Microbes and Genes
One somewhat surprising potential risk factor is the presence of bacteria and viruses in the blood. While these microbes may not directly cause heart disease, the infection they do cause appears to affect the endothelium, a thin, protective layer of cells that lines blood vessels. The result may be atherosclerosis, in which deposits of smooth muscle cells, calcium, and cholesterol build up, reducing blood flow through the coronary arteries that provide blood to the heart. Such deposits, called plaques, also provide sites where clots may form, further blocking blood flow and setting the stage for heart attack.
Researchers at Cornell University have done pioneering work implicating an avian herpesvirus as the cause of an atherosclerosis-like disease in chickens. Biochemist David P. Hajjar of Cornell Medical School has expanded that work to humans. He has demonstrated that the common herpes simplex virus can stimulate the production of “blood factor X,” a binding protein that helps anchor other proteins to the blood vessel wall, where they form atherosclerotic plaques. The lab team has also shown that herpesvirus prompts the production of thrombin, a blood-clotting enzyme, which makes impaired blood flow even more likely.
The U.S.-based study Atherosclerosis Risk in Communities, begun in 1987 and conducted on 16,000 men and women ranging in age from 45 to 64, is providing still more evidence that viruses may help bring on atherosclerosis in people. The project manager, epidemiologist A. Richey Sharrett of the National Heart, Lung, and Blood Institute in Bethesda, Md., says the subjects’ blood samples, which have been checked for antibodies that the body manufactures in response to specific viruses, have also been tested for clot-promoting factors, as well as for lipoproteins, the fatty proteins that envelop cholesterol and carry it through the bloodstream. One type is high-density lipoproteins (HDLs), which appear to protect against atherosclerosis; another major kind, low-density lipoproteins (LDLs), tend to promote the development of cholesterol-laden plaques within arteries.
Interestingly, blood samples with antibodies for type one and type two herpesviruses have turned up the kinds of clot-promoting factors and lipoproteins suggestive of heart-attack risk. And researchers have found that the same is true of blood samples with antibodies to cytomegalovirus, another virus of the herpes family. They have also noted a strain of bacteria called chlamydia pneumoniae in people with atherosclerotic plaques. University of Utah scientists reported in June 1996 that they had discovered this strain of bacteria in diseased tissue taken from 66 of 90 patients who underwent surgery to clear a blocked coronary artery. Evidence of the bacteria appeared in only 1 of 24 patients who did not have coronary disease.
Another promising area of study is genetics: researchers, including many cardiologists, are intrigued by the possibility of a family of heart-attack genes. Some especially troublesome members of this family are the recently discovered genes for “long QT syndrome,” a disease affecting children and young adults. It strikes insidiously, much like crib death. The warning signs are spells of fainting during exercise, unconsciousness during sleep, or episodes of sudden fright or other unexplained emotional distress. The peculiar name of the syndrome derives from the way electrocardiograms, which track electrical activity in the heart, are recorded: readings for each heartbeat are divided into a waveform with key reference points called P-Q-R-S-T. With long QT, the interval between Q and T is 500 to 600 milliseconds at a heart rate of 60 beats per minute, in contrast to the normal interval of 400 to 440 milliseconds. Long QT engenders irregular heartbeat and an insufficient supply of blood to the brain. This can cause a brain seizure, leading to death.
Other genes can increase the likelihood of a heart attack by causing structural problems in major blood vessels and in the muscle walls of the heart. For instance, cardiomyopathies, inherited disorders that make the muscle walls either too thick or too thin, result in enlarged hearts with dramatically reduced pumping efficiency. Still other gene defects interfere with the way the body handles salt, thereby bringing on high blood pressure, a notorious heart-attack risk factor: it wears down blood vessels and thus promotes atherosclerosis. An estimated 15 to 20 percent of the U.S. population has a genetically determined sensitivity to salt that is expressed as high blood pressure when they consume too much of it.
Even more leads are pouring in from genetic studies on the enzymes and lipoproteins that determine how effectively the body deals with cholesterol. Geneticists Joseph Goldstein and Michael Brown at the University of Texas Southwestern Medical Center have isolated the “LDL receptor”-the cellular mechanism that keeps harmful LDL cholesterol from accumulating in the body’s tissues and bloodstream. Those who lack the gene that allows them to manufacture such receptors develop a life-threatening condition called familial hypercholesteremia (FH), which can result in astronomical levels of cholesterol and early death from heart attack.
And physician Ronald Krauss and his associates at the University of California, Berkeley, have discovered a particle called “small, dense LDL” that they believe is the form of LDL most likely to cause atherosclerosis, because of its ability to penetrate the blood vessel wall. This particle seems to be influenced by a single dominant gene, Krauss says, and he estimates that up to one-third of people over age 40 have that gene and run triple the heart-attack risk of those without it. Moreover, levels of small, dense LDL are closely related to blood levels of triglycerides, another lipoprotein that has itself been proposed as a major risk factor for coronary artery disease.
Research in other areas is also advancing scientists’ understanding of the genes behind atherosclerosis. Physician Daniel Steinberg of the University of Southern California in San Diego believes that LDL molecules do their damage when they are oxidized-and that this happens when they are captured by oxygen-like molecules called free radicals. The connection with genetics comes from physician Alan M. Fogelman at UCLA’s Atherosclerosis Research Unit, who has shown that when mildly oxidized LDL is injected into mice, troublesome genes similar to those found in humans begin to create harmful proteins; those proteins in turn cause the endothelium to become inflamed. These results suggest that “the inheritance of one or more major genes can determine susceptibility or resistance to the development of the inflammatory component of atherosclerosis,” he notes.