PHYSIOLOGICAL CHANGES, ORGAN SYSTEMS: CARDIOVASCULAR

The cardiovascular system undergoes a large number of changes with advancing age, some of which occur in the apparent absence of disease; and many of which are either caused by, or exacerbated by, disease. Cardiovascular diseases comprise a group that accounts for nearly one-half of all deaths in the United States. The incidence of noncongenital cardiovascular maladies, e.g., congestive heart failure, increases dramatically with advancing age (see Figure 1). Cardiovascular diseases conspire with advancing age and a number of unhealthful lifestyle factors (e.g., smoking, physical inactivity, high-fat diet) to create the dangerous scenario that leads to a high incidence of cardiovascular events (heart attack, stroke) in older persons. To understand how aging contributes to cardiovascular disease and dysfunction, it is necessary to define the changes that occur "naturally" with advancing age in apparently healthy individuals without detectable cardiovascular disease.

Heart structure and function at rest

Changes in heart size and shape with advancing age. The left ventricle (LV) is the largest heart chamber in terms of muscle mass and pumps blood, under pressure, to the entire body (see Figure 2, Panels A and B). Studies of volunteer subjects without cardiovascular disease, indicate that, at rest, the LV cavity size at enddiastole (filled) and end-systole (emptied), increases moderately with age in healthy, normotensive, sedentary men, but does not vary with age in women. The LV wall thickness increases progressively with age in both sexes. The age-associated increase in left ventricular wall thickness is caused mostly by an increase in the average size of cardiac myocytes (muscle cells). An increase in the amount of, and a change in the physical properties of, collagen (a protein that holds the myocytes together) also occurs within the myocardium with aging. In summary, the heart of a normal healthy older individual is somewhat larger, and slightly stiffer, than that of a younger person.

There is an increase in elastic and collagenous tissue in all parts of the heart's conduction system with advancing age (see Figure 2C). Fat accumulates around the sinoatrial (SA) node, sometimes producing a partial or complete separation of the node from the atrial musculature. Beginning by age sixty, there is a pronounced decrease in the number of pacemaker cells in the SA node, and by age seventy-five less than 10 percent of the pacemaker-cell number found in the young adult remains. A variable degree of calcification of the left side of the cardiac skeleton, which includes the aortic and mitral annuli, the central fibrous body, and the summit of the interventricular septum, occurs with aging. Because of their proximity to these structures, the atrioventricular (AV) node, AV bundle, bifurcation, and proximal left and right bundle branches may be affected by this process. These structural changes in the cardiac conduction system are associated with a number of functional changes that can be observed in the electrocardiogram of an elderly person.

Age-associated changes in heart function at rest. When a person is in the sitting position, the resting heart rate decreases slightly with age (in both men and women). Tiny beat-to-beat variations in resting heart rate are normal, and become diminished with advancing age. This decreased heart-rate variability is likely related to changes in the parasympathetic and sympathetic nervous systems as an age. The P-R interval is the time it takes for the signal that initiates the heartbeat to travel from the conduction system in the heart (the AV node and the AV bundle). A modest prolongation of the P-R interval (see Figure 2D) of the electrocardiogram occurs with aging in healthy individuals, and is localized to the proximal P-R interval, probably reflecting delay within the atrioventricular junction. An increase in the number of premature beats occurs in healthy older men and women compared to their younger counterparts. These changes in the regulation of the heartbeat by the nervous system and the cardiac conduction system are observed in normal healthy individuals as they age, and although they do not by themselves interfere with heart function, they are associated with an increased risk of adverse heart events. More severe changes in the cardiac conduction system are associated with diseases and are often treated by implanting an artificial pacemaker.

The peak rate at which the LV fills with blood during early diastole is reduced by 50 percent between the ages of twenty and eighty. The time course of early myocardial relaxation becomes prolonged by 40 percent with adult aging in both men and women, probably due to alterations in LV wall structure and collagen properties and changes in the relaxation phase of cardiac muscle contraction. Different parts of the ventricle relax at different rates in hearts of older individuals, and this contributes to the reduction in the filling rate. The age-associated reduction in the early filling rate does not result in a reduced end-diastolic volume in healthy older individuals, because greater filling occurs later in diastole, particularly during the atrial contraction. The enhanced atrial contribution to ventricular filling with advancing age is associated with left atrial enlargement, and a more forceful atrial contraction. So, although ventricular filling in a resting older person is accomplished differently, it is as adequate as ventricular filling in a younger person.

The contractility, or strength, of heart muscle contraction is not reduced at rest with age in either healthy men or women. The LV ejection fraction (EF) is also not altered with aging in healthy men or women at rest. The stroke volume index (SVI; amount of blood pumped per beat/ body surface area) is increased in males, due to a slight increase in the LV end-diastolic volume. Thus, in healthy older men, the cardiac output (amount of blood pumped per minute) is not reduced, because the stroke volume index is increased, due to end-diastolic enlargement Cardiac output at rest is slightly decreased in older women (compared to younger healthy women) as neither the resting end-diastolic volume (EDV) nor SV increases with age to compensate for the modest reduction in heart rate. These gender differences appear to be an artificial effect of differences in body composition—the proportion of body fat increases with age in women to a greater extent than in men. If one compares the younger and older heart at any point during the resting heartbeat, the older heart contains more blood. Therefore, at rest, the heart of an older healthy individual pumps blood as well as the heart of a younger person, but does so in a slightly different manner.

Reserve capacity of the heart

At rest, the heart of an average person pumps approximately five liters of blood per minute (cardiac output). The cardiac output can increase dramatically when demand for blood flow increases during physical activity. During maximal exercise, the cardiac output can be as high as thirty-five liters per minute. This tremendous capacity of the heart to increase its pumping ability is accomplished by increasing the heart rate and stroke volume and is termed the reserve capacity of the heart. The heart rate and stroke volume can be measured during exercise to assess the reserve capacity of the heart, and the overall capacity of the body to exercise is assessed by measuring the maximal rate of oxygen consumption (VO ₂ max). The reserve capacity of the body is important for two reasons. First, it allows an individual to meet the needs required by physical work and play. Second, the reserve capacity of the heart provides a margin of safety that allows one to survive the effects of cardiovascular diseases.

Exercise response. The peak work rate and oxygen consumption of healthy, sedentary men and women during upright, seated, bicycle exercise, declines by approximately 50 percent with advancing age between twenty and eighty years of age. This is attributable to approximate declines of 25 percent in cardiac output and 25 percent in oxygen utilization (the ability of the skeletal muscles to extract oxygen from the blood and the ability of the vascular system to deliver blood [(A-V)O ₂ difference, see Table 2]). The age-associated decrease in cardiac output is during peak exercise is due entirely to a reduction in maximal heart rate, as the stroke volume index does not decline with age in either men or women. However, the manner in which stroke volume is achieved during exercise varies dramatically with aging. The EDV increases during vigorous exercise in older, but not younger, men and women (see Figure 4). But, because the end-systolic volume (ESV) in older persons fails to become reduced to the same extent as in a younger individual, the percentage of the total blood ejected per beat (EF) decreases, and the SV is not greater, in older persons. In other words, while the Frank-Starling mechanism (a unique property of the heart that results in a stronger heartbeat when more blood is present in the heart at the beginning of a contraction) is utilized in older persons during exercise, its effectiveness is reduced because the LV of an older person does not empty to the extent to which it does in younger individual. Thus, the older heart, while contracting from a larger preload (amount of blood in the ventricle at beginning of contraction) than the younger heart at all levels of exercise, delivers a stroke volume that equals that of the younger heart.

The deficiency in the ability of the old heart to "squeeze down" and reduce LV end-systolic volume during exercise in healthy older individuals likely results from increased stiffness of the arteries, from decreased contractility of the heart muscle, and from a decline in the response of the heart to the sympathetic nervous system (β-adrenergic responsiveness).

β-Adrenergic modulation of cardiovascular performance. During exercise, excitement or stress, the sympathetic nervous system becomes activated and releases norepinephrine and epinephrine (commonly referred to as adrenaline). Norepinephrine and epinephrine act in the heart by binding to β-adrenergic receptors and increases both the heart rate and the strength of contraction. β-adrenergic receptors mediate the effects of the hormones/neuro-transmitters norepinephrine and epinephrine (commonly referred to as adrenaline). They are important in regulating the heart rate and strength of each beat. Without β-adrenergic receptors, the adrenaline produced by the nerves and adrenal gland, would have no effect on the heart. One of the most prominent changes in the cardiovascular response to exercise stress that occurs with aging in healthy individuals, is a reduction in the ability of norepinephrine and epinephrine to activate the β-adrenergic system of the heart, thereby limiting the maximum heart rate and the strength of contraction in the aging heart. Resting sympathetic nervous activity increases progressively with aging, as does the sympathetic response to any perturbation from the resting state. Plasma levels of epinephrine and norepinephrine increase with age, due to enhanced spillover into the circulation and to reduced clearance. The increased spillover does not occur from all body organs, but is increased within the heart, and is thought to be due, in part at least, to a reduced reuptake by the nerve endings following release. The net result is likely an enhanced post-synaptic receptor occupancy by neurotransmitter, leading to β-adrenergic receptor desensitization. Deficits in β-adrenergic signaling with aging are attributable, in large part, to changes in enzymes and proteins that relay the signals from the β-adrenergic receptor to the molecules inside the heart muscle cell that control the rate and force of contraction.

Vascular structure and function at rest

Vascular changes occur with aging among sedentary volunteers who are considered to be otherwise healthy. The large elastic arteries exhibit an increase in wall thickness and become dilated. Age-associated changes within the vessel media (middle muscular layer of the artery wall), which account for the increase in the diameter of conduit arteries, result from many factors including a relative decrease of elastin (a structural protein with elastic properties) and an increase of collagen (a rigid structural protein). Many chemical properties of elastin deteriorate and the elastin fibers become frayed, resulting in an increased stiffness of the arteries.

With advancing age, the increased pulse-wave velocity, due to increased arterial stiffness, causes pulse-wave reflections from distal arterial branch points to arrive back at the origin of the large arteries prior to closure of the aortic valve, imparting a late augmentation of the systolic pressure and the pulse pressure (the difference between systolic and diastolic pressures). The diastolic pressure amplification due to the normal occurrence of the reflected waves in diastole is reduced in older individuals, and this is associated with a poorer prognosis for patients with cardiovascular diseases.

As a result of arterial stiffening and early reflected pulse waves, the average systolic blood pressure within a healthy, normotensive population increases (within the normal range) with aging, whether measured in a cross-sectional study design or longitudinally. Many individuals show little or no longitudinal increase in systolic pressure, and age-associated increases in blood pressure are therefore neither universal nor inevitable. The average increase in diastolic pressure with aging is modest and is not as marked as the average increase in systolic pressure. An increase in peripheral vascular resistance (PVR; opposition to flow) accompanies aging in some, but not all, individuals, and may be secondary to a reduction in skeletal muscle mass with aging and its a concomitant reduction in capillary density. In healthy men PVR, measured at rest, increases minimally with aging, and it increases moderately in women.

Effects of regular exercise

Regular aerobic exercise impacts cardiovascular function directly by improving the reserve capacity of the heart. The exercise capacity of both inactive persons and highly trained athletes declines with age at a similar rate (see Figure 5). While regular exercise does not prevent aging, individuals at any age can improve their cardiovascular fitness to the same extent by engaging in a program of regular aerobic exercise. For example, a highly trained and fit seventy-five year-old may achieve a maximal oxygen consumption (VO _2max) similar to that of a thirty-five year-old inactive individual. Physical inactivity is a major risk factor for cardiovascular diseases in industrialized countries—it has been estimated that 250,000 Americans die prematurely from improper diet and lack of exercise each year. Thus, older individuals may benefit from regular aerobic exercise as much as, or even more than, younger persons.

Figure 2: figure legend

Figure 2 shows the basic anatomy of the human heart and its conduction system. Here is a more detailed version of the caption that accompanies that image: Panel A shows the front view of the heart cut vertically. Panel B shows a front view of the heart cut horizontally. Panel C is a front view of the heart cut vertically to show how the signal to begin a heart beat is initiated in the sinoatrial node and conducted to the rest of the heart by the atrioventricular node and bundle, the bundle branches, and the purkinje fibers. Panel D is an electrocardiogram showing how electrical events in the cardiac conduction system relate to P, QRS, and T waves.

Marvin O. Boluyt Edward G. Lakatta

See also Excercise; Heart Disease; High Blood Pressure.

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