DNA

DNA is the building block of human life . Its double helical structure is deceptively simple, yet the rules encoded within this structure specify the form and function of all cells within an organism. DNA consists of two long strands of polydeoxyribonucleotides that twist around each other clockwise to form an unbroken double helix. Alternating deoxyribose-phosphate groups form the backbone of the helix, with the phosphate group making a 5′-3′ phosphodiester bond between the fifth carbon of one pentose ring and the third carbon of the next pentose ring . Nucleic acid bases attached to the sugar groups of each strand face each other within the helix, perpendicular to the strand axis. The order of the nucleic acids specifies the eventual sequence of the protein product of the gene. Only four bases exist: the purines adenine and guanine (A and G) and the pyrimidines cytosine and thymine (C and T). During assembly of the double helix, a purine can pair only with a pyrimidine, and a pyrimidine with a purine. Each base pair (bp) forms one of the rungs in the twisted ladder of the DNA molecule, which can be millions of bases long. The two strands of DNA, which are held together by hydrogen bonds between complementary base pairs, have opposite chemical polarities. One strand is oriented in a 5′ to 3′ direction, while the other is in a 3′ to 5′ direction. Enzymes that recognize specific DNA sequences also recognize the polarity of the strand. An enzyme “reads” the nucleotide sequences on the two strands in opposite directions. Because the structure of the helical backbone is invariant, enzymes responsible for DNA copying, cleavage, and repairing strand breaks can act anywhere along the length of the DNA strand.

ABNORMALITIES OF RIGHT VENTRICULAR INFLOW

The right ventricular inflow tract and tricuspid valve are visualized using the apical and subcostal four-chamber views, the short-axis view at the base, and the medially angulated parasternal long-axis view. The most important congenital pathologic entities involving the tricuspid valve are Ebstein anomaly and tricuspid atresia (discussed subsequently). Ebstein anomaly consists of apical displacement of the septal and posterior (and sometimes the anterior) leaflets of the tricuspid valve into the right ventricle. Typically, the leaflets are elongated and redundant with abnormal chordal attachments. This results in atrialization of the basal portion of
the right ventricle as the functional orifice is displaced apically relative to the anatomic anulus. Ebstein anomaly is a spectrum of abnormalities, depending on the extent of apical displacement of the valve, the distal attachments of the leaflets, the size and function of the remaining right ventricle, the degree of tricuspid regurgitation, and the presence of right ventricular outflow tract obstruction (usually from the redundant anterior tricuspid valve leaflet).

The best echocardiographic view for the evaluation of Ebstein anomaly is the four-chamber view. The characteristic features identified in this plane are shown schematically in Figure 18.7. Of principal importance is the accurate recording of the level of insertion of the septal leaflet of the tricuspid valve relative to the anulus. Apical displacement of this insertion site is optimally assessed in this view and is the key to diagnosis (Fig. 18.8). Because the tricuspid valve is normally positioned more apically than the mitral valve, abnormal apical displacement is relative, and some investigators have suggested measuring the distance between insertion sites of the two atrioventricular valves. When normalized for body surface area, a distance of greater than 8 mm/m² is indicative of Ebstein anomaly. Other investigators have advocated a maximal displacement of more than 20 mm as the diagnostic criterion in adults.

The four-chamber and medially angulated parasternal views may be used to assess the severity of Ebstein anomaly and to determine surgical options. The degree of atrialization of the ventricle, the extent of leaflet tethering, and the magnitude of deformity or dysplasia of the valve leaflets are important features with implications for surgical repair (Fig. 18.9). The extent of chordal attachments between the anterior leaflet and the anterior free wall should be assessed in multiple views. If tethering is significant, valve replacement rather than repair may be required. The greater the degree of atrialization is, the worse the prognosis. If the area of the functional right ventricle is less than one-third of the total right ventricular area, overall prognosis is poor. Because of the complexity of right ventricular geometry, an accurate measure of the size of the functional right ventricle is difficult, and all available views should be used (Fig. 18.10). Doppler echocardiography should be used to detect tricuspid regurgitation, which is commonly seen in patients with Ebstein anomaly (Fig. 18.11). A redundant anterior tricuspid valve leaflet may cause functional right ventricular outflow tract obstruction, which can also be detected with Doppler imaging. In severe cases, pulmonary atresia may be present, although it is rarely seen in adults.

FIGURE 18.7. Schematic of anatomic abnormalities in Ebstein anomaly. RA, right atrium; LA, left atrium; LV, left ventricle; MV, mitral valve; MVA, mitral valve anulus; TVA, tricuspid valve anulus; AnRV, anatomic right ventricle; FRV, functional right ventricle; AtRV, atrialized right ventricle

FIGURE 18.8. A four-chamber view from a patient with Ebstein anomaly is shown. The arrows indicate the degree of apical displacement of the tricuspid valve (TV), which had restricted motion. Note that the functional portion of the right ventricle (RV) is fairly well preserved. LV, left ventricle; RA, right atrium.


FIGURE 18.9. A more extreme form of Ebstein anomaly is demonstrated. The tricuspid valve (arrows) is markedly abnormal, and there is tethering of the leaflets, which prevented normal coaptation and resulted in significant tricuspid regurgitation. The right atrium (RA) is severely dilated. LV, left ventricle

Ebstein anomaly may be associated with a variety of other abnormalities that can be detected with echocardiography, namely, atrial septal defect, mitral valve prolapse, and left ventricular dysfunction. The etiology of the left ventricular dysfunction is not known, but its presence is associated with a poor prognosis. Surgical options in patients with Ebstein anomaly include tricuspid valve repair or replacement. After surgical repair, echocardiography plays a role in assessing the success of the procedure and the function of the tricuspid valve.

Role of Echocardiography in Mitral Valve Surgery

When performing transesophageal echocardiography for the purpose of assessing mitral valve anatomy before intended mitral valve repair, it is important that a thorough and detailed evaluation of the mitral valve be undertaken in a systematic fashion. The primary purpose of the examination is to determine the underlying anatomic abnormality responsible for the regurgitation or stenosis. It is important to recognize that there are three different viewing perspectives on mitral valve anatomy (Fig. 19.14). The surgeon will be viewing the mitral valve from within the left atrium so that the anterolateral commissures will be to the left of the field of view and the medial commissures to the right. When viewed with either transesophageal or transthoracic echocardiography, this orientation will be reversed (assuming traditional recommended viewing formats on a video screen). Also, depending on whether the reference is a transthoracic or transesophageal echocardiogram, the anterior and posterior leaflets of the mitral valve will vary in position compared with the surgical perspective. Figure 19.14 depicts all three perspectives of the mitral valve in relation to the aorta and left atrial appendage.

History of Echocardiography part 1

Many histories of diagnostic ultrasound, and cardiac ultrasound in particular, have been written.^1,2,3,4,5,6 They all seem to address this field from a different perspective. One can begin the history in the twentieth century, Roman times, or any of the centuries in between. It is stated that a Roman architect, Vitruvius, first coined the word echo.⁷ A Franciscan friar, Marin Mersenne (1588–1648), is frequently called the “father of acoustics” because he first measured the velocity of sound.⁷ Another early physicist, Robert Boyle (1627–1691), recognized that a medium was necessary for the propagation of sound.⁷ Abbe Lazzaro Spallanzani (1727–1799) is frequently referred to as the “father of ultrasound.”⁸ He demonstrated that bats were blind and in fact navigated by means of echo reflection using inaudible sound. In 1842, Christian Johann Doppler (1803–1853) noted that the pitch of a sound wave varied if the source of the sound was moving.⁹ He worked out the mathematical relationship between the pitch and the relative motion of the source and the observer. The ability to create ultrasonic waves came in 1880 with the discovery of piezoelectricity by Curie and Curie.^10,11 They noted that if certain crystalline materials are compressed, an electric charge is produced between the opposite surfaces. They then noted that the reverse was also true. If an electrical potential is applied to a crystal, it is compressed and decompressed depending on the polarity of the electric charge, and thus very high frequency sound can be produced. In 1912, a British engineer, L. F. Richardson, suggested that an echo technique could be used to de- tect underwater objects. Later during World War I, Paul Langevin was given the duty of detecting enemy submarines using sound, which culminated in the development of sonar.³ Sokolov¹² described a method for using reflected sound to detect metal flaws in 1929. In 1942, Floyd Firestone,¹³ an American engineer, began to apply this technique and received a patent. It is this flaw detection technique that ultimately was used in medicine.

An Austrian, Karl Dussik,¹⁴ was probably the first to apply ultrasound for medical diagnosis in 1941. He initially attempted to outline the ventricles of the brain. His approach used transmission ultrasound rather than reflected ultrasound. After World War II, many of the technologies developed during that war, including sonar, were applied for peaceful and medical uses. In 1950, W. D. Keidel,¹⁵ a German investigator, used ultrasound to examine the heart. His technique was to transmit ultrasonic waves through the heart and record the effect of ultrasound on the other side of the chest. The purpose of his work was to try to determine cardiac volumes. The first effort to use pulse-reflected ultrasound, as described by Firestone, to examine the heart was initiated by Dr. Helmut Hertz of Sweden. He was familiar with Firestone's observations and in 1953 obtained a commercial ultrasonoscope, which was being used for nondestructive testing. He then collaborated with Dr. Inge Edler who was a practicing cardiologist in Lund, Sweden. The two of them began to use this commercial ultrasonoscope to examine the heart. This collaboration is commonly accepted as the beginning of clinical echocardiography as we know it today.¹⁶

The original instrument (Fig. 1.1) was quite insensitive. The only cardiac structures that they could record initially were from the back wall of the heart. In retrospect, these echoes probably came from the posterior left ventricular wall. With some modification of their instrument, they were able to record an echo from the anterior leaflet of the mitral valve. However, they did not recognize the source of this echo for several years and originally attributed the signal to the anterior left atrial wall. Only after some autopsy investigations did they recognize the echo's true origin. Edler¹⁷ went on to perform a number of ultrasonic studies of the heart. Many of the cardiac echoes currently used were first described by him. However, the principal clinical application of echocardiography developed by Edler was the detection of mitral stenosis.¹⁸ He noted that there was a difference between the pattern of motion of the anterior mitral leaflet in patients who did or did not have mitral stenosis. Thus, the early studies published in the mid-1950s and early 1960s primarily dealt with the detection of this disorder.

Adalat

GENERIC NAME: nifedipine

BRAND NAMES: Adalat, Procardia, Afeditab, Nifediac

DRUG CLASS AND MECHANISM: Nifedipine belongs to a class of medications called calcium channel blockers (CCBs) that are used to treat angina (heart pain), high blood pressure, and abnormal heart rhythms. Other drugs in the same class include amlodipine (Norvasc), diltiazem (Cardizem LA, Tiazac), felodipine (Plendil), isradipine (Dynacirc), nicardipine (Cardene), nimodipine (Nimotop), and verapamil (Covera-HS, Veralan PM, Calan). Like other CCBs, nifedipine works by blocking the flow of calcium into the muscle cells surrounding the arteries that supply blood to the heart (coronary arteries) as well as other arteries of the body. Since the inflow of calcium is what causes the muscle cells to contract, blocking the entry of calcium relaxes the muscles and dilates (widens) the arteries. By dilating coronary arteries, nifedipine increases the flow of blood to the heart. This treats and prevents angina which occurs when the flow of blood to the heart is not adequate to supply the heart with enough oxygen necessary to pump blood. Relaxing the muscles surrounding other arteries of the body lowers blood pressure and thereby reduces the pressure against which the heart must pump blood and function. This reduces the demand of the heart for oxygen--another mechanism by which CCBs treat and prevent angina. In addition, nifedipine slows conduction of the electrical current that travels through the heart that causes the muscle of the heart to contract. This effect can be used to correct abnormally rapid heartbeats.

PRESCRIPTION: Yes

GENERIC AVAILABLE: Yes

PREPARATIONS: Capsules:10 and 20 mg. Tablets: 30, 60, and 90 mg

STORAGE: Tablets should be stored at room temperature 15-25 C (59-77 F). They should be protected from light, moisture, and humidity.

PRESCRIBED FOR: Nifedipine is used for the treatment and prevention of angina resulting from either an increased workload on the heart (as with exercise) or spasm of the coronary arteries. It is used in the treatment of high blood pressure, to treat abnormally fast heart rhythms such as atrial fibrillation, and in the prevention of episodes of rapid heart rhythm originating from the atria of the heart.

It also is used to dilate blood vessels that go into spasm such as those causing Raynaud's phenomenon, a painful condition of the hands caused by spasm of the arteries supplying blood to the hands. Non-FDA approved uses include anal fissures (applied to the fissures), prevention of migraine headaches in adults, ureteral stones (as secondary therapy) and wound healing (applied to the skin).

DOSING: The usual dose for nifedipine capsules is 10 to 20 mg three times daily. It is important to swallow capsules whole. For extended release tablets, the usual dose is 30 or 60 mg once daily. The tablets should be swallowed whole and not bitten or cut in half. Nifedipine can be taken with or without food.

DRUG INTERACTIONS: In rare instances, congestive heart failure has been associated with nifedipine, usually in patients already on a beta blocker, for example, propranolol (Inderal), metoprolol (Lopressor), etc. Excessive lowering of blood pressure (hypotension) during initiation of nifedipine treatment can occur, especially in patients already taking another blood pressure lowering drug.

Generally, nifedipine is avoided in children.

Nifedipine decreases the elimination of digoxin (Lanoxin) by the kidneys which can increase digoxin blood levels in the blood and give rise to digoxin toxicity. It is important, therefore, to monitor blood levels of digoxin in order to avoid toxicity.

Nifedipine interferes with the breakdown of tacrolimus (Prograf) by the liver, which in turn causes elevated blood levels of tacrolimus and may increase the risk of toxicity from tacrolimus.

Nifedipine reduces the blood levels of quinidine (Quinaglute, Quinidex, Quinora) which may reduce the effectiveness of quinidine. Conversely, blood levels of nifedipine are increased by quinidine and may lead to side effects from nifedipine.

Cimetidine (Tagamet) interferes with breakdown by the liver of nifedipine and increases nifedipine blood levels. Therefore, cautious dosing is necessary when both medications are administered concurrently.

Nifedipine should not be taken with grapefruit juice since grapefruit juice (one glass, approximately 200 ml) inhibits the breakdown of nifedipine by the liver and increases the levels of nifedipine in the blood.

PREGNANCY: There are no adequate studies of nifedipine in pregnant women, and in general, it is avoided during pregnancy.

NURSING MOTHERS: Nifedipine is excreted in human breast milk. Generally, nifedipine is avoided in nursing mothers.

SIDE EFFECTS: Side effects of nifedipine are generally mild, and reversible. Most side effects are expected consequences of the dilation of the arteries. The most common side effects include headache, dizziness, flushing, and edema (swelling) of the lower extremities. Less common side effects include dizziness, nausea and constipation.

Reference: FDA Prescribing Information

Heart Attack (Myocardial Infarction)

What is a heart attack?

A heart attack (also known as a myocardial infarction) is the death of heart muscle from the sudden blockage of a coronary artery by a blood clot. Coronary arteries are blood vessels that supply the heart muscle with blood and oxygen. Blockage of a coronary artery deprives the heart muscle of blood and oxygen,causing injury to the heart muscle. Injury to the heart muscle causes chest pain and chest pressure sensation. If blood flow is not restored to the heart muscle within 20 to 40 minutes, irreversible death of the heart muscle will begin to occur. Muscle continues to die for six to eight hours at which time the heart attack usually is "complete." The dead heart muscle is eventually replaced by scar tissue.

Approximately one million Americans suffer a heart attack each year. Four hundred thousand of them die as a result of their heart attack.

What causes a heart attack?

Atherosclerosis

Atherosclerosis is a gradual process by which plaques (collections) of cholesterol are deposited in the walls of arteries. Cholesterol plaques cause hardening of the arterial walls and narrowing of the inner channel (lumen) of the artery. Arteries that are narrowed by atherosclerosis cannot deliver enough blood to maintain normal function of the parts of the body they supply. For example, atherosclerosis of the arteries in the legs causes reduced blood flow to the legs. Reduced blood flow to the legs can lead to pain in the legs while walking or exercising, leg ulcers, or a delay in the healing of wounds to the legs. Atherosclerosis of the arteries that furnish blood to the brain can lead to vascular dementia (mental deterioration due to gradual death of brain tissue over many years) or stroke (sudden death of brain tissue).

In many people, atherosclerosis can remain silent (causing no symptoms or health problems) for years or decades. Atherosclerosis can begin as early as the teenage years, but symptoms or health problems usually do not arise until later in adulthood when the arterial narrowing becomes severe. Smoking cigarettes, high blood pressure, elevated cholesterol, and diabetes mellitus can accelerate atherosclerosis and lead to the earlier onset of symptoms and complications, particularly in those people who have a family history of early atherosclerosis.

Coronary atherosclerosis (or coronary artery disease) refers to the atherosclerosis that causes hardening and narrowing of the coronary arteries. Diseases caused by the reduced blood supply to the heart muscle from coronary atherosclerosis are called coronary heart diseases (CHD). Coronary heart diseases include heart attacks, sudden unexpected death, chest pain (angina), abnormal heart rhythms, and heart failure due to weakening of the heart muscle.

Atherosclerosis and angina pectoris

Angina pectoris (also referred to as angina) is chest pain or pressure that occurs when the blood and oxygen supply to the heart muscle cannot keep up with the needs of the muscle. When coronary arteries are narrowed by more than 50 to 70 percent, the arteries may not be able to increase the supply of blood to the heart muscle during exercise or other periods of high demand for oxygen. An insufficient supply of oxygen to the heart muscle causes angina. Angina that occurs with exercise or exertion is called exertional angina. In some patients, especially diabetics, the progressive decrease in blood flow to the heart may occur without any pain or with just shortness of breath or unusually early fatigue.

Exertional angina usually feels like a pressure, heaviness, squeezing, or aching across the chest. This pain may travel to the neck, jaw, arms, back, or even the teeth, and may be accompanied by shortness of breath, nausea, or a cold sweat. Exertional angina typically lasts from one to 15 minutes and is relieved by rest or by taking nitroglycerin by placing a tablet under the tongue. Both resting and nitroglycerin decrease the heart muscle's demand for oxygen, thus relieving angina. Exertional angina may be the first warning sign of advanced coronary artery disease. Chest pains that just last a few seconds rarely are due to coronary artery disease.

Angina also can occur at rest. Angina at rest more commonly indicates that a coronary artery has narrowed to such a critical degree that the heart is not receiving enough oxygen even at rest. Angina at rest infrequently may be due to spasm of a coronary artery (a condition called Prinzmetal's or variant angina). Unlike a heart attack, there is no permanent muscle damage with either exertional or rest angina.

Atherosclerosis and heart attack

Occasionally the surface of a cholesterol plaque in a coronary artery may rupture, and a blood clot forms on the surface of the plaque. The clot blocks the flow of blood through the artery and results in a heart attack (see picture below). The cause of rupture that leads to the formation of a clot is largely unknown, but contributing factors may include cigarette smoking or other nicotine exposure, elevated LDL cholesterol, elevated levels of blood catecholamines (adrenaline), high blood pressure, and other mechanical and biochemical forces.

Unlike exertional or rest angina, heart muscle dies during a heart attack and loss of the muscle is permanent, unless blood flow can be promptly restored, usually within one to six hours.

While heart attacks can occur at any time, more heart attacks occur between 4:00 A.M. and 10:00 A.M. because of the higher blood levels of adrenaline released from the adrenal glands during the morning hours. Increased adrenaline, as previously discussed, may contribute to rupture of cholesterol plaques.

Approximately 50% of patients who develop heart attacks have warning symptoms such as exertional angina or rest angina prior to their heart attacks, but these symptoms may be mild and discounted.

What are the symptoms of a heart attack?

Although chest pain or pressure is the most common symptom of a heart attack, heart attack victims may experience a variety of symptoms including:

• Pain, fullness, and/or squeezing sensation of the chest

• Jaw pain, toothache, headache

• Shortness of breath

• Nausea, vomiting, and/or general epigastric (upper middle abdomen) discomfort

• Sweating

• Heartburn and/or indigestion

• Arm pain (more commonly the left arm, but may be either arm)

• Upper back pain

• General malaise (vague feeling of illness)

• No symptoms (Approximately one quarter of all heart attacks are silent, without chest pain or new symptoms. Silent heart attacks are especially common among patients with diabetes mellitus.)

Even though the symptoms of a heart attack at times can be vague and mild, it is important to remember that heart attacks producing no symptoms or only mild symptoms can be just as serious and life-threatening as heart attacks that cause severe chest pain. Too often patients attribute heart attack symptoms to "indigestion," "fatigue," or "stress," and consequently delay seeking prompt medical attention. One cannot overemphasize the importance of seeking prompt medical attention in the presence of symptoms that suggest a heart attack. Early diagnosis and treatment saves lives, and delays in reaching medical assistance can be fatal. A delay in treatment can lead to permanently reduced function of the heart due to more extensive damage to the heart muscle. Death also may occur as a result of the sudden onset of arrhythmias such as ventricular fibrillation.

What are the complications of a heart attack?

Heart failure

When a large amount of heart muscle dies, the ability of the heart to pump blood to the rest of the body is diminished, and this can result in heart failure. The body retains fluid, and organs, for example, the kidneys, begin to fail.

Ventricular fibrillation

Injury to heart muscle also can lead to ventricular fibrillation. Ventricular fibrillation occurs when the normal, regular, electrical activation of heart muscle contraction is replaced by chaotic electrical activity that causes the heart to stop beating and pumping blood to the brain and other parts of the body. Permanent brain damage and death can occur unless the flow of blood to the brain is restored within five minutes.

Most of the deaths from heart attacks are caused by ventricular fibrillation of the heart that occurs before the victim of the heart attack can reach an emergency room. Those who reach the emergency room have an excellent prognosis; survival from a heart attack with modern treatment should exceed 90%. The 1% to 10% of heart attack victims who later die frequently had suffered major damage to the heart muscle initially or additional damage at a later time.

Deaths from ventricular fibrillation can be avoided by cardiopulmonary resuscitation (CPR) started within five minutes of the onset of ventricular fibrillation. CPR requires breathing for the victim and applying external compression to the chest to squeeze the heart and force it to pump blood. In 2008, the American Heart Association modified the mouth-to-mouth instruction of CPR, and recommends that chest compressions alone are effective if a bystander is reluctant to do mouth-to-mouth. When paramedics arrive, medications and/or an electrical shock (cardioversion) can be administered to convert ventricular fibrillation back to a normal heart rhythm and allow the heart to pump blood normally. Therefore, prompt CPR and a rapid response by paramedics can improve the chances of survival from a heart attack. In addition, many public venues now have automatic external defibrillators (AEDs) that provide the electrical shock needed to restore a normal heart rhythm even before the paramedics arrive. This greatly improves the chances of survival.

What are the risk factors for atherosclerosis and heart attack?

Factors that increase the risk of developing atherosclerosis and heart attacks include increased blood cholesterol, high blood pressure, use of tobacco, diabetes mellitus, male gender, and a family history of coronary heart disease. While family history and male gender are genetically determined, the other risk factors can be modified through changes in lifestyle and medications.

• High Blood Cholesterol (Hyperlipidemia). A high level of cholesterol in the blood is associated with an increased risk of heart attack because cholesterol is the major component of the plaques deposited in arterial walls. Cholesterol, like oil, cannot dissolve in the blood unless it is combined with special proteins called lipoproteins. (Without combining with lipoproteins, cholesterol in the blood would turn into a solid substance.) The cholesterol in blood is either combined with lipoproteins as very low-density lipoproteins (VLDL), low-density lipoproteins (LDL) or high-density lipoproteins (HDL).
  
  The cholesterol that is combined with low-density lipoproteins (LDL cholesterol) is the "bad" cholesterol that deposits cholesterol in arterial plaques. Thus, elevated levels of LDL cholesterol are associated with an increased risk of heart attack.
  
  The cholesterol that is combined with HDL (HDL cholesterol) is the "good" cholesterol that removes cholesterol from arterial plaques. Thus, low levels of HDL cholesterol are associated with an increased risk of heart attacks.
  
  Measures that lower LDL cholesterol and/or increase HDL cholesterol (losing excess weight, diets low in saturated fats, regular exercise, and medications) have been shown to lower the risk of heart attack. One important class of medications for treating elevated cholesterol levels (the statins) have actions in addition to lowering LDL cholesterol which also protect against heart attack. Most patients at "high risk" for a heart attack should be on a statin no matter what the levels of their cholesterol.

• High Blood Pressure (Hypertension). High blood pressure is a risk factor for developing atherosclerosis and heart attack. Both high systolic pressure (when the heart beats) and high diastolic pressure (when the heart is at rest) increase the risk of heart attack. It has been shown that controlling hypertension with medications can reduce the risk of heart attack.

• Tobacco Use (Smoking). Tobacco and tobacco smoke contain chemicals that cause damage to blood vessel walls, accelerate the development of atherosclerosis, and increase the risk of heart attack.

• Diabetes (Diabetes Mellitus). Both insulin dependent and non-insulin dependent diabetes mellitus (type 1 and 2, respectively) are associated with accelerated atherosclerosis throughout the body. Therefore, patients with diabetes mellitus are at risk for reduced blood flow to the legs, coronary heart disease, erectile dysfunction, and strokes at an earlier age than non-diabetic subjects. Patients with diabetes can lower their risk through rigorous control of their blood sugar levels, regular exercise, weight control, and proper diets.

• Male Gender. At all ages, men are more likely than women to develop atherosclerosis and coronary heart disease. Some scientists believe that this difference is partly due to the higher blood levels of HDL cholesterol in women than in men. However, this gender difference narrows as men and women grow older.

• Family History of Heart Disease. Individuals with a family history of coronary heart diseases have an increased risk of heart attack. Specifically, the risk is higher if there is a family history of early coronary heart disease, including a heart attack or sudden death before age 55 in the father or other first-degree male relative, or before age 65 in the mother or other female first-degree female relative.

How is a heart attack diagnosed?

When there is severe chest pain, suspicion that a heart attack is occurring usually is high, and tests can be performed quickly that will confirm the heart attack. A problem arises, however, when the symptoms of a heart attack do not include chest pain. A heart attack may not be suspected, and the appropriate tests may not be performed. Therefore, the initial step in diagnosing a heart attack is to be suspicious that one has occurred.

Electrocardiogram. An electrocardiogram (ECG) is a recording of the electrical activity of the heart. Abnormalities in the electrical activity usually occur with heart attacks and can identify the areas of heart muscle that are deprived of oxygen and/or areas of muscle that have died. In a patient with typical symptoms of heart attack (such as crushing chest pain) and characteristic changes of heart attack on the ECG, a secure diagnosis of heart attack can be made quickly in the emergency room and treatment can be started immediately. If a patient's symptoms are vague or atypical and if there are pre-existing ECG abnormalities, for example, from old heart attacks or abnormal electrical patterns that make interpretation of the ECG difficult, the diagnosis of a heart attack may be less secure. In these patients, the diagnosis can be made only hours later through detection of elevated cardiac enzymes in the blood.

Blood tests. Cardiac enzymes are proteins that are released into the blood by dying heart muscles. These cardiac enzymes are creatine phosphokinase (CPK), special sub-fractions of CPK (specifically, the MB fraction of CPK), and troponin, and their levels can be measured in blood. These cardiac enzymes typically are elevated in the blood several hours after the onset of a heart attack. A series of blood tests for the enzymes performed over a 24-hour period are useful not only in confirming the diagnosis of heart attack, but the changes in their levels over time also correlates with the amount of heart muscle that has died.

The most important factor in diagnosing and treating a heart attack is prompt medical attention. Rapid evaluation allows early treatment of potentially life-threatening abnormal rhythms such as ventricular fibrillation and allows early reperfusion (return of blood flow to the heart muscle) by procedures that unclog the blocked coronary arteries. The more rapidly blood flow is reestablished, the more heart muscle that is saved.

Large and active medical centers often have a "chest pain unit" where patients suspected of having heart attacks are rapidly evaluated. If a heart attack is diagnosed, prompt therapy is initiated. If the diagnosis of heart attack is initially unclear, the patient is placed under continuous monitoring until the results of further testing are available.

What about heart attacks in women?

What are the risk factors for heart attack in women?

Coronary artery disease (CAD) and heart attacks are erroneously believed to occur primarily in men. Although it is true that the prevalence of CAD among women is lower before menopause, the risk of CAD rises in women after menopause. At age 75, a woman's risk for CAD is equal to that of a man's. CAD is the leading cause of death and disability in women after menopause. In fact, a 50-year-old woman faces a 46% risk of developing CAD and a 31% risk of dying from coronary artery disease. In contrast, her probability of contracting and dying from breast cancer is 10% and 3%, respectively.

The risk factors for developing CAD in women are the same as in men and include:

• increased blood cholesterol,
  
  
• high blood pressure,
  
  
• smoking cigarettes,
  
  
• diabetes mellitus, and a
  
  
• family history of coronary heart disease at a young age.

Smoking cigarettes

Even "light" smoking raises the risk of CAD. In one study, middle-aged women who smoked one to 14 cigarettes per day had a twofold increase in strokes (caused by atherosclerosis of the arteries to the brain) whereas those who smoked more than 25 cigarettes per day had a risk of stroke 3.7 fold higher than that of nonsmoking women. Furthermore, the combination of smoking and the use of birth control pills increase the risk of heart attacks even further, especially in women over 35.

Quitting smoking immediately begins to reduce the risk of heart attacks. The risk gradually returns to the same risk of nonsmoking women after several years of not smoking.

Cholesterol treatment guidelines in women

Current NCEP (National Cholesterol Education Program) treatment guidelines for undesirable cholesterol levels are the same for women as for men.

What are the symptoms of heart attack in women and how is heart attack diagnosed?

Women are more likely to encounter delays in establishing the diagnosis of heart attack than men. This is in part because women tend to seek medical care later than men, and in part because diagnosing heart attacks in women can sometimes be more difficult than diagnosing heart attacks in men. The reasons include:

1. Women are more likely than men to have atypical heart attack symptoms such as:

• neck and shoulder pain,
  
  
• abdominal pain,
  
  
• nausea,
  
  
• vomiting,
  
  
• fatigue, and
  
  
• shortness of breath.

1. Silent heart attacks (heart attacks with little or no symptoms) are more common among women than among men.
   
   
2. Women have a higher occurrence than men of chest pain that is not caused by heart disease, for example chest pain from spasm of the esophagus.
   
   
3. Women are less likely than men to have the typical findings on the ECG that are necessary to diagnose a heart attack quickly.
   
   
4. Women are more likely than men to have angina (chest pain due to lack of blood supply to the heart muscle) that is caused by spasm of the coronary arteries or caused by disease of the smallest blood vessels (microvasculature disease). Cardiac catheterization with coronary angiograms (x-ray studies of the coronary arteries that are considered the most reliable tests for CAD) will reveal normal coronary arteries and therefore cannot be used to diagnose either of these two conditions.
   
   
5. Women are more likely to have misleading, or "false positive" noninvasive tests for CAD then men.

Because of the atypical nature of symptoms and the occasional difficulties in diagnosing heart attacks in women, women are less likely to receive aggressive thrombolytic therapy or coronary angioplasty, and are more likely to receive it later than men. Women also are less likely to be admitted to a coronary care unit.

What is the treatment for heart attack in women?

Thrombolytic (fibrinolytic or clot dissolving) therapy has been shown to reduce death from heart attacks similarly in men and women; however, the complication of strokes from the thrombolytic therapy may be slightly higher in women than in men.

Emergency percutaneous transluminal coronary angioplasty (PTCA) or coronary stenting for acute heart attack is as effective in women as in men; however women may have a slightly higher rate of procedure-related complications in their blood vessels (such as bleeding or clotting at the point of insertion of the PTCA catheter in the groin) and death. This higher rate of complications has been attributed to women's older age, smaller artery size, and greater severity of angina. The long-term outcome of angioplasty or stenting however, is similar in men and women, and should not be withheld due to gender.

The immediate mortality from coronary artery bypass graft surgery (CABG) in women is higher than that for men. The higher immediate mortality rate has been attributed to women's older age, smaller artery size, and greater severity of angina (the same as for PTCA). Long term survival, rate of recurrent heart attack and/or need for reoperation, however, are similar in men and women after CABG.

What about hormone therapy and heart attack in women?

After menopause, the production of estrogen by the ovaries gradually diminishes over several years. Along with this reduction, there is an increase in LDL ("bad" cholesterol) and a small decrease in HDL ("good" cholesterol). These changes in lipid levels are believed to be one of the reasons for the increased risks of developing CAD after menopause. Women who have had their ovaries surgically removed (oophorectomy) or experience an early menopause, also have an accelerated risk of CAD.

Since treatment with estrogen hormone results in higher HDL and lower LDL cholesterol levels, doctors thought for many years that estrogen would protect women against CAD (as well protect against dementia and stroke). Many studies have found that postmenopausal women who take estrogen have lower CAD rates than women who do not. Unfortunately many of the studies were observational studies (studies in which women are followed over time but decide on their own whether or not they wish to take estrogen). Observational studies have serious shortcomings because they are subject to selection bias; for example, women who choose to take estrogen hormones may be healthier and have a lower risk of heart attacks than those who do not. In other words, something else in the daily habits of women who take estrogen (such as exercise or healthier diet) may make them less likely to develop heart attacks. Therefore, only a randomized trial (a study in which women agree to be assigned to estrogen or a placebo or sugar pill at random but are not told which pills they took until the end of the study) can establish the whether hormone therapy after menopause can prevent CAD.

HERS trial results

The Heart and Estrogen/progestin Replacement Study (HERS), was a randomized placebo-controlled trial of the effect of the daily use of estrogens plus medroxyprogesterone (progestin) on the rate of heart attacks in postmenopausal women who already had CAD. The HERS trial did not find a reduction in heart attacks in women who took hormone therapy. This lack of benefit in preventing heart attacks occurred despite an 11% lower LDL and a 10% higher HDL cholesterol level in the women treated with hormones. The study also found that more women in the hormone-treated group experienced blood clots in the veins and gallbladder disease than women in the placebo-treated group. (Blood clots in the veins are dangerous because these clots can travel to the lungs and cause pulmonary embolism, a condition with chest pain, shortness of breath, and even shock and death.) However, the increase in gallbladder disease and blood clots among healthy users of estrogen who do not have heart disease is very small.

Based on the results of this study, researchers concluded that estrogen is not effective in preventing coronary artery disease and heart attacks in postmenopausal women who already have CAD. It should be noted, however, that the results of the HERS trial only apply to women who have known CAD prior to starting hormone therapy and not to women without known coronary artery disease.

WHI trial results

The Women's Health Initiative (WHI) was the first randomized controlled trial designed to determine the long-term benefits and risks of treatment with estrogens plus medroxyprogesterone (progestin) in healthy menopausal women (women without CAD). The results were reported in a series of articles in 2002, 2003, and 2004. The estrogen + progestin portion of the WHI study had to be stopped earlier than planned, after just 5.2 years, because the increase in coronary heart disease, stroke, and pulmonary embolism among women who use estrogen + progesterone outweighed the benefits of reduced bone fractures and colon cancer. The estrogen-alone portion of the WHI was stopped because women who took estrogen alone had no reduction in heart attack risk, yet there was a significant increase in stroke risk.

The increase in breast cancer became apparent after three to five years, but the increase in heart disease and pulmonary emboli occurred early on, in the first year.

Recommendations for the use of estrogens plus medroxyprogesterone (progestin) in women

Medicinenet Medical Editors believe that:

• Decision regarding use of hormone therapy has to be individualized, and all women should discuss with their physicians what is best for her.

• Estrogens plus medroxyprogesterone (progestin) is still the best therapy for hot flashes. Despite the WHI study, many women remain good candidates for estrogens plus medroxyprogesterone (progestin) therapy (or estrogen alone if they have had hysterectomy). This is especially true if hormone therapy is limited to the shortest duration, optimally less than five years.

• Estrogens with or without medroxyprogesterone (progestin) should not be used to prevent or treat either Alzheimer's disease, heart disease, or stroke.

While estrogens plus medroxyprogesterone (progestin) are effective in preventing osteoporosis and related bone fractures, women concerned about the risk of hormone therapy should discuss with their doctors, the use of other non-hormonal alternatives to prevent and treat osteoporosis.

What is new in heart attack?

Greater public awareness about heart attacks and changes in lifestyle have contributed to a dramatic reduction in the incidence of heart attacks during the last four decades. Improved anticoagulant drugs such as hirudin and hirulog, are being tested and may complement current therapies. The role of the "super aspirins" [abciximab (Reopro) and eptifibatide (Integrilin)] is currently being investigated as well.

More effective versions of TPA are being developed. Increasingly, paramedics can do ECGs in the field, diagnose a heart attack, and take patients directly to hospitals that have the ability to do PTCA and stenting. This can save time and reduce damage to the heart. At present, the accepted best treatment for a heart attack is identification promptly of the diagnosis, and transport to a hospital that can perform prompt catheterization and PTCA or stenting within the first 90 minutes of the cardiac event.

Recent data has shown that lowering blood LDL levels even further than previously suggested may further decrease the risk of heart attacks.

Research also has shown that inflammation may play a role in the development of atherosclerosis, and this is an active area of current investigation. There also is early evidence that with genetic engineering it may be possible to develop a drug that can be administered to clear plaques from arteries (a "scavenger molecule").

Heart Attack At A Glance

• A heart attack results when a blood clot completely obstructs a coronary artery supplying blood to the heart muscle and heart muscle dies.

• The blood clot that causes the heart attack usually forms at the site of rupture of an atherosclerotic, cholesterol plaque on the inner wall of a coronary artery.

• The most common symptom of heart attack is chest pain.
  
  
• The most common complications of a heart attack are heart failure, and ventricular fibrillation.

• The risk factors for atherosclerosis and heart attack include elevated cholesterol levels, increased blood pressure, tobacco use, diabetes, male gender and a family history of heart attacks at an early age.

• Heart attacks are diagnosed with electrocardiograms and measurement of cardiac enzymes in blood

• Early reopening of blocked coronary arteries reduces the amount of damage to the heart and improves the prognosis for a heart attack.

• Medical treatment for heart attacks may include anti-platelet, anti-coagulant, and clot dissolving drugs as well as angiotensin converting enzyme (ACE) inhibitors, beta blockers and oxygen.

• Interventional treatment for heart attacks may include coronary angiography with percutaneous transluminal coronary angioplasty (PTCA), coronary artery stents, and coronary artery bypass grafting (CABG).

• Patients suffering a heart attack are hospitalized for several days to detect heart rhythm disturbances, shortness of breath, and chest pain.

• Further heart attacks can be prevented by aspirin, beta blockers, ACE inhibitors, discontinuing smoking, weight reduction, exercise, good control of blood pressure and diabetes, following a low cholesterol and low saturated fat diet that is high in omega-3-fatty acids, taking multivitamins with an increased amount of folic acid, decreasing LDL cholesterol, and increasing HDL cholesterol.

amiodarone

GENERIC NAME: amiodarone

BRAND NAME: Cordarone

DRUG CLASS AND MECHANISM: Amiodarone is used to correct abnormal rhythms of the heart. (It is an antiarrhythmic medication.) Amiodarone was discovered in 1961 and approved by the FDA in December of 1985. Although amiodarone has many side effects, some of which are severe and potentially fatal, it has been successful in treating many arrhythmias where other antiarrhythmic drugs have failed. Amiodarone is considered a "broad spectrum" antiarrhythmic medication, that is, it has multiple and complex effects on the electrical activity of the heart which is responsible for the heart's rhythm. Among its most important electrical effects are:

1. a delay in the rate at which the heart's electrical system "recharges" after the heart contracts (repolarization);
2. a prolongation in the electrical phase during which the heart's muscle cells are electrically stimulated (action potential);
3. a slowing of the speed of electrical conduction (how fast each individual impulse is conducted through the heart's electrical system);
4. a reduction in the rapidity of firing of the normal generator of electrical impulses in the heart (the heart's pacemaker);
5. a slowing of conduction through various specialized electrical pathways (called accessory pathways) which can be responsible for arrhythmias.

In addition to being an antiarrhythmic medication, amiodarone also causes blood vessels to dilate (enlarge). This effect can result in a drop in blood pressure. Because of this effect, it also may be of benefit in patients with congestive heart failure.

PRESCRIPTION: Yes

GENERIC AVAILABLE: Yes

PREPARATIONS: Tablets (pink), round in shape: 200 mg.

STORAGE: Tablets should be kept at room temperature, less than 30°C (86°F).

PRESCRIBED FOR: Amiodarone is used for many serious arrhythmias of the heart including ventricular fibrillation, ventricular tachycardia, atrial fibrillation, and atrial flutter.

DOSING: Amiodarone usually is given in several daily doses to minimize stomach upset which is seen more frequently with higher doses. For this same reason, it is also recommended that amiodarone be taken with meals.

DRUG INTERACTIONS: Amiodarone may interact with beta-blockers such as atenolol (Tenormin), propranolol (Inderal), metoprolol (Lopressor), or certain calcium channel blockers, such as verapamil (Calan, Isoptin, Verelan, Covera-HS) or diltiazem (Cardizem, Dilacor, Tiazac), resulting in an excessively slow heart rate or a block in the conduction of the electrical impulse through the heart.

Amiodarone increases the blood levels of digoxin (Lanoxin) when the two drugs are given together. It is recommended that the dose of digoxin be cut by 50% when amiodarone therapy is started.

Flecainide (Tambocor) blood concentrations increase by more than 50% with amiodarone. Procainamide (Procan-SR, Pronestyl) and quinidine (Quinidex, Quinaglute) concentrations increase by 30%-50% during the first week of amiodarone therapy. Additive electrical effects occurs with these combinations, and worsening arrhythmias may occur as a result. Some experts recommend that the doses of these other drugs be reduced when amiodarone is started.

Amiodarone can result in phenytoin (Dilantin) toxicity because it causes a two- or three-fold increase in blood concentrations of phenytoin. Symptoms of phenytoin toxicity including unsteady eye movement (temporary and reversible), tiredness and unsteady gait.

Ritonavir (Norvir) can inhibit the enzyme that is responsible for the metabolism of amiodarone. Although no clinical problems have been recognized as a result of this interaction yet, it would be prudent to avoid this combination for fear of the potential for amiodarone toxicity.

Amiodarone also can interact with tricyclic antidepressants (for example, amitriptyline, Elavil), or phenothiazines (for example, chlorpromazine, Thorazine) and potentially cause serious arrhythmias.

Amiodarone interacts with warfarin (Coumadin) and increases the risk of bleeding. The bleeding can be serious or even fatal. This effect can occur as early as 4-6 days after the start of the combination of drugs or can be delayed by a few weeks.

Amiodarone can interact with some cholesterol-lowering medicines of the "statin" class, such as simvastatin (Zocor), atorvastatin (Lipitor), and lovastatin (Mevacor), increasing the risk of severe muscle breakdown and kidney failure or liver disease. This interaction is dose-related, meaning that lower doses of statins are safer than higher doses when used with amiodarone. An alternative statin, pravastatin (Pravachol), does not share this interaction and is safer in patients taking amiodarone.

Amiodarone inhibits the metabolism of dextromethorphan, the cough suppressant found in most over-the-counter (and some prescription) cough and cold medications (for example, Robitussin-DM). Although the significance of the interaction is unknown, these two drugs probably should not be taken together if possible.

Reference: FDA Prescribing Information