation and subsequent aldosterone synthesis, thereby reducing vasoconstriction and sodium and water retention. ARBs (losartan, valsartan, telmisartan, etc.) are similar to ACEIs.  While ACEI’s block formation of angiotensin II, ARBs block the effects of angiotensin II by antagonizing AT₁ receptors. ARBs are recommended for patients that are unable to tolerate ACEIs, usually due to dry cough or rare incidences of angioedema. ARBs should not be initiated in patients with a history of angioedema, hypotension, hyperkalemia, or renal insufficiency with ACEIs

2. CCBs reduce calcium ion influx during depolarization of cardiac and/or vascular smooth muscle leading to muscle relaxation.  Non-dihydropyridine CCBs (diltiazem, verapamil) are more cardioselective, have negative inotropic effects, and decrease CO.  On the other hand, the dihydropyridine CCBs (amlodipine, nicardipine, nifedipine, etc.) act mostly on vascular smooth muscle to decrease PVR.

3. Thiazides (hydrochlorothiazide, chlorthalidone, etc.) inhibit sodium reabsorption in the renal distal tubules causing increased excretion of sodium, water, potassium and hydrogen ions. While their diuretic effect is not as potent as loop diuretics, thiazides exhibit significant antihypertensive activity and have a longer duration of action. Loop diuretics, however, should replace thiazides in patients with impaired kidney function and a reduced estimated glomerular filtration rate.

Comorbidities drive therapeutic decision-making. Beta-blockers are not recommended as monotherapy for the treatment of hypertension and should only be considered if heart failure or other comorbidities are also present. Dihydropyridine CCBs should be avoided in patients with heart failure. Alpha-blockers are not recommended due to orthostasis risk unless the patient has benign prostatic hyperplasia.

1. Resistant hypertension

This occurs when BP is not at goal while taking a 3-drug complementary regimen which typically includes a longer-acting thiazide like chlorthalidone, ACEI or ARB, and a CCB. Mineralocorticoid (aldosterone) receptor antagonists like spironolactone are advantageous additions in this setting and have shown evidence of greater BP reduction than beta or alpha blockers. Vasodilators like hydralazine or minoxidil have also shown significant reductions in BP in these patients. Direct renin inhibitors like aliskiren show similar reductions in BP to ACEIs or ARBs but should not be used in combination with them due to increased likelihood of angioedema and hyperkalemia. Central alpha-2 agonists like clonidine are generally reserved as last line therapy due to adverse effects in the central nervous system, particularly in elderly populations.

2. Pregnancy

Women with hypertension who become pregnant or are planning to become pregnant, should be transitioned to methyldopa, nifedipine, and/or labetalol during pregnancy. Hydralazine is a reasonable addition to these medications if BP remains above goal, however, it should not be used as monotherapy. ACEIs, ARBs, and direct renin inhibitors are contraindicated in pregnancy.

Abigail Elmes, Kelly Karpa

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.

Kuniaki Ishii