J. David Schnatz, M.D.
Director, Lipid Education Service
Saint Francis Hospital and Medical Center
114 Woodland Street, Hartford, CT 06105
Telephone: (860) 714-5555
June 1998
Introduction
Last month we dealt with the question of how low should we get the LDL in treating patients with coronary artery disease (CAD), using presentations from the recent American College of Cardiology meeting. This month we will use presentations at those meetings to deal with the question, "Are there other factors, not traditionally considered, that contribute to the incidence of CAD?"
A whole session dealt with "New Risk Factors for Coronary Artery Disease" (1). The factors, discussants and selected comments were as follows:
Serum Markers of Inflammation - Paul M. Ridker, M.D.
As early as 1984, correlation was noted between fibrinogen levels and future coronary artery disease as well as stroke.
C Reactive protein (CRP) is the best studied. The baseline levels are increased, but at the upper quartile of normal, for those who go on to have a myocardial infarction.
CRP predicts future peripheral vascular disease.
CRP is additive to cholesterol elevation in increasing relative risk of CAD.
He hypothesizes that it mediates change through cellular adhesion molecules and that the effect takes 4 to 8 years.
The relative risk from increased CRP can be attenuated by aspirin and Pravastatin. The latter was seen on analysis of CRP in patients in the CARE study.
Inflammatory cells may be mediating unstable plaques.
Gene Polymorphisms - Jerome Rotter, M.D.
There are many genetic variants underlying the lipid abnormalities we see clinically.
The atherogenic lipoprotein phenotype, and particularly LDL patterns A and B, is inherited.
Four chromosomal loci contribute to LDL size.
Familial combined hyperlipidemia is present in 1 to 2 percent of the U.S. population and in 10 percent of individuals with CAD.
Three genes relate to response to dietary fat and these may be the same as LDL subclass.
In the CABG trial, there were gradations of effect for aggressive therapy, based on LPL phenotype.
Infectious Agents: CMV, Chlamydia and Herpes - Jeffrey L. Anderson, M.D.
Inflammation plays an important role in atherogenesis. Could infectious agents be involved?
Contributions to atherosclerosis by infectious agents are currently in the hypothesis generating and testing phase.
CMV and other herpes viruses cause atherosclerosis in chickens, and can cause endothelial dysfunction.
Long term survival after heart transplantation is 90 percent, if the patient is CMV negative and 70 percent, if positive.
Restenosis of coronary arteries was shown to be 43 percent when CMV was positive and 8 percent when negative.
Chlamydia was shown to be present in 79 percent of patients with CAD and 1 percent of controls.
Chlamydia causes accelerated atherogenesis in animals. Treatment renders the atherogenesis similar to uninfected controls.
Studies on chlamydia are just beginning in humans.
Homocysteine - Killian C. Robinson, M.D.
Homocysteine is a risk factor for CAD.
The risk from hypertension and smoking is aggravated by hyperhomocysteinemia. This is not so for cholesterol.
There is no real treatment difference between 400 micrograms and 5 milligrams of folic acid.
LDL Subtypes - H. Robert Superko, M.D.
Small, dense LDL increase the risk of CAD three-fold.
The inheritance of small, dense LDL is dominant and linked to chromosome 19.
Obesity brings to clinical light the syndrome of small, dense LDL. Weight loss may turn off the production of these particles.
Small, dense LDL are commonly associated with hypertriglyceridemia, low HDL and diabetes mellitus.
A triglyceride level of less than 70 mg/dl is associated with buoyant particles (pattern A), and greater than 250 mg/dl with small, dense LDL particles (pattern B). Between 70 and 250 mg/dl, there is overlap with both types of particles being present.
When LDL is less than 125 mg/dl and pattern A exists, there is no benefit from treatment. When LDL is less than 125 mg/dl but pattern B is present, it is detrimental not to treat.
In those patients where a very low fat diet leads to increased triglyceride and low HDL, there may be a turning on of this syndrome.
In a separate session (2), it was pointed out that even though this is a real phenomenon, there is no evidence that intervening to treat small dense LDL, specifically, makes a difference, and also that TG and CHOL/HDL are equally good markers. In another presentation (3), B. Greg Brown, M.D. referred to the FATS study (4), noting that change in LDL particle buoyancy was the best predictor of CAD.
Cytomegalovirus and Vascular Disease - Salim Yusuf, M.D.
Cytomegalovirus is one of eight human herpes viruses.
Cytomegalovirus is associated with atherosclerosis, transplant atherosclerosis and transplant thickening.
There is no data to indicate that suppression of this virus benefits the atherosclerosis.
Clinical trials are needed.
REFERENCES
(1) ACC '98. New Risk Factors for Coronary Artery Disease.
(2) ACC '98. Primary Prevention of Coronary Disease.
(3) ACC '98. New Findings in Lipid Disorders That Affect Your Practice.
(4) NEJ Med 323:1289, 1990.
