Chest pain is the most common symptom associated with coronary artery disease. It is usually described as dull and can often radiate down the arm or to the jaw. It does not worsen with a deep breath and can be associated with shortness of breath, diaphoresis, nausea, and vomiting. This entire symptom complex has been termed as ANGINA PECTORIS or A PAIN IN THE CHEST.

Clinically, angina is classified according to the precipitant and the duration of symptoms. If the pain occurs only with exertion and has been stable over a long period of time, it is termed stable angina. If the pain occurs at rest, it is termed unstable angina. Finally, regardless of the precipitant, if the chest pain persists without interruption for prolonged periods and irreversible myocyte damage has occurred, it is termed myocardial infarction.

ETIOLOGY:

Atherosclerotic obstruction of the large epicardial vessels is by far the most common cause of coronary artery disease. Spasm of the coronary arteries from various mediators such as serotonin and histamine. Rarely, congenital abnormalities can cause coronary artery diseases .

Other causes of angina symptoms include the following:

• Blockage of a coronary artery by a blood clot or by compression from something outside the artery
• Inflammation or infection of the coronary arteries
• Injury to one or more coronary arteries
• Poor functioning of the tiny blood vessels of the heart (microvascular angina)

EPIDEMIOLOGY:

The syndrome of angina pectoris is reported to occur with an average annual incidence rate (number of new cases per time period per total number of persons in the population for the same time period) of about 1.5% (range 0.1 to 5 per 1000) depending on the patient’s age, gender, and risk-factor profile. The presenting manifestation in women is more commonly angina, whereas men more frequently have MI as the initial event. Estimates of the incidence and prevalence of angina are not entirely accurate owing to waxing and waning of symptoms;

angina may disappear in up to 30% of patients with angina that is less severe and of recent onset.

PATHOPHYSIOLOGY:

Coronary blood flow brings oxygen to myocytes and removes waste products such as carbon dioxide, lactic acid, and hydrogen ions. The heart has a tremendously high metabolic requirement; although it accounts for only 0.3% of body weight, it is responsible for 7% of the body’s resting oxygen consumption. Cellular ischemia occurs when there is either increased demand for oxygen relative to maximal arterial supply or an absolute reduction in oxygen supply. Although situations of increased demand such as thyrotoxicosis and aortic stenosis can cause myocardial ischemia, most clinical cases are due to decreased oxygen supply. Reduced oxygen supply can rarely arise from decreased oxygen content in blood such as occurs in carbon monoxide poisoning or anemia but more commonly stems from coronary artery abnormalities , particularly atherosclerotic disease. Myocardial ischemia may arise from a combination of increased demand and decreased supply; cocaine abuse increases oxygen demand (by inhibiting reuptake of norepinephrine at adrenergic nerve endings in the heart) and can reduce oxygen supply by causing vasospasm.

The heart receives its energy primarily from ATP generated by oxidative phosphorylation of free fatty acids, although glucose and other carbohydrates can be utilized. Within 60 s after coronary artery occlusion, myocardial oxygen tension in the affected cells falls essentially to zero. Cardiac stores of high-energy phosphates are rapidly depleted, and the cells shift rapidly to anaerobic metabolism with consequent lactic acid production. Dysfunction of myocardial relaxation and contraction occurs within seconds, even before depletion of high-energy phosphates occurs. The biochemical basis for this abnormality is not known. If perfusion is not restored within 40-60 min, an irreversible stage of injury characterized by diffuse mitochondrial swelling, damage to the cell membrane, and marked depletion of glycogen begins. The exact mechanism by which irreversible damage occurs is not clear, but severe ATP depletion, increased extracellular calcium concentrations, lactic acidosis, and free radicals have all been postulated as possible causes.

CLINICAL MANIFESTATIONS:

1. CHEST PAIN: Chest pain has traditionally been ascribed to ischemia. However, more recent evidence suggests that, in patients with coronary artery disease, 70-80% of episodes of ischemia are actually asymptomatic. When present, the chest pain is thought to be mediated by sympathetic afferent fibers that richly innervate the atrium and ventricle.
2. FOURTH HEART SOUND AND SHORTNESS OF BREATH: Both of these findings may occur because of diastolic and systolic dysfunction of the ischemic myocardium.
3. SHOCK
4. BRADYCARDIA
5. NAUSEA AND VOMITING:Nausea and vomiting may arise from activation of the vagus nerve in the setting of an inferior wall myocardial infarction.
6. TACHYCARDIA:Levels of catecholamines are usually raised in patients with myocardial infarction. This helps to maintain stroke volume but leads to an increased heart rate.

DIAGNOSIS:

Laboratory Tests

Troponin I or T and creatine kinase (CK) MB are measured. Blood chemistry tests are performed, with particular attention given to potassium and magnesium, which may affect heart rhythm.The serum creatinine is measured to identify patients who may need dosing adjustments for some pharmacotherapy, as well as to identify  patients who are at high risk of morbidity and mortality. Baseline complete blood count (CBC) and coagulation tests (activated partial thromboplastin time and international normalized ratio) should be obtained because most patients will receive antithrombotic therapy, which increases the risk for bleeding.

Other Diagnostic Tests

The 12-lead electrocardiogram (ECG) is the first step in management. Patients are risk-stratified into two groups, ST-segment-elevation ACS and suspected non-ST-segment-elevation ACS. During hospitalization, a measurement of left ventricular function, such as an echocardiogram, is performed to identify patients with low ejection fractions (<40%).

TREATMENT:

ORGANIC NITRATES

Organic nitrates (and nitrites) used in the treatment of angina pectoris are simple nitric and nitrous acid esters of glycerol. They differ in their volatility. For example, isosorbide dinitrate and isosorbide mononitrate are solids at room temperature, nitroglycerin is only moderately volatile, and amyl nitrite is extremely volatile. These compounds cause a rapid reduction in myocardial oxygen demand, followed by rapid relief of symptoms. They are effective in stable and unstable angina as well as in variant angina pectoris.

1. Mechanism of action

Nitrates decrease coronary vasoconstriction or spasm and increase perfusion of the myocardium by relaxing coronary arteries. In addition, they relax veins, decreasing preload and myocardial oxygen consumption. Organic nitrates, such as nitroglycerin, which is also known as glyceryl trinitrate, are thought to relax vascular smooth muscle by their intracellular conversion to nitrite ions, and then to nitric oxide, which in turn activates guanylate cyclase and increases the cells’ cyclic guanosine monophosphate (GMP). Elevated cGMP ultimately leads to dephosphorylation of the myosin light chain, resulting in vascular smooth muscle relaxation.

CA²⁺ CHANNEL ANTAGONISTS
Voltage-sensitive Ca²⁺ channels (L-type or slow channels) mediate the entry of extracellular Ca²⁺ into smooth muscle and cardiac myocytes and sinoatrial (SA) and atrioventricular (AV) nodal cells in response to electrical depolarization. In both smooth muscle and cardiac myocytes, Ca²⁺ is a trigger for contraction, albeit by different mechanisms. Ca²⁺ channel antagonists, also called Ca ²⁺ entry blockers, inhibit Ca²⁺ channel function. In vascular smooth muscle, this leads to relaxation, especially in arterial beds. These drugs also may produce negative inotropic and chronotropic effects in the heart. Relaxes smooth muscle in the bronchi and gastrointestinal (GI) tract.

ADRENERGIC RECEPTOR ANTAGONISTS

Adrenergic blocking agents decrease the oxygen demands of the myocardium by lowering both the rate and the force of contraction of the heart . They suppress the activation of the heart by blocking   receptors, and they reduce the work of the heart by decreasing heart rate, contractility, cardiac output, and blood pressure. With  -blockers, the demand for oxygen by the myocardium is reduced both during exertion and at rest. Propranolol is the prototype for this class of compounds, but it is not cardioselective. Thus, other blockers, such as metoprolol or atenolol, are preferred. Agents with intrinsic sympathomimetic activity (for example, pindolol) are less effective and should be avoided in angina. The -blockers reduce the frequency and severity of angina attacks. These agents are particularly useful in the treatment of patients with myocardial infarction and have been shown to prolong survival. The blockers can be used with nitrates to increase exercise duration and tolerance. They are, however, contraindicated in patients with asthma, diabetes, severe bradycardia, peripheral vascular disease, or chronic obstructive pulmonary disease.

ANTI-PLATELET, ANTI-INTEGRIN, AND ANTI-THROMBOTIC AGENTS

Aspirin reduces the incidence of MI and death in patients with unstable angina. In addition, low doses of aspirin appear to reduce the incidence of MI in patients with chronic stable angina. Aspirin, given in doses of 160 to 325 mg at the onset of treatment of MI, reduces mortality in patients presenting with unstable angina. The addition of clopidogrel to aspirin therapy reduces mortality in patients with acute coronary syndromes . Heparin , in its unfractionated form and as low-molecular-weight heparin, also reduces symptoms and prevents infarction in unstable angina. Thrombin inhibitors, such as hirudin or bivalirudin, are being investigated; these agents directly inhibit even clot-bound thrombin, are not affected by circulating inhibitors, and function independently of antithrombin III. Thrombolytic agents, on the other hand, are of no benefit in unstable angina. Intravenous inhibitors of the platelet GPIIb/IIIa receptor (abciximab, tirofiban, and eptifibatide) are effective in preventing the complications of PCIs and in the treatment of patients presenting with acute coronary syndromes.

Newer Antianginal Drugs

Because of the high incidence of angina, new drugs are actively sought for its treatment. The metabolic modulators (eg, ranolazine, trimetazidine) are known as pFOX inhibitors because they partially inhibit the fatty acid oxidation pathway in myocardium. Because metabolism shifts to oxidation of fatty acids in ischemic myocardium, the oxygen requirement per unit of ATP produced increases. Partial inhibition of the enzyme required for fatty acid oxidation (long chain 3-ketoacyl thiolase, LC-3KAT) appears to improve the metabolic status of ischemic tissue. However, blockade of a late sodium current that facilitates calcium entry may play a larger role in the action of ranolazine.