Hearts & Arteries

The exercise physiology laboratory at the National Institute on Aging looks like a den of electronic wizardry. Computer terminals dot the room, one right next to the treadmill, two perched high on a cabinet, one on a rolling cart, one mounted on the wall. Here and there other instruments rest, quiet at the moment or blinking just a little. So the sound of splashing liquid comes as a surprise. "I keep thinking how noisy the body must be," says Eileen Shields, a marketing director for Carroll County, Maryland, who is here for an echocardiogram. The rhythmic, echoing splashes that fill the room come from a slim, silver-colored tube held gently against the pulse in her carotid artery. The sound is matched by digital waves that dance across the nearby computer terminal, recording the flow and pressure of blood. Shields is a volunteer in a study that is looking for fresh clues to heart health in a well-known phenomenon: the gradual stiffening of arteries that occurs as people grow older. Arterial stiffening has been known by various names - hardening of the arteries, vascular stiffness, arteriosclerosis - and scientists have long thought that it played a role in diseases like atherosclerosis and high blood pressure. But they now have evidence that its impact may reach beyond the blood vessels. "We suspect that stiffness affects both the heart's structure and its function," says Jerome Fleg, a scientist in the NIA's cardiovascular laboratory, "and we want to know how they match up. Do people with the stiffest arteries have the thickest heart walls? Do their hearts pump out smaller volumes of blood with each beat?" As they sort out the links between the arteries and the heart, Fleg and his colleagues hope they'll also gain insight into exactly how stiffness relates to disease. Arterial stiffening has long been considered a normal part of aging in industrialized societies. However, in some people, for reasons not yet understood, this common condition turns into a disease process. Stiffening of the arteries is the major cause of high blood pressure in older people, which in turn is a leading risk factor for stroke, coronary artery disease, heart attack, and heart failure. And now stiffening is suspected of making arteries more prone to the cellular processes that underlie atherosclerosis, another key precursor of heart disease and stroke (see What Happens During Atherosclerosis). Aging is still considered the major risk factor for these diseases. But some early evidence from the Fleg's studies and those of others suggest that lifestyle may also play a key role. Low-salt diets and regular aerobic exercise may reduce arterial stiffness.

Age and Arteries

What made scientists think there might be a link between blood vessel stiffness and heart function in the first place? It goes back to what they have learned about both over the last few decades, partly through the Baltimore Longitudinal Study of Aging, in which Eileen Shields is one of about 1,200 participants. The volunteers range in age from 20 through 90 plus. And the scientists, by comparing younger and older volunteers, have been able to put together a picture of what happens in both heart and blood vessels as people age. The heart, they have learned, adjusts to age in many subtle and interconnecting ways: It develops thicker walls, and it fills with blood and pumps the blood out in a different pattern and even by somewhat different mechanisms than when young. The large, elastic arteries that are closest to the heart also change in complex ways. Picture an animated computer graphic of the arteries at, say, age 25, when the walls are compliant. The largest artery in the body, the aorta, leads away from the heart, first up toward the neck, where the carotid artery branches off to take blood to the head and brain, and then down toward the rest of the body. When the aortic valve opens, the aorta receives the rushing pulse of blood from the heart. It also receives pressure spreading from the walls of the heart to its own walls. This pressure travels along the aorta's walls in wave after wave until it reaches the walls of the smaller, branching arteries that take the blood to the rest of the body. There the waves of pressure slow and some are sent back through the aorta walls, becoming what are called wave reflections. Now add, say, 50 years to this picture. The arteries, including the aorta, grow stiffer, their walls thicker, the diameters larger. The stiffer walls no longer expand as much as blood flows through them. Eventually, the resistance of the stiffer aorta walls increases significantly. Commonly it doubles over a lifespan and contributes to the increase in systolic blood pressure that often accompanies aging. Along the walls of the stiffer aorta, the pressure waves now move more rapidly, and as a result, the wave reflection occurs sooner than it did before. The timing of the wave reflection, in fact, is one of the effects of arterial stiffness that can be measured noninvasively (see Measuring Stiffness). As the blood moves on into the smaller arteries, the hydraulics change. The pulse smooths out, the flow becomes more steady. The opposition to this steady flow is known as peripheral vascular resistance or PVR; so far studies show that among men, resting PVR does not change with normal aging, but that it does rise somewhat in women. In most people with high systolic blood pressure, PVR is elevated. Next, picture the effects of movement-when a person sits up, stands up, or begins to walk or run. The heart rate increases and blood pressure rises. A group of pressure-sensitive nerves in the aorta respond to the changes in pressure by sending a message to the brain. The brain in turn sends a message back to the heart, which changes its rate and strength of contraction. This aorta/brain/heart message system is called the baroceptor response. Blood vessels also dilate to allow for the extra blood flow. In addition, blood is turned away temporarily from those muscles that don't need it (for instance, the stomach), so that more can be delivered to the working muscles. Blood flows from the heart through the arteries (red blood vessels) and back to the heart through the veins (blue blood vessels). Age brings changes in the arteries. In the older picture, the baroceptor response is blunted, perhaps as a result of stiffer arteries; the nerves in the aorta could be affected by increasing stiffness. Also at maximum exercise, the large arteries do not dilate as much as in the younger picture. These in brief outline are some of the major changes that occur in blood vessel hydraulics with age. One reason these changes intrigue scientists is that they could have a major impact on heart dynamics. Stiffening increases the amount of resistance the heart must overcome to eject blood into the arteries, and any resistance to flow places a load on the heart. The study in which Eileen Shields is a participant will show the impact of this load.

Exercise and Diet

Perhaps most intriguing of all is the difference that lifestyle may make in arterial stiffness. In one of the tests that study participants routinely take, they walk on a treadmill at increasing speeds until they are exhausted. The test measures physical fitness by gauging oxygen consumption at peak exercise or VO2 max. The individuals who can walk on the treadmill for the longest period, i.e., those who are most physically fit, have the least stiff arteries, according to a study by Fleg and his colleagues. The more the volunteers in this study were able to exercise, the less stiff their arteries. Having learned that physical fitness was linked to less stiff, more compliant arteries, the scientists wondered about cause and effect: Does regular exercise, which increases physical fitness, actually cause less stiff, more compliant arteries? The answer is a cautious "maybe" according to the next study. In this one, the researchers measured arterial stiffness in a group of endurance-trained men, age 54 to 75, and compared them to sedentary men of the same age. The scientists also compared the older group to younger sedentary men. The exercise capacity of the older athletes was similar to that of younger men and greatly surpassed that of the older group. Most striking of all,the arterial stiffening in the older athletes was far less than in their sedentary counterparts. "This demonstrates that endurance training may give us at least some control over the condition of our arteries, a variable we thought controlled us," says the NIA's Edward Lakatta.

Over time, changes in arterial stiffness are much more marked than changes in blood pressure and may be a better gauge of cardiovascular health. New, reliable measures of arterial stiffness are currently used only by researchers but could someday be a prognostic and clinical tool. The new tests gauge stiffness by measuring the speed of pulse waves - the waves of pressure that travel down artery walls as blood pulses through them. In one test, researchers monitor pulse waves at two spots, one near the ascending aorta and one on the femoral artery in the thigh, then calculate the time it takes the wave to travel from neck to thigh. The faster the blood flows, the stiffer the arteries. "It's pure hydraulics," says Amit Nussbacher, a post-doctoral fellow in NIA's Laboratory of Cardiovascular Science, who conducts these tests as part of the laboratory's studies of vascular stiffness. In still-compliant arteries, he explains, waves of pressure travel more slowly; stiffness speeds them up. The second test monitors wave reflections in the walls of the aorta. Wave reflections occur when the pulse waves encounter the smaller arteries that branch off this large artery. The waves of pressure are bounced or reflected back along the walls of the aorta, augmenting the pressure from the oncoming waves. This means that if the wave reflection shows up soon after the heart's contraction (as measured by a simultaneous electrocardiogram), then the aorta is relatively stiff. If it occurs later in the cardiac cycle, i.e., after the aortic valve closes, there is less stiffness. A computer program translates the timing of the wave reflection into a number known as the augmentation index. The higher the augmentation index, the greater the stiffness of the arteries.

Control over the condition of our arteries may also lie in how much salt we consume. In cultures where little sodium (in the form of salt) is consumed, blood pressures do not rise with age as they do in western countries. Cultural differences have also been found in arterial stiffness. One study compared rural and urban populations in China. The urban population consumed much higher levels of salt than the rural groups. And they had stiffer arteries. Now a study in Taiwan is following up on this finding by comparing two other rural and urban groups. However this one is looking not only at arterial stiffness but also at heart structure and function. Early results show that among those with the stiffest arteries, heart walls were thicker, according to Harold Spurgeon who heads this study at the NIA's Baltimore laboratory. Some of the next questions facing cardiovascular researchers center on the cells and molecules of the cardiovascular system. How, can exercise keep arteries more compliant? It may be that exercise triggers a chain of events within the cells of the arterial walls that ends by reducing collagen and increasing elastin. Ultimately, cardiovascular scientists think, the puzzle of arterial stiffening will come down to the biochemistry and biophysics of the cardiovascular system, a vast territory with many regions still to be explored. Selected Readings Avolio AP, Chen SG, Wang RP, Zhang CL, Li MF, and O'Rourke MF. Effects of aging on changing arterial compliance and left ventricular load in a northern Chinese urban community. Circulation 68:50-58, 1983. Avolio AP, Deng FQ Li WQ Luo YF, Huang ZD, Xing LF, and O'Rourke MF. Effects of aging on arterial distensibility in populations with high and low prevalence of hypertension: Comparison between urban and rural communities in China. Circulation 71:202-210, 1985. Vaitkevicius PV, Fleg JL, Engel JH, O'Connor FC, Wright JG, Lakatta LE, Yin FCP, and Lakatta EG. Effects of age and aerobic capacity on arterial stiffness in healthy adults. Circulation 88:1456-1462, 1993. Yin FCP, Weisfeldt ML, and Milnor WR. Role of aortic input impedance in the decreased cardiovascular response to exercise with aging in dogs. Journal of Clinical Investigation 68:28-38, 1981.

The brain talks to the heart through the nervous system, using the language of biochemistry. Substances called neurotransmitters travel from nerve cell to heart cell, deliver the brain's message by binding with special receptors on the membranes of the heart cells, and set off a chain of molecular events that ends with a faster beating heart, stronger contractions, and faster relaxation between beats. Or, depending on what neurotransmitter is used, the brain can tell the heart to reverse all these effects. This, in broad outline, is the autonomic nervous system which controls involuntary muscles, such as the heart. Somewhere in the lines of communication, as we age, a weak link appears. Where it is and how it muffles the brain's messages are two of cardiovascular science's unsolved mysteries. Scientists have narrowed the search, however. One class of neurotransmitters, catecholamines, abound during exercise or other kinds of stress. They could be involved. Also suspect are the beta adrenergic receptors to which catecholamines bind. Researchers like Frank Yin at NIA, now at Johns Hopkins, have tried to determine whether the supply of catecholamines could be the problem. Yin infused catecholamines into the blood streams of older and younger volunteers to simulate the effect of exercise. He found, as expected, that the young men's heart rates increased. But the older men's heart rates increased less, even though they received the same supply of catecholamines. So the problem was not the supply. Could the problem then be somewhere in the aging cardiovascular system's response to catecholamines? Studies have shown that this is probably the case. There is a drug called propranolol, which blocks the body's response to catecholamines by blocking the beta adrenergic receptors on heart and blood vessel cells. Propranolol and aging have the same effect, according to a number of studies. Older hearts and blood vessels, apparently, have blocked beta adrenergic receptors. What could be the underlying causes of the blunted response? Scientists turned to the beta receptors on heart cells: Did their number decline with age? Not according to studies of circulating human blood cells with receptors similar to those on animal hearts. But the researchers found that something else about the receptors does change; the number ready to bind with the catecholamines, i.e., those in a "high affinity state," seems to decline with age.The reason for the reduced response could lie anywhere in the cascade of events in heart muscle cells that occurs after the catecholamine binds to the receptor. Scientists are finding a host of possible cellular mechanisms that might explain the reduced response. They hope that once the mechanisms are understood, they will be able to find a way to mend the link or prevent it from muffling messages in the first place. Eventually such findings could lead to new ways to prevent heart failure. Yin FCP, Spurgeon HL, Raizes GS, Greene HL, Weisfeldt ML, and Shock NW. Age-associated decrease in chronotropic response to isoproterenol. Circulation 4/Supplement 2:II-167, 1976.