Hearts & Arteries

The last two decades have revolutionized scientists' ideas about what happens in aging hearts and arteries. The next two could be just as rich in findings, particularly concerning the cells, molecules, and genes of the cardiovascular system. Here is a sampling of current questions that interest cardiovascular scientists.

Why do heart muscle cells grow larger?

Myocytes have to work harder when arteries get stiffer or when heart disease sets in; this may be one reason they get larger. But what actually happens in these cells to trigger their growth? So far, there are only a few clues. One part of the process may involve chemical substances called growth factors, such as norepinephrine and angiotensin. Another factor may be the death of some myocytes. These cells are connected, so when one dies, others must stretch to maintain the connections. This observation leads to another key research question.

Why do some myocytes die?

One hypothesis is that they are killed by a lack of oxygen or ischemia. Myocytes begin to die at about the same time that the blood vessels carrying oxygen to the heart begin to degenerate, according to studies with aging rats by Piero Anversa at New York Medical College in Valhalla, New York. Anversa has also observed that the capillaries nourishing the heart decline in aging rats. Another reason that myocytes die could be something quite different. Anversa speculates that programmed cell death or apoptosis could cause the cells to self destruct. "It's simply a hypothesis," he says, "but it is possible that if the myocytes are overloaded, say in response to high blood pressure, that a built-in mechanism activates a suicide program." Apoptosis is a process that has been observed in other cells of the body, where it may be a mechanism for adjusting to development or avoiding harm.

What are the molecular mechanisms that underlie arterial stiffness?

We know that older, stiffer arteries have more collagen in proportion to elastin than younger, more compliant arteries. And we know that the vascular smooth muscle cells in artery walls produce elastin and collagen. But scientists would like to know if there is some change in the vascular smooth muscle cells that affects the production and degradation of the two proteins. And how does this relate to the thickening of the intima layer near the inside wall of the artery?

What is the link between lifestyle and arterial stiffness?

There is mounting evidence that age-associated increases in arterial stiffness and pressure can be modified by diet. With advancing age,the link between stiffness and sodium chloride (salt) becomes stronger. The next step may be intervention studies to learn if cutting down on salt consumption does prevent or slow arterial stiffening. The evidence showing a connection between sedentary lifestyles and stiffer arteries is also growing. The next step here is the design of prospective, longitudinal studies to see how much regular exercise and what kinds of exercise are most likely to prevent stiffness.

Atherosclerosis and stiffness: Is there a link?

Both increase with age, but is there a biological link? One hypothesis is that stiffness triggers the process that leads to atherosclerosis. Normally vascular smooth muscle cells in the artery are constantly contracting and relaxing, imparting physiologic tone to artery walls. Stiffness could hinder this process. The disruption of vascular smooth muscle cells' natural state could be the trigger that starts them on their migratory path toward the inside surface of the artery, leading to atherosclerosis. This idea is currently under study.

Why and how does the production of some proteins change with age?

Scientists know that the production of certain proteins seems to change with age - for instance the pump protein that removes calcium from a heart muscle cell's inner fluid after each contraction. But where in the production process does the hitch occur? Genes do not constantly produce their proteins; they need to be turned on or activated. How does the message get to a gene that it needs to activate the codes for its proteins? Do these signals changewith age or disease? Figuring out such signal transduction pathways is another critical issue in heart research.

Is it possible and feasible to intervene in the process of normal aging to prevent disease?

If the processes of normal aging do increase the risk of disease, could we intervene in those processes before they get to the danger point? One such intervention is already fairly common: estrogen replacement therapy for women after menopause. Estrogen replacement is thought to reduce the risk of cardiovascular disease and have other benefits, although it may also carry some risk. But what about interventions to keep the heart from enlarging, heart cells from dying, arteries compliant, or the intimal layer of the artery walls from thickening?Some treatments could simply involve changes in lifestyle - starting a regular exercise program, for instance, to prevent arterial stiffening. Several major questions to be answered in the next few decades do center on exercise. For instance: How much and what kind is effective, and what conditions specifically could it prevent? Other interventions could involve drugs. The more we understand about the changes that take place in cells and molecules during aging, the closer we get to the possibility of designing drugs targeted to those changes. Gene therapies can also target specific cellular changes and could potentially be a way to intervene in the aging process. On the level of cells and molecules, however, many mysteries remain. "We still don't know much about the exact mechanisms of how the heart makes the transition from an adaptive to a failure state," says Lakatta. "Why should an organ that has been adapting up to a certain point begin to fail? This is one of the big remaining mysteries." Selected Readings Anversa P, Sonnenblick EH, Olivetti G, Meggs LG, and Capasso JM. Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart. Circulation Research 67:871-885, 1990. Lakatta EG. Cardiovascular regulatory mechanisms in advanced age. Physiological Reviews 73:413-467, 1993. Pauly RR, Passaniti A, Crow M, Kinsella JL, Papadopoulos N, Monticone R, Lakatta EG, and Martin GR. Experimental models which mimic the differentiation and dedifferentiation of vascular cells. Circulation 86 (Supplement III):III68-73, 1992.

Two of the most devastating and common heart problems - coronary heart disease and heart attack - are ischemic diseases; that is they involve a lack of oxygen. Coronary heart disease blocks the coronary arteries and cuts off the heart's supply of oxygen. Heart attack occurs when the heart muscle cells lack so much oxygen that they die. One strategy for increasing the heart's oxygen supply is to increase the number of small arteries, or capillaries, carrying blood to the heart. The body is able to generate new blood vessels, a process called angiogenesis, and it does this with the help of certain growth factors. According to one exciting new hypothesis, if more growth factors could be produced, they might simulate the growth of new capillaries, and new capillaries might alleviate coronary heart disease and prevent heart attack. In NIA's cardiovascular laboratory, Maurizio Capogrossi has been experimenting with ways to increase the supply of these growth factors through gene therapy. Knowing the genes that code for the growth factors, he and his colleagues have found ways to add copies of these genes to heart muscle. To get the genes to the myocytes, they have engineered special carriers for the genes, called adenovirus vectors. Capogrossi and his colleagues first experimented with the adenovirus vectors in laboratory dishes. There, the gene-carrying vectors did include the formation of capillary-like structures in heart muscle tissue. Next they tried injecting the vectors into rats. In this experiment, one of the vectors stimulated capillary growth. The next step will be with larger animals. If this form of gene therapy can stimulate capillary growth, relieve ischemia, and reduce the impact of heart attacks in large mammals, the scientists will begin to consider clinical trials in humans.