Coronary artery disease (CAD) is one of the leading causes of death in the United States. Eighty percent of people having heart attacks have normal cholesterol levels. A quarter of the population have a condition called low-density lipoprotein (LDL) pattern B that has been associated with a threefold risk of myocardial infarction. Although early intervention can often prevent an otherwise fatal event, these patients often go unrecognized until after a myocardial infarction has occurred because they may not have the usual risk factors associated with cardiovascular disease. In patients with LDL pattern B, the standard lipid panel may be normal and inadequate for diagnosis and treatment of the condition.
This article discusses how to identify a potentially high risk patient, available laboratory tests, management options, and the role of nurses in identifying high risk patients. The second author tells his personal story of surviving multiple cardiac arrests at a young age before being diagnosed with this condition.
Key Words: genetics, cardiovascular, coronary artery disease, cholesterol, lipoproteins
As nurses, we are all aware of the well-known fact that coronary artery disease (CAD) is one of the leading causes of death in the United States. What is less well known is that 25% of the population have a familial lipid disorder with an autosomal dominant pattern of inheritance associated with a condition known as low-density lipoprotein (LDL) pattern B.
...25% of the population have a familial lipid disorder with an autosomal dominant pattern of inheritance associated with a condition known as low-density lipoprotein (LDL) pattern B.
This condition has been associated with a threefold risk of myocardial infarction (Austin, et al., 1988). Although both family studies and twin studies have demonstrated genetic influences of LDL pattern B, the specific gene(s) involved remain to be identified (Austin, Stephens, Walden, & Wijsman, 1999). In addition, the standard lipid panel may be normal in many patients who have this condition and inadequate for diagnosis and treatment (Superko, 1998).
LDL pattern B is only one of a number of cardiovascular conditions with a genetic component. There are several hereditary cardiac syndromes associated with atherosclerosis and increased risk for cardiac disease including familial hypercholesterolemia (FH), apolipoprotein B (Apo B), high Lp(a), and dominant and recessive variants of ApoE (Williams, Hopkins, Stephenson, Wu, & Hunt, 1999). For a more complete list of related hereditary cardiac conditions, the reader is referred to Williams et al., 1999, p. S41.
The importance of an adequate family history cannot be overemphasized when assessing cardiac disease risk. In one study, 77% of coronary artery disease patients and 54% of their first and second degree relatives were found to have a genetically linked dyslipidemia (Genest, et al., 1992). Since many primary care providers do not have the time to take a thorough family history, the nurse may be the first person to identify a person at risk for a genetically linked lipid disorder such as LDL pattern B. The purpose of this article is to tell a dramatic personal story of a man who survived multiple cardiac arrests at age 45 related to LDL pattern B that had not been previously identified by his health care providers. This remarkable man has gone on to write a book telling his personal story with the purpose of educating the public and health care professionals about how to identify and treat this condition (book Web site listed in web resources).
The Second Author's Personal Story
What do you think the typical heart disease patient looks like?
The image that may come to mind is an overweight, fifty-five-year-old male who smokes, doesn't exercise, and eats a diet high in saturated fat. We would expect his total blood cholesterol to be well over 200 mg/dL. He would probably have high blood pressure, high salt intake, and high fat and sugar consumption.
So, what would we think when confronted with a forty-five-year-old man who is tall and thin, does not smoke, does not have high blood pressure, exercises every day, and is on a low-fat diet? Sounds like the poster child for good health, doesn't he, especially if he had never had chest pains or shortness of breath?
How, then, do we explain it when he is awakened from a sound sleep by a massive heart attack? Five weeks earlier he had a complete cardiac work-up: EKG, stress echocardiogram, lipid panel, and serum CPK enzyme analysis. He was told he had a strong heart, no arterial blockage, and could take up any sport he liked. How did he slip under the radar?
I was this patient. I barely survived my cardiac arrests. I would not be here today if not for a very persistent ER cardiologist.
...eighty percent of patients with heart disease have normal lipid levels...
At first, it looked like a fluke or some strange combination of random factors that intersected to cause a myocardial infarction and subsequent cardiac arrests. But in the weeks following my heart attack, a strange thing occurred. My lipid panels were getting worse and worse. Though my total cholesterol had dropped, so had my high-density lipoprotein (HDL); but my LDL was rising and my triglycerides more than doubled to over 415 mg/dL. I was headed for another heart attack even though I was on a diet that contained almost no fat! It just didn't make sense. Fortunately for me, I met another cardiologist who immediately had me tested for the existence of small-particle LDL syndrome, something I had never even heard of. Unfortunately for me, my first cardiologist had not heard of it either.
I entered the world of HeartStopper genes, where all my assumptions about heart disease were challenged. I learned that eighty percent of patients with heart disease have normal lipid levels (Dawber, 1980; Superko, 1997); that hereditary factors are strongly linked to cardiovascular risk (Genest, et al., 1992) and that a very low-fat diet can actually be harmful to persons with LDL pattern B (Dreon, Fernstrom, Williams, & Krauss, 1999).
... hereditary factors are strongly linked to cardiovascular risk...
This would be bad enough if LDL pattern B, sometimes called small particle LDL syndrome, were an exotic condition that affected only a tiny fraction of the population. However, this is not the case. Roughly one in four persons may carry an allele that leads to LDL pattern B, although the specific genes remain to be identified (Austin, et al., 1988; Austin, et al., 1999). There is no typical heart disease patient. There are many forms and causes of heart disease (Superko, 1998). The thirty-year-old marathon runner, the thin, thirty-seven year old mother who has never been sick a day in her life, the forty-six-year-old health-conscious businessman who exercises every night; any one of these people can be struck down. The only accurate way to determine their true heart attack risk is to perform lipid subclass testing.
But here's the good news. These genetically-induced forms of heart disease are very responsive to treatment. I know. The coronary blockage that was found during my angiogram at the time of my heart attack is now gone. My cardiologist and I have reversed the plaque-forming propensities of my HeartStopper gene.
...a very low-fat diet can actually be harmful to persons with LDL pattern B
Why does current cardiac management sometimes have little effect or make matters worse? Let's look first at the diagnostic tools that were used before my heart attack. Five weeks before this event, I underwent the full range of cardiac diagnosis because I had felt a twitching in my chest that had scared the daylights out of me. A lipid panel showed higher than normal total cholesterol at 258 mg/dL. My HDL was 43 mg/dL, LDL was 169 mg/dL, and triglycerides were 172 mg/dL. This did not set off any alarm bells, even though my cholesterol was over 200. My CPK enzymes were normal, meaning that I had not suffered any heart damage. However, an experimental marker called troponin was also examined. Unfortunately for me, at the time, troponin testing had not been around long enough to be properly calibrated. My level of 1.9 ng/mL was well over today's recognized damage threshold of .8 ng/mL. In 1996, they were not alarmed at anything under 3 ng/mL.
What about a stress echocardiogram? This is a pretty accurate test that measures heart function to determine if any portions of the heart become ischemic during exercise. In my case, no abnormalities were discovered. The blockage I had in my left anterior descending artery (LAD) was not sufficiently large to block blood flow and the transient blood clot that had probably caused my episode was now dissolved. My EKG was normal. An X-ray of my chest could not show the unstable plaque that had formed in the LAD.
What else could have been done? The ultimate test would have been an angiogram. However, with no other evidence to suggest heart disease, only the most aggressive cardiologist would have suggested an angiogram. The procedure is expensive and there is a one in ten thousand chance that it will trigger a stroke.
Result? I was given a clean bill of health and told to take Mylanta. The discomfort I had felt was attributed to acid reflux. In fact, I had experienced a cardiac event that had caused a small amount of heart damage. I had unstable plaque that was causing local blood clotting and unstable angina. This time, the clot had begun to cause serious blockage, but then had dissolved. Five weeks later, I would not be so lucky. I suffered a massive myocardial infarction and only the persistence of an emergency room cardiologist saved me. I was defibrillated seventy-two times. That's not a typographical error; my arteries were too blocked for chemical defibrillation. The hair never grew back on my chest.
What then should a health professional look for?
...a family history of myocardial infarction, especially at a young age, is a major red flag and should trigger further evaluation.
In my case, the biggest mistake made was ignoring my family history. I was asked if any members of my family had ever had heart attacks. I answered that my father and grandfather both died of them, my father at 50 and my grandfather at 57. Yet, this piece of valuable information did not trigger any further analysis. No further family history was charted. Further questions would have revealed that both of my paternal uncles also died of myocardial infarctions in their 50s. I have no paternal aunts. In addition, I now know that one of my uncles had two sons who died of cardiac arrests before age 50.
I know today that a family history of myocardial infarction, especially at a young age, is a major red flag and should trigger further evaluation, even for a patient with normal blood lipid values. Further evaluation of my lipid values found me to have LDL pattern B and also an elevated ApoB level.
Laboratory Testing for Hereditary LDL Syndrome
Though the lipid panel is inaccurate from twenty to fifty percent of the time in diagnosing small-particle LDL syndrome, it can be used as a preliminary guide if no other information is available (Superko, 1998). If a patient's triglycerides are above 140-160 mg/dL and if HDL is under 45 for men and 55 for women, this is strong incentive to test further. Many labs test for apolipoprotein B (ApoB). Though not conclusive, this can be a marker for small-particle LDL syndrome. A patient with high ApoB should also be tested for the existence of small-particle LDL syndrome.
ApoB is a protein projection that can occur on both HDL and LDL cholesterol, though usually, ninety-percent of it is found on LDL. Familial defective Apo B may be associated with severe hypercholesterolemia and cannot always be distinguished from familial hypercholesterolemia phenotypically (Raungaard, 2000).
If a patient's triglycerides are above 140-160 mg/dL and if HDL is under 45 for men and 55 for women, this is strong incentive to test further.
A comparison of two methods for measurement of apoB can be found in Parhofer, Barrett, & Schwandt, (1999). Familial combined hyperlipidemia (FCH) is a common lipid disorder characterized by elevations of plasma cholesterol and/or triglyceride in first-degree relatives. A predominance of small, dense LDL particles and elevated apolipoprotein B (apoB) levels is commonly found in members of FCH families. In one study, genetic analysis found that in 66% of FCH families, both abnormalities were due to shared genetic components (Juo, Bredie, Kiemeney, Demacker, & Stalenhoef, 1998). The purpose of LDL and/or HDL subclass analysis is to determine the sizes of the various component particles. The smaller LDL particles are much more atherogenic than larger particles (Superko, 1998). If these particles are abundant, the patient is classified as being subclass B, a condition that results in a threefold to six-fold increase in heart arrest risk. Subclass A is the designation for a normal individual.
Three technologies are available for LDL subclass analysis. Since each technology is patented, a test from one lab cannot necessarily be directly compared to the test from another lab (see lab contact information).
The first is called segmented gradient gel electrophoresis or S(3)GGE. Berkeley HeartLab developed and uses this technology, which is referenced to sequential ultracentrofucation (ANUC). In addition to determining pattern A or pattern B, the LDL S(3)GGE provides the important sub-classification information (e. g. LDL IIIa and LDL IIIb) used to evaluate the severity of the small particle LDL syndrome. The smaller the particle size, the more chance that blockage of arteries can occur. Testing can also determine if the production of HDL2b is impaired. Since this particle is responsible for scavenging of LDL off arterial walls, its absence also increases heart attack risk. HDL is broken down into five subclassifications, and HDL2b is most protective. Some LDLs aren't as harmful as others, which is why the sub-breakdown is important.
A different technology has been developed using Nuclear Magnetic Resonance (NMR) to determine the numbers and sizes of lipoprotein particles in a blood sample. NMR testing is currently available from LipoMed, Inc. LDL particle sizes are referenced to those measured by electron microscopy and are 5 nm smaller than gradient gel measurements. Pattern A and B definitions correspond to those of Austin et al., (1988).
VAP (vertical auto profile) is a patented technology used by Atherotech to separate lipid particles by size and density. The VAP Cholesterol Test uses density gradient ultracentrifugation to directly measure size and concentration of cholesterol particles in mg/dL. A list of all components measured are posted on their web page (www.atherotech.com). All lipid risk factors are directly measured in a single test using 40 micro liters of plasma (as little as a finger stick sample). Atherotech's technology uses ultracentrifugation, which is the gold standard for the measurement of cholesterol.
Management of Small Particle LDL Syndrome
Aggressive high-dose niacin therapy is very effective in neutralizing abnormal HDL and LDL production, bringing the patient toward a more normal lipid risk profile (Superko, 1996). Alternative therapies include bile-acid binding agents and fibrates. Daily aspirin therapy is also beneficial to prevent the sudden clotting which is the product of ruptured, unstable plaques.
Dietary changes are also beneficial. Fat-switching away from saturated fats to monounsaturated fats has a profound effect on LDL sub-fraction composition. Olive oil, peanut butter, avocados, and deep-sea fish are good sources of monounsaturated fats. Patients should stop using butter, whole milk, eggs, fatty meats, bacon, and a wide spectrum of snack foods that contain hydrogenated or partially hydrogenated fats.
Research indicates predominance of small, dense LDL particles (subclass pattern B) is associated with higher levels of triglyceride-rich lipoproteins and lower levels of HDL compared with those of individuals with predominantly larger LDL (pattern A). This trait appears to be under the influence of one or more genes and is expressed more in adult males, with pre-menopausal women having some protection. Genetic and metabolic factors underlying LDL subclass pattern B were found to enhance LDL and triglyceride responsiveness to substitution of dietary carbohydrate for fat in premenopausal women, which is similar to a previous study involving men (Dreon, Fernstrom, Williams, & Krauss, 1997). A very-low-fat (10%), high-carbohydrate diet consumed by children of parents who both have LDL pattern B caused a significant proportion of these children to convert from pattern A to pattern B when compared to children of parents where one or both parents exhibit pattern A (Dreon, Fernstrom, Williams, & Krauss, 2000). Men with LDL pattern B consuming high-fat diets (40-46% fat) showed two times the reduction in LDL-C from a low-fat diet (20-24% fat) compared to men with LDL pattern A. In addition, plasma apolipoprotein (apo) B levels decreased significantly (Dreon, Fernstrom, Miller, Krauss, 1994). Lipid response to dietary management is complex and lowering dietary fat is not always beneficial. One-third of men with LDL pattern A consuming a very low-fat diet (10%) converted to LDL pattern B and exhibited higher ApoB compared to men on a diet of 20-24% fat (Dreon, Fernstrom, Williams, & Krauss, 1999).
Cardiovascular disease is a result of a complex interaction of inherited susceptibility and environmental issues (Superko, 1997). Most individuals with coronary artery disease do not have hypercholesterolemia. LDL pattern B is only one of a number of cardiovascular conditions with a hereditary component. The importance of taking a complete and accurate family history cannot be overemphasized. With heart disease as the number one cause of death in the United States, nurses in all areas of practice are likely to encounter patients who may have unrecognized hereditary factors that increase their risk for a heart attack at an early age. As frontline care-providers, nurses can provide crucial screening for heart disease that can trigger the proper diagnostics to identify those patients at high risk of heart attack.
Karen Greco, MN, RN, ANP
Karen Greco, MN, RN, ANP is an oncology nurse practitioner in Portland, Oregon. She is currently pursuing her doctorate in nursing with a minor in genetics at Oregon Health Sciences University where she also received her Masters in Nursing. Karen received her undergraduate degree in Nursing from the University of Nevada. Her recent experience and interest is in the management of patients with a genetic predisposition to cancer.
Matthew Bayan has over twenty-five years experience managing health-related programs, holding positions such as: New England Regional Director of the USDA Special Supplemental Food Program for Women, Infants, and Children (WIC), Chief of the Bureau of Nutrition in the Iowa Health Department, and Chief of Operations in the Nevada Medicaid Program. He is now a full-time writer and speaker on a mission to inform the medical community of the dangers of HeartStopper genes.
Atherotech. (2000). Test benefits. Birmingham, AL: Author. Retrieved September 11, 2000 from the World Wide Web: www.atherotech.com/test_ben.htm
Austin M. A., Breslow, J. L., Hennekens, C. H., Buring, J. E., Willett, W. C., Krauss, R. M. (1988). Low-density lipoprotein subclass patterns and risk of myocardial infarction. Journal of the American Medical Association, 260(13), 1917-1921.
Austin, M. A., Stephens, K., Walden, C. E., & Wijsman, E. (1999). Linkage analysis of candidate genes and the small, dense low-density lipoprotein phenotype. Atherosclerosis, 142(1), 79-87.
Dawber T. R. (1980). The Framingham Study. Cambridge, MA; Harvard University Press, 1980
Dreon, D. M., Fernstrom, H., Miller, B., Krauss, R. M. (1994). Low density lipoprotein subclass patterns and lipoprotein response to a reduced-fat diet in men. Federation of American Societies for Experimental Biology (FASEB) Journal, 8,121-126.
Dreon, D. M., Fernstrom, H. A., Williams, P. T., & Krauss, R. M. (2000). Reduced LDL particle size in children consuming a very-low-fat diet is related to parental LDL-subclass patterns [see comments]. American Journal of Clinical Nutrition, 71(6), 1611-6.
Dreon, D. M., Fernstrom, H. A., Williams, P. T., & Krauss, R. M. (1999). A very low-fat diet is not associated with improved lipoprotein profiles in men with a predominance of large, low-density lipoproteins. American Journal of Clinical Nutrition, 69(3), 411-8.
Dreon, D. M., Fernstrom, H. A., Williams, P. T., & Krauss, R. M. (1997). LDL subclass patterns and lipoprotein response to a low-fat, high-carbohydrate diet in women. Arteriosclerosis, Thrombosis & Vascular Biology, 17(4), 707-14.
Genest, J. J., Martin-Munley, S. S., McNamara, J. R., Ordovas, J. M., Jenner, J., Myers, R.H., Silberman, S. R., Wilson, P. W., Salem, D. N., Schaefer, E. J. (1992). Familial lipoprotein disorders in patients with premature CAD. Circulation, 85, 2025-2033.
Juo, S. H., Bredie, S. J., Kiemeney, L. A., Demacker, P. N., & Stalenhoef, A. F. (1998). A common genetic mechanism determines plasma apolipoprotein B levels and dense LDL subfraction distribution in familial combined hyperlipidemia. American Journal of Human Genetics, 63(2), 586-94.
Parhofer, K. G., Barrett, P. H., & Schwandt, P. (1999). Low density lipoprotein apolipoprotein B metabolism: comparison of two methods to establish kinetic parameters. Atherosclerosis, 144(1), 159-66.
Raungaard, B., Heath, F., Hansen, P. S., Brorholt-Petersen, J. U., Jensen, H. K., & Faergeman, O. (2000). Flow cytometric assessment of LDL ligand function for detection of heterozygous familial defective apolipoprotein B-100. Clinical Chemistry, 46(2), 224-33.
Superko, H. R. (1998). Small Dense LDL: the new coronary artery disease risk factor and how it is changing the treatment of CAD. Preventive Cardiology, Winter 1998, 17-24.
Superko, H. R. (1997). The New Thinking on Lipids and Coronary Artery Disease. Current Opinion in Cardiology, 12, 180-187.
Superko, H. R. (1996). Lipid Disorders Contributing to Coronary Heart Disease -- An Update. Current Problems in Cardioliology, 21, 733-780.
Williams, R., Hopkins, P., Stephenson, S., Wu, L., Hunt, S. (1999). Primordial prevention of cardiovascular disease through applied genetics. Preventative Medicine, 29, S41-S49
American Heart Association:
Author's Web site including information about his book, which tells his personal story about living with small particle lipid syndrome, and information about the condition itself:
National Heart, Lung & Blood Institute:
Periodic mailing of an online literature summary, Medscape Cardiology MedPulse, from peer reviewed cardiac journals with hyperlinks to the articles without charge:
Laboratories offering testing for small-particle lipid syndrome:
1311 Harbor Bay Parkway, Suite 1004
Alameda, CA 94502
877 - 454-7437 (toll free)
3009 New Bern Avenue
Raleigh, NC 27610
877-547-6837 (toll free)