Atherosclerosis and the Metabolic Syndrome

Atherosclerosis or the progressive narrowing of the blood vessels, is the primary mechanism for heart diseases and stroke. It results from the interaction of multiple genetic and environmental risk factors. Although, at this stage, one may say that we are basking in the light of new medical findings which lend us a better understanding of the atherosclerotic disease process, so many questions remain incompletely answered.

"This highlights the complexity of the disease as reflected by the many cardiovascular risk factors and pathophysiologic mechanisms associated with atherosclerotic cardiovascular diseases," says Dr. Rody Sy, overall chairman of the forthcoming Third Congress of the Asian Pacific Society of Atherosclerosis and Vascular Diseases (APSAVD) to be held at the Waterfront Convention Center in Cebu City on Feb. 17-20.

A case in point is that of Edwin T., a 26-year-old computer programmer, who decided to stop by the emergency room (ER) of the Manila Doctor’s Hospital for what seemed like a bum stomach after a few rounds of drinks with his friends. He merely asked for an antacid or something to relieve his "gastric upset."

The ER physician, however, took note that Edwin was obese (220 pounds); his blood pressure was 160/100; his recent laboratory tests showed elevated blood sugar, triglyceride and a low high-density lipoprotein or HDL which is the good cholesterol. This cluster of findings drew the suspicion of the doctor and he requested for an electrocardiogram. It showed an evolving heart attack in the inferior portion of the heart which occasionally may simulate the symptoms of a bum stomach.

The clustering of risk factors such as high blood pressure, diabetes, cholesterol abnormalities and obesity has caught the interest of many medical researchers. Multiple metabolic derangements have been identified in patients with heart attacks and stroke, and the interaction of these metabolic abnormalities are believed to be responsible for accelerating the atherosclerotic process.

Of particular interest is the Insulin-Resistance Syndrome (IRS), also called by some as the Metabolic Syndrome (MS). This syndrome is characterized by the presence of increased level of and resistance to insulin, obesity, decreased HDL, elevated triglyceride, hypertension and decreased ability to dissolve a blood clot. IRS or MS has been associated with an increased risk of atherosclerotic heart disease.

Insulin resistance has been associated with endothelial dysfunction, an abnormality in the inner lining of the blood vessels which is now known to be the basic mechanism that triggers the cascade of events leading to atherosclerosis. A consequence of IRS or MS is reduced synthesis of the protective endothelium-derived relaxing factor (EDRF), making the blood vessels prone to a constrictive narrowing of its lumen and to the development of endothelial dysfunction.

Clinical recognition

In clinical practice, the National Cholesterol Education Program (Adult Treatment Panel III) in the United States has recommended practical guidelines in the identification of patients with the MS. The syndrome is diagnosed if any three of the following abnormalities are present:

• Abdominal obesity, defined as waist circumference of more than 102 cm. (40 in.) in men and 88 cm. (35 in.) in women;

• Serum triglyceride level: equal or more than 150 mg/dL;

• HDL: less than 40 mg/dL in men, and less than 50 mg/ dL in women;

• Blood pressure: more than 130/85 mmHg; and

• FBS: equal or more than 110 mg/dL.

Physicians are now encouraged by most guidelines to treat not only elevated LDL (bad cholesterol), but also low HDL, high triglycerides and blood pressure – all components of the Metabolic Syndrome – more aggressively both by therapeutic lifestyle changes (TLC) and drug therapy until target levels are attained.

MS prevalence

Insulin resistance is common in patients with metabolic disorders and is found in the vast majority of those with multiple metabolic disorders. Various researchers have found insulin resistance in the following percentages of patients:

• 66 percent of subjects with impaired glucose tolerance;

• 84 percent of those with non-insulin diabetes mellitus (NIDDM);

• 54 percent of patients with high cholesterol;

• 84 percent of those with high triglycerides;

• 88 percent of subjects with low HDL cholesterol;

• 63 percent of patients with elevated uric acid levels; and

• 58 percent of those with hypertension.

Another interesting finding in most researches was that in individuals with combined metabolic disorders, nearly all demonstrated insulin resistance. In particular, high triglyceride and low HDL cholesterol almost never occurred as isolated disorders, and were associated with insulin resistance in nearly 100 percent of cases.

MS predictors

Varying correlations emerged between different measures of obesity and insulin resistance. There is a slight disagreement by authors as to which marker of overall obesity was a more powerful predictor of the Metabolic Syndrome. Some consider the body-mass index (BMI) as a slightly more powerful predictor than the waist-hip (WH) ratio, which is contrary to earlier findings.

In some studies, the most powerful predictor of the Metabolic Syndrome was waist circumference (WC). According to these data, a WC over 100 centimeters or nearly 40 inches was most likely to be associated with the metabolic abnormalities, being approximately similar in men and women. The NCEP ATP III now recommends the WC but with a different cut-off value for men and women (40 inches for men and 35 inches for women).

Management implications

Recognition of the Metabolic Syndrome should influence the way physicians evaluate and manage patients with atherosclerotic cardiovascular disease. Taskinen, in 1993, proposed that the diagnosis of any one of the multiple metabolic abnormalities should be an indication to screen for the other components. Considering the prevalence of the MS, high-risk groups should be targeted in the screening, such as hypertensives, patients with non-insulin diabetes mellitus (NIDDM), overweight subjects with abdominal obesity, first-degree relatives of diabetics and patients with primary hypertriglyceridemia.

As early as 1993, Taskinen deemed it prudent to diagnose the MS if three or more of the biochemical measures and other markers were present, including blood pressure, body fat distribution, total cholesterol, HDL cholesterol, triglyceride, glucose and uric acid.

In terms of therapeutic consideration, some drugs may be preferred over others in patients diagnosed to have the metabolic syndrome. The newer oral hypoglycemic agents such as thizolinediones and metformin have beneficial effects on cardiovascular tissues that may ameliorate diabetic cardiovascular disease.

There are now increasing data showing the favorable effects of angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) in patients with the Metabolic Syndrome, even in those without elevated blood pressure.

The beneficial effects of ACEIs and ARBs have extended beyond blood-pressure lowering and are now accepted indications for other complications associated with the Metabolic Syndrome such as coronary artery disease which may lead to heart attacks, and diabetic nephropathy which may be a cause of kidney failure.

In summary, the metabolic cluster of abnormalities should always be at the back of one’s mind whenever one deals with a hypertensive, diabetic, obese or any patient with atherosclerotic cardiovascular disease.

The concept of total risk assessment dictates that the physician should always screen for these metabolic derangements in high-risk patients and consider the therapeutic rationale of some drugs in preventing the serious complications of the Metabolic Syndrome.

(For inquiries on the APSAVD congress in Cebu, contact the secretariat at (632) 687-2841 and 687-7073 or e-mail at [email protected].)