CAD (Coronary Artery Disease)

Coronary artery disease (CAD) (or atherosclerotic heart disease) is the end result of the accumulation of atheromatous plaques within the walls of the arteries that supply the myocardium (the muscle of the heart) with oxygen and nutrients. It is sometimes also called coronary heart disease (CHD), but although CAD is the most common cause of CHD, it is not the only cause.

CAD is the leading cause of death in the U.S. While the symptoms and signs of coronary artery disease are noted in the advanced state of disease, most individuals with coronary artery disease show no evidence of disease for decades as the disease progresses before the first onset of symptoms, often a "sudden" heart attack, finally arise. After decades of progression, some of these atheromatous plaques may rupture and (along with the activation of the blood clotting system) start limiting blood flow to the heart muscle. The disease is the most common cause of sudden death, and is also the most common reason for death of men and women over 20 years of age. According to present trends in the United States, half of healthy 40-year-old males will develop CAD in the future, and one in three healthy 40-year-old women. According to the Guinness Book of Records, Northern Ireland is the country with the most occurrences of CAD. By contrast, the Maasai of Africa have almost no heart disease.

As the degree of coronary artery disease progresses, there may be near-complete obstruction of the lumen of the coronary artery, severely restricting the flow of oxygen-carrying blood to the myocardium. Individuals with this degree of coronary artery disease typically have suffered from one or more myocardial infarctions (heart attacks), and may have signs and symptoms of chronic coronary ischemia, including symptoms of angina at rest and flash pulmonary edema.

A distinction should be made between myocardial ischemia and myocardial infarction. Ischemia means that the amount of oxygen supplied to the tissue is inadequate to supply the needs of the tissue. When the myocardium becomes ischemic, it does not function optimally. When large areas of the myocardium becomes ischemic, there can be impairment in the relaxation and contraction of the myocardium. If the blood flow to the tissue is improved, myocardial ischemia can be reversed. Infarction means that the tissue has undergone irreversible death due to lack of sufficient oxygen-rich blood.

An individual may develop a rupture of an atheromatous plaque at any stage of the spectrum of coronary artery disease. The acute rupture of a plaque may lead to an acute myocardial infarction (heart attack).

Pathophysiology

Limitation of blood flow to the heart causes ischemia (cell starvation secondary to a lack of oxygen) of the myocardial cells. When myocardial cells die from lack of oxygen, this is called a myocardial infarction (commonly called a heart attack). It leads to heart muscle damage, heart muscle death and later scarring without heart muscle regrowth.

Myocardial infarction usually results from the sudden occlusion of a coronary artery when a plaque ruptures, activating the clotting system and atheroma-clot interaction fills the lumen of the artery to the point of sudden closure. The narrowing of the lumen of the heart artery before sudden closure is often not severe, according to clinical research completed in the late 1990s and using IVUS examinations within 6 months prior to a heart attack. High grade stenoses as such exceeding 75% blockage, such as detected by stress testing while carrying much higher individual risk for sudden closure, were found to be responsible for only 14% of acute heart attacks because they are rarer compared to less severe narrowings. The events leading up to plaque rupture are not understood despite many theories. Myocardial infarction is almost never caused by temporary spasm of the artery wall occluding the lumen, a condition also associated with atheromatous plaque and CAD.

CAD is associated with smoking, diabetes, and hypertension. A family history of early CAD is one of the less important predictors of CAD. Most of the familial association of coronary artery disease are related to common dietary habits. Screening for CAD includes evaluating high-density and low-density lipoprotein (cholesterol) levels and triglyceride levels. Despite much press, most of the alternative risk factors including homocysteine, C-reactive protein (CRP), Lipoprotein (a), coronary calcium and more sophisticated lipid analysis have added little if any additional value to the conventional risk factors of smoking, diabetes and hypertension.

Angina

Angina that occurs regularly with activity, after heavy meals, or at other predictable times is termed stable angina and is associated with high grade narrowings of the heart arteries. The symptoms of angina are often treated with betablocker therapy such as metoprolol or atenolol. Nitrate preparations such as nitroglycerin, which come in short-acting and long-acting forms are also effective in relieving symptoms but are not known to reduce the chances of future heart attacks. Many other more effective treatments, especially of the underlying atheromatous disease, have been developed.

Angina that changes in intensity, character or frequency is termed unstable. Unstable angina may precede myocardial infarction, and requires urgent medical attention. It may be treated with oxygen, intravenous nitroglycerin, and aspirin. Interventional procedures such as angioplasty may be done.

Sex characteristics of coronary artery disease

Special Pathophysiology

Typically, coronary artery disease occurs when part of the smooth, elastic lining inside a coronary artery (the arteries that supply blood to the heart muscle) develops atherosclerosis. With atherosclerosis, the artery's lining becomes hardened, stiffened, and swollen with all sorts of "grunge" - including calcium deposits, fatty deposits, and abnormal inflammatory cells - to form a plaque. Deposits of calcium phosphates (hydroxyapatites) in the muscular layer of the blood vessels appear to play not only a significant role in stiffening arteries but also for the induction of an early phase of coronary arteriosclerosis. This can be seen in a so-called metatstatic mechanism of calcification as it occurs in chronic kidney disease and haemodialysis (Rainer Liedtke 2008). Although these patients suffer from a kidney dysfunction, almost fifty percent of them die due to coronary artery disease. Plaques can be thought of as large "pimples" that protrude into the channel of an artery, causing a partial obstruction to blood flow. Patients with coronary artery disease might have just one or two plaques, or might have dozens distributed throughout their coronary arteries. However, there is a term in medicine called “Cardiac Syndrome X”, which describes chest pain (Angina pectoris) and chest discomfort in people who do not show signs of blockages in the larger coronary arteries of their hearts when an angiogram (coronary angiogram) is being performed.

No one knows exactly what causes “Cardiac Syndrome X” and it is unlikely to have a single cause. Today, we speculate that the major contributing factor to “Cardiac Syndrome X” is “microvascular dysfunction”: The term “microvascular” refers to very small blood vessels and, in this case, very small arteries (arterioles, capillaries) of the heart. Studies have also shown that people with “Cardiac Syndrome X” have enhanced pain perception, meaning they feel chest pain more intensely than the average person.

The large majority of women have the garden variety of coronary artery disease. Rarely, women with “Cardiac Syndrome X” have typical anginal syndromes that are not associated with the presence of atherosclerotic plaques; that is, the localized blockages are absent. Scientists speculate that the blood vessels in these women are diffuse abnormal. Some have falsely claim that the entire lining of the artery becomes thickened throughout, making the plaques flush with the wall of the artery without any scientific proof. On cardiac catheterization their coronary arteries appear smooth-walled and normal, though they may look "small" in diameter. By the way: in general, female coronary arteries (like all arteries) are somewhat smaller than in males.

 “Cardiac Syndrome X” have never been shown to cause acute heart attacks (myocardial infarction) despite much speculation. The prognosis with syndrome-X coronary artery disease is also known to be better than with typical coronary artery disease, but this is not a benign condition since it can be quite disabling. It is not completely clear why women are more likely than men to suffer from "Syndrome X"; however, hormones and other risk factors unique to women may play a role[. Women’s blood vessels are exposed to changing levels of oestrogen throughout their lives, first during regular menstrual cycles and later during and after menopause as oestrogen levels decline with age. Oestrogen affects how blood vessels narrow and widen and how they respond to injury, so changes in oestrogen levels mean changes in the reactivity of the blood vessels. Women’s vessels may be “programmed” for more changes than men’s vessels, which could increase the risk of having problems in the lining of the arteries (endothelial cells) and the smooth muscle cells in the walls of the arteries. The endothelial dysfunction is likely to be multifactorial in these patients and it is conceivable that risk factors such as hypertension, hypercholesterolemia, diabetes mellitus and smoking can contribute to its development. Most patients with Syndrome X are postmenopausal women and oestrogen deficiency has been therefore proposed as a pathogenic factor in female patients. In addition to changing hormone levels, there are several other risk conditions for blood vessel problems that are unique to women, such as preeclampsia (a problem associated with high blood pressure during pregnancy) and delivering a low-birth weight baby. Of course, despite these issues women, the female gender as a whole is protective against coronary artery disease.

Symptoms

Cardiac Syndrome X often is a diagnosis of exclusion where the presence of typical chest pains is not accompanied by coronary artery narrowings on angiography. In considering Syndrome-X, it is important to understand that about 80% of chest pains have nothing to do with the heart. Therefore, the characteristics of typical chest pains must be carefully documented to avoid unnecessary labelling patients with heart disease:

• Chest pain or Angina with physical stress; the pain may spread to the left arm or the neck, back, throat, or jaw. There might be present a numbness (paresthesia) or a loss of feeling in the arms, shoulders, or wrists.
• Coronary angiography demonstrates “normal” coronary arteries, i. e. no blockages or stenoses can be detected in the larger epicardial vessels.
• No inducible coronary artery spasm present during cardiac catheterization.
• Characteristic ischemic ECG changes during exercise testing.
• ST segment depression and angina in the presence of left ventricular wall perfusion abnormalities during thallium or other stress perfusion test.
• Consistent response to sublingual nitrates.
• Postmenopausal or menopausal status.

The diagnosis of “Cardiac Syndrome X” - the rare coronary artery disease that is more common in women, as mentioned, an “exclusion” diagnosis. Therefore, usually the same tests are used as in any patient with the suspicion of coronary artery disease:

• Baseline ECG
• Exercise ECG – Stress test
• Exercise radioisotope test (nuclear stress test, myocardial scintigraphy).
• Echocardiography (including stress echocardiography).
• Coronary angiography.
• Intravascular ultrasound.
• MRI scan.

Therapy

A variety of drugs are used in the attempt to treat the Syndrome-X coronary artery disease: nitrates, calcium channel antagonists, ACE-inhibitors, statins, imipramin (analgesia), aminophylline, hormone replacement therapy (oestrogen), even electrical spinal cord stimulation are tried to overcome the symptomatology -all with mixed results. Quite often the quality of life for these women remains poor. While not enough is known about Syndrome-X coronary artery disease to list specific prevention techniques, adopting heart-healthy habits can be a good start. These include monitoring cholesterol and blood pressure levels, maintaining a low-fat diet, exercising regularly, quitting smoking, avoiding recreational drugs, and moderating alcohol intake. It is also important to remember that garden variety coronary atherosclerosis remains a much, much larger threat to women then Syndrome-X.

Risk factors

The following are confirmed independent risk factors for the development of CAD:

1. Hypercholesterolemia (specifically, serum LDL concentrations)
2. Smoking
3. Diabetes
4. Hypertension (high systolic pressure seems to be most significant in this regard)
5. Type A Behavioural Patterns, TABP. Added in 1981 as an independent risk factor after a majority of research into the field discovered that TABP's were twice as likely to exhibit CAD than any other personality type.

Significant, but indirect risk factors include:

• Lack of exercise
• Stress
• Diet rich in saturated fats
• Obesity
• Men over 60; Women over 65

Risk factors can be classified as

1. Fixed (minor importance): age, sex, family history
2. Modifiable (major importance): smoking, hypertension, diabetes mellitus, obesity, etc.

Prevention

Coronary artery disease is the most common form of heart disease in the Western world. Prevention centers on the modifiable risk factors, which include decreasing cholesterol levels, addressing obesity and hypertension, avoiding a sedentary lifestyle, making healthy dietary choices, and stopping smoking. There is some evidence that lowering homocysteine levels may contribute to more heart attacks (NORVIT trial). In diabetes mellitus, there is little evidence that very tight blood sugar control actually improves cardiac risk although improved sugar control appears to decrease other undesirable problems like kidney failure and blindness. Some recommend a diet rich in omega-3 fatty acids and vitamin C. The World Health Organization (WHO) recommends "low to moderate alcohol intake" to reduce risk of coronary artery disease although this remains without scientific cause and effect proof.

An increasingly growing number of other physiological markers and homeostatic mechanisms are currently under scientific investigation. Patients with CAD and those trying to prevent CAD are advised to avoid fats that are readily oxidized (e.g., saturated fats and trans-fats), there is no proof of any kind that carbohydrates and processed sugars increases production of Low density lipoproteins while increasing High density lipoproteins. It is also important to keep blood pressure normal, exercise and stop smoking. These measures reduces the development of heart attacks. Recent studies have shown that dramatic reduction in LDL levels can cause regression of coronary artery disease in as many as 2/3 of patients after just one year of sustained treatment.

Despite much initial enthusiasm, vitamin therapies including various forms of A (beta carotene included), B (folate included), C, E or K have not demonstrated any significant effect in reducing coronary artery disease. In fact, excessive amount of vitamin B may lead to more heart attacks while large doses of beta carotene or Vitamin E appears to lead to increases in cancer. The entire theory of anti-oxidant therapy upon which some of these is based has never been proved and remains areas of basic research.

Exercise

Separate to the question of the benefits of exercise; it is unclear whether doctors should spend time counseling patients to exercise. The U.S. Preventive Services Task Force (USPSTF), based on a systematic review of randomized controlled trials, found 'insufficient evidence' to recommend that doctors counsel patients on exercise, but "it did not review the evidence for the effectiveness of physical activity to reduce chronic disease, morbidity and mortality", it only examined the effectiveness of the counseling itself.  However, the American Heart Association, based on a non-systematic review, recommends that doctors counsel patients on exercise.

Aspirin

Aspirin, in doses of less than 75 to 81 mg/d, can reduce the incidence of cardiovascular events. The U.S. Preventive Services Task Force 'strongly recommends that clinicians discuss aspirin chemoprevention with adults who are at increased risk for coronary artery disease'. The Task Force defines increased risk as 'Men older than 40 years of age, postmenopausal women, and younger persons with risk factors for coronary artery disease (for example, hypertension, diabetes, or smoking) are at increased risk for heart disease and may wish to consider aspirin therapy'. More specifically, high-risk persons are 'those with a 5-year risk ≥ 3%'. A risk calculator is available.

Regarding healthy women, the more recent Women's Health Study randomized controlled trial found insignficant benefit from aspirin in the reduction of cardiac events; however there was a signficant reduction in stroke. Subgroup analysis showed that all benefit was confined to women over 65 years old. In spite of the insignficant benefit for women < 65 years old, recent practice guidelines by the American Heart Association recommend to 'consider' aspirin in 'healthy women' <65 years of age 'when benefit for ischemic stroke prevention is likely to outweigh adverse effects of therapy'.

Omega-3 fatty acids

The benefit of fish oil is controversial with conflicting conclusions reached by a negative meta-analysis of randomized controlled trials by the international Cochrane Collaboration and a partially positive systematic review[24] by the Agency for Healthcare Research and Quality. Since these two reviews, a randomized controlled trial reported a reduction on coronary events in Japanese hypercholesterolemic patients.

Omega-3 fatty acids are also found in some plant sources including flax seed oil, hemp seed oil, and walnuts. Plant sources may be safer as fish products have been shown to contain heavy metals and other fat soluble pollutants.

Secondary prevention

Secondary prevention is preventing further sequelae of already established disease. Regarding coronary artery disease, this can mean risk factor management that is carried out during cardiac rehabilitation, a 4-phase process beginning in hospital after MI, angioplasty or heart surgery and continuing for a minimum of three months. Exercise is a main component of cardiac rehabilitation along with diet, smoking cessation, and blood pressure and cholesterol management. Beta blockers may also be used for this purpose.

Anti-platelet therapy

A meta-analysis of randomized controlled trials by the international Cochrane Collaboration found "that the use of clopidogrel plus aspirin is associated with a reduction in the risk of cardiovascular events compared with aspirin alone in patients with acute non-ST coronary syndrome. In patients at high risk of cardiovascular disease but not presenting acutely, there is only weak evidence of benefit and hazards of treatment almost match any benefit obtained."

Therapy - Principles of Treatment

Therapeutic options for coronary artery disease today are based on three principles: 1. Medical treatment - drugs (e.g. cholesterol lowering medications, beta-blockers, nitroglycerin, calcium antagonists, etc.); 2. Coronary interventions as angioplasty and stent-implantation; 3. Coronary artery bypass grafting (CABG - coronary artery bypass surgery). Recent research efforts focus on new angiogenic treatment modalities (angiogenesis) and various (adult) stem cell therapies.

Recent research

A 2006 study by the Cleveland Clinic found a region on Chromosome 17 was confined to families with multiple cases of myocardial infarction.

A more controversial link is that between Chlamydophila pneumoniae infection and atherosclerosis. While this intracellular organism has been demonstrated in atherosclerotic plaques, evidence is inconclusive as to whether it can be considered a causative factor. Treatment with antibiotics in patients with proven atherosclerosis has not demonstrated a decreased risk of heart attacks or other coronary vascular diseases.

Since the 1990s the search for new treatment options for coronary artery disease patients, particularly for so called "no-option" coronary patients, focused on usage of angiogenesis and (adult) stem cell therapies. Numerous clinical trials were performed, either applying protein (angiogenic growth factor) therapies, such as FGF-1 or VEGF, or cell therapies using different kinds of adult stem cell populations. Research is still going on - with first promising results particularly for FGF-1and utilization of endothelial progenitor cells.

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