Cardiovascular Function

Cardiovascular function is determined by the interaction of several variables, which may be affected by age (see Table 83-2). However, aging does not alter overall systolic cardiac pump function at rest in normotensive elderly persons.

Compliance, Cardiac Filling, and Preload

An age-associated reduction in ventricular compliance remains unproved, because proof would require the simultaneous measurement of pressure and volume; such invasive measurements are not usually attempted in healthy persons.

The early diastolic left ventricular filling rate progressively slows after age 20, so that by age 80, the rate is reduced by up to 50% (see Figure 83-1). This reduction is attributed to structural (fibrous) changes in the left ventricular myocardium or to residual myofilament Ca⁺⁺ activation from the preceding systole, resulting in prolonged isovolumic relaxation.

Although left ventricular filling in early diastole is less in older than in younger persons, filling in later diastole is greater, because the atrial contraction is augmented. Thus, end-diastolic volume in the supine or seated position is not usually decreased in healthy older women and increases slightly with age in men as long as the atrial contraction is normal. The augmented atrial contraction is accompanied by atrial enlargement and is manifested on auscultation as a fourth heart sound (atrial gallop). Lack of an augmented atrial contraction in elderly patients with acute atrial fibrillation or with a pacemaker that does not stimulate atrial contraction can be clinically significant if ventricular function is compromised for other reasons. The result may be heart failure, particularly if the ventricular rate is rapid.

Afterload

The extent to which aging affects afterload (which depends on peripheral vascular resistance, aortic impedance, and aortic pulse wave velocity) varies dramatically from person to person. Some studies have reported that peripheral vascular resistance at rest increases with age. An age-associated increase has been measured in aortic impedance, which is usually < 10% of total vascular impedance.

Aortic pulse wave velocity increases with age. As a result, pressure waves from peripheral sites are returned to the heart more quickly in elderly persons. In healthy elderly men and women, pressure in the aortic root continues to rise and peaks later in systole, thereby altering the pressure pulse contour (see Figure 83-2) and causing a late augmentation of systolic blood pressure. Arterial stiffening, the resulting increase in pulse wave velocity, and late augmentation of systolic blood pressure may explain the overall increase in systolic blood pressure with age. The increase in systolic blood pressure may reflect a resetting of the baroreceptor reflex to a higher level in the elderly. The same structural changes that make the aorta stiffer and cause pulse wave velocity to increase may explain the decreased baroreceptor stimulation required for a given change in aortic pressure. Alternatively, the baroreceptor response may be blunted because of age-associated changes in afferent nerve impulses from the baroreceptors or in efferent nerve impulses to the arterial system.

The increase in resting systolic blood pressure affects resting left ventricular afterload. However, if the increase in systolic pressure remains within normal limits, left ventricular wall thickness may increase sufficiently to normalize wall stress and thus maintain a nearly normal cavity size and ejection fraction.

Myocardial Contractility

Myocardial contractility involves Ca⁺⁺ activation of myofilaments (excitation-contraction coupling). The effects of age on the mechanisms that govern excitation-contraction coupling in cardiac muscle have been studied in animal models. Some of the age-associated changes are partly related to alterations in gene expression. In rats, contractile force production, at least at low stimulation rates, is preserved in old age. Although passive stiffness in isolated cardiac muscle has not been shown to increase with age, stiffness during contraction increases. The increase in myoplasmic Ca⁺⁺ after excitation at low rates and the affinity of myofibrils for Ca⁺⁺ do not change with age. At higher rates of excitation, the amplitude of the Ca⁺⁺ transient (a brief increase in the cytosolic concentration of calcium) is not well characterized with respect to aging.

Relaxation is prolonged in senescent cardiac muscle, probably because Ca⁺⁺ is removed more slowly from the myoplasm during diastole. This slow removal probably occurs because the sarcoplasmic reticulum sequesters less calcium. The action potential lasts longer in senescent cardiac muscle, but the role of this change in prolonging contraction is unclear. Action-potential changes may reflect age-associated changes in sarcolemmal ionic conductances or may result from the prolonged myoplasmic Ca⁺⁺ transient elicited by excitation.

In isolated senescent cardiac muscle, myosin isoenzymes shift to slower forms, and adenosine triphosphatase activity decreases. These changes may explain why shortening velocity decreases during isotonic contraction.

A reduction in the myocardial relaxation rate results in less complete myocardial relaxation when the mitral valve opens and in a reduction in the early diastolic left ventricular filling rate.

Ejection Fraction and Stroke Volume

The resting ejection fraction is not reduced in healthy older men and women. Resting stroke volume increases slightly in older men (commensurately with the slightly larger end-diastolic volume) and remains constant in older women.

Heart Rate

With age, the supine resting heart rate does not change in healthy men; the heart rate while seated decreases slightly in men and women. Spontaneous variations in heart rate during a 24-hour period decrease in men without coronary artery disease, as do variations in the sinus rate with respiration. The intrinsic sinus rate (ie, measured after sympathetic and parasympathetic blockade) decreases significantly with age. For example, the average intrinsic sinus rate is 104 beats/minute at age 20 compared with 92 beats/minute at age 45 to 55. Data from persons > 55 are lacking.

Cardiac Output

The resting cardiac index (cardiac output per unit of time [L/minute], measured while seated and divided by body surface area [m²]) is not reduced in healthy older men who have been rigorously screened to exclude occult heart disease and who live independently in the community. However, in older women, resting cardiac output decreases slightly because neither end-diastolic volume nor stroke volume increases to compensate for the modest reduction in heart rate. These sex-related differences appear to be due in part to differences in fitness, even between sedentary men and women.

Aerobic Capacity and Cardiovascular Function During Exercise

Aging affects aerobic capacity and cardiovascular performance during exercise (see Table 83-2). Peak exercise capacity and peak oxygen (O₂) consumption decrease with age, but interindividual variation is substantial. Aerobic capacity decreases by 50% between ages 20 and 80, because maximum cardiac output decreases by 25% and peripheral O₂ utilization decreases (ie, the arteriovenous O₂ difference decreases by 25%) as a result of age-associated reductions in muscle mass and strength. Other possible mechanisms include inefficient redistribution of blood flow to working muscles and reduced O₂ extraction and utilization per unit of muscle. With age, heart rate during exhaustive exercise decreases, but heart volume at end-diastole and throughout the cardiac cycle (including end-systole) is larger during exercise in older than in younger persons. Thus, in older persons, the early diastolic left ventricular filling volume increases during exercise. As a result, the end-diastolic volume, even at peak exercise, is not compromised because of a "stiff heart," and stroke volume during exercise is maintained in older persons. The 25% reduction in maximum cardiac index that occurs between ages 25 and 85 is completely due to the age-associated reduction in maximum heart rate.

During all levels of exercise, the older heart, on average, pumps blood from a larger filling volume. However, stroke volume in older persons does not exceed that in younger persons, because the end-systolic volume in older persons remains larger than it does in younger persons. Consequently, the ejection fraction does not increase as much in response to an increase in end-diastolic volume. Thus, although the stroke volume during exercise is maintained at the same level in older persons as in younger persons, the Frank-Starling mechanism is blunted with age. These changes result from a combination of age-associated factors, including augmented vascular and cardiac components of afterload, reduced maximal intrinsic myocardial contractility, and reduced augmentation of contractility by -adrenergic stimulation.

-Adrenergic Modulation

The activity of the sympathetic nervous system seems to increase with age, as suggested by higher blood levels of norepinephrine and epinephrine in older than in younger persons during any effort. Because levels of norepinephrine and epinephrine are higher, more -adrenergic receptors on cardiac and vascular cell surfaces are occupied. The result is a desensitization of -adrenergic receptors, thereby causing a down-regulation of associated intracellular signaling pathways. Such desensitization may account for all or a substantial portion of the age-associated postsynaptic reduction in responsiveness to -adrenergic stimulation.

-Adrenergic stimulation of pacemaker cells partially accounts for an increased heart rate during exercise. When a rapid intra-arterial infusion of a -adrenergic agonist (eg, isoproterenol) is used to mimic exercise, the increase in heart rate and in ejection fraction is smaller and forearm vascular dilation and venorelaxation are less in older than in younger men. (In isolated human cardiac muscle and in myocytes, response to -adrenergic stimulation is also reduced with age.) However, -adrenergic-mediated venoconstriction during exercise is not impaired with age and is a major factor in facilitating the return of blood to the heart.

-Adrenergic blockade during exercise abolishes age-associated differences in heart rate, in early diastolic left ventricular filling rate, and in end-diastolic volume. Thus, the cardiovascular response to exercise is similar in younger persons during acute -blockade and in older persons.

Animal studies confirm the age-associated reduction in contractile response of cardiac myocytes to -adrenergic stimulation. The contractile response is reduced because with age, -adrenergic stimulation is less able to increase L-type sarcolemmal Ca⁺⁺ channel availability and thus to augment the brief increase in cytosolic calcium concentration (Ca⁺⁺ transient). The age-associated reduction in the postsynaptic response of myocytes to -adrenergic stimulation appears to be due to multiple changes in coupling of ₁- and ₂-adrenergic receptors to postreceptor intracellular machinery. The major age-associated change that limits this signaling pathway appears to involve the coupling of the -adrenergic receptor to adenylyl cyclase via the stimulatory G (Gs) protein. Because of this change, not enough intracellular cyclic adenosine monophosphate (cAMP) is produced to adequately activate protein kinase A, which phosphorylates key proteins, leading to altered protein function and augmented cardiac function. The reduced response to -adrenergic stimulation in healthy older persons resembles that in patients with chronic heart failure. However, unlike the case in chronic heart failure, neither -adrenergic kinase activity nor inhibitory G (Gi) protein activity (Gi inhibits intracellular adenylyl cyclase) appears to be involved in the age-associated blunting of -adrenergic effects.

Cardiovascular Function in Hypertension

The same vascular and cardiac (hemodynamic) changes that are observed in normotensive persons as they age also occur in hypertensive persons but at a younger age, and in some, the changes are exaggerated. However, with age, hypertensive persons undergo some changes that do not occur in normotensive persons. In hypertensive persons, peripheral vascular resistance increases substantially with age. The increase in peripheral vascular resistance elevates diastolic and mean arterial pressures and plays a greater role in the vascular afterload of the heart than it does in normotensive persons. Also, resting stroke volume and cardiac output are lower in hypertensive persons than in normotensive persons.