Explore the unexplored in angina: Ranolazine

Atherosclerotic disease is a progressive disease. Many therapeutic interventions are aimed at specific cardiovascular conditions. These interventions may be directed at alleviating symptoms or preventing progression to more serious stages or both. Angiotensin-converting enzyme (ACE) inhibitors have been studied, for example, in patients with hypertension, who are at the top of this progression pathway. These studies looked only at the effects on blood pressure, however, and did not address the long-term question of risk reduction. Other clinical trials with ACE inhibitors have been designed to investigate the effects of these agents on the morbidity and mortality following an acute myocardial infarction.

Angina pectoris occurs due to a mismatch between the myocardial oxygen supply and demand, most often due to coronary artery disease. Oxygen demand can be increased by increase in heart rate, blood pressure or force of contraction. Oxygen supply can be decreased by decrease in the coronary blood flow or the lumen size of the coronary artery. Atherothrombosis is an interaction between lipids, inflammation and thrombosis within the vascular lumen. A lipid filled plaque can rupture leading to thrombosis at the site and occlusion of the coronary lumen.

Types of coronary artery disease (CAD)

Chronic CAD includes stable angina (effort angina) and silent ischemia, while acute coronary syndrome (ACS) includes unstable angina and myocardial infarction. Stable angina is the most common form caused by atherosclerosis and occurs during stress, activity or exposure to cold. It is relieved by rest and nitrates. Silent myocardial ischemia can occur with activity or stress. Prinzmetal’s angina usually occurs at night and is caused by vasospasm. Unstable angina is increasing frequency / duration / severity of angina, occurring at rest or with activity and carries great risk for myocardial infarction.

Factors provoking / exacerbating ischemia

Non-cardiac factors provoking / exacerbating ischemia include hyperthermia, hyperthyroidism, cocaine abuse, hypertension, anxiety and arteriovenous fistula. Cardiac causes include hypertrophic cardiomyopathy, aortic stenosis, dilated cardiomyopathy and tachycardia – either ventricular or supraventricular. All these factors increase myocardial oxygen demand and precipitate angina. Factors which decrease oxygen supply include anemia, hypoxemia due to pneumonia, chronic obstructive pulmonary disease, interstitial fibrosis, obstructive sleep apnoea and sickle cell disease. Cocaine use can cause coronary vasospasm and decrease supply. Hyperviscosity due polycythemia, leukemia and thrombocytosis can also decrease the delivery of oxygen.

Modifiable risk factors

Modifiable risk factors for CAD include smoking, unhealthy diet, decreased physical activity, hypertension and diabetes mellitus.

Canadian cardiovascular society classification for angina pectoris

Canadian cardiovascular society classification for angina pectoris can be mentioned in a simplified form as:
I. Ordinary physical activity does not cause angina
II. Slight limitation of ordinary activity
III. Marked limitation of ordinary physical activity
IV.Unable to carry on any physical activity without discomfort

Clinical manifestations of angina

Clinical manifestations of angina include chest pain / pain at sites of radiation, tachycardia, pallor, dyspnea, anxiety and sweating.

Evaluation of ischemia in stable angina

Evaluation of ischemia in stable angina is done by a good history, baseline ECG and exercise testing. ECG may show ST segment depression and T wave inversion, which reverses after ischemia disappears. ST segment elevation is noted in Prinzmetal’s angina during pain. Please note that the resting ECG may be normal or show show evidence of old myocardial infarction, heart block or left ventricular hypertrophy.

Exercise testing in stable angina

The aim of exercise testing in stable angina is to induce a controlled ischemic state during clinical and ECG observation. Treadmill exercise test and bicycle ergometry are the two common types of exercise tests. High risk patients are those with significant ST depression at low levels of exercise or at heart rate <120; those with fall in systolic blood pressure or diminished exercise capacity.

Indications for cardiac catheterization in stable angina

Indications for cardiac catheterization in stable angina include suspicion of multi-vessel / left main CAD to determine if CABG/PTCA are feasible / needed and in those with persistent / disabling chest pain with equivocal results of non-invasive testing.

Management of stable angina

Treatment of chronic stable angina can be broadly divided into medical treatment and revascularization which could be either by percutaneous intervention or coronary artery bypass grafting.

Basis of drug therapy in angina pectoris

Drugs can help to correct the supply demand imbalance by:

1. Decreasing myocardial oxygen demand by reducing cardiac workload, which could be by reducing heart rate, reducing force of myocardial contraction or reducing after load.
2. Increasing myocardial oxygen supply.

Principles of management of angina

Non-pharmacological measures include relaxation, weight reduction and moderate exercise. Pharmacological agents include conventional anti-anginal drugs like nitrates, beta blockers, calcium channel blockers and newer antianginal drugs, statins, antihypertensive agents including ACE inhibitors and antiplatelet agents. Nitrates are available in different forms which include tablets, intravenous solutions, sublingual sprays, transdermal patches and ointments. Nitrates can be used to treat anginal attacks as sublingual tablets or sprays. To prevent attacks, longer acting topical or oral agents are needed. Adverse effects include headache, dizziness and rarely hypotension. Interaction with sildenafil is always worth remembering.

Beta blockers are very useful in stable angina and act by reducing heart rate, contractility and blood pressure. They are contraindicated in asthma / COPD, bradycardia and Prinzmetal’s angina.
Calcium channel blockers block calcium entry into cells, producing decreased contractility, heart rate and blood pressure. They also produce coronary vasodilatation.

Other anti-anginal drugs include potassium channel opener nicorandil, late sodium channel blocker ranolazine, trimetazidine and ivabradine. Nicorandil acts on ATP-sensitive K+ channel, dilates the coronaries and acts as nitric oxide (NO) donor. Trimetazidine inhibits fatty acid oxidation (beta oxidation) and promotes glucose oxidation. This decreases oxygen utilization by the ischemic myocardium. Ivabradine is a pure heart rate reducing agent which acts by blocking I_f current (funny current, pacemaker current).

Consequences associated with dysfunction of late sodium current

Ischemia and heart failure leads to production of reactive oxygen species and ischemic metabolites which cause a dysfunction of the late sodium current. This in turn causes excess entry of sodium into the cell. The sodium calcium exchanger exchanges this extra sodium for calcium leading to calcium overload. Calcium overload causes mechanical dysfunction by abnormal relaxation and increase in the left ventricular wall stiffness. There is increased ATP consumption in the face of decreased ATP production. Electrical instability in the form of early after potentials can lead to ventricular arrhythmias as well. Relaxation failure leads to increased myocardial diastolic tension and increases myocardial oxygen consumption, compresses intramural small vessels, reduces myocardial blood flow and worsens ischemia and angina. This sets up a vicious cycle in which ischemia causes increased sodium entry leading to calcium overload and increased left ventricular diastolic tension, which in turn further worsens ischemia.

Ranolazine

Reduces angina by a different mechanism of action and does not affect heart rate or blood pressure. In 2006, ranolazine was approved by FDA for use in patients with chronic angina who are symptomatic while on beta blockers, calcium channel blockers and nitrates. In 2008 it was approved as first line anti-anginal therapy. Ranolazine inhibits the late inward sodium current, thereby avoiding the vicious cycle of ischemia leading to further ischemia as described above. It is also a partial inhibitor of beta oxidation of fatty acids. In addition ranolazine has a favourable effect in reducing HbA1c in diabetics. The effect is higher with higher doses. At the same time it has not been reported to increase the incidence of hypoglycemia. The incidence of new onset impaired glucose tolerance is also lower. Incidence of side effects of ranolazine is rather low, with a few cases of constipation, nausea, dizziness and headache. A slight prolongation of QTc has also been reported with ranolazine, of the order of 6 – 9 msec. But this effect was independent of age, body weight, gender, race, heart rate, NYHA class or the presence of diabetes mellitus. No cases of torsades de pointes were reported with ranolazine.