Health Articles

Compared with younger persons, heahhy elderly persons have a substantially lower heart rate during high levels of physical exertion (see FIG. 33-fvl). The peak rate of left ventricular filling increases during exercise in boih younger and older persons, but the peak rate is 50% less in older than in younger persons both during exercise and at rest. However, cardiac dilatation at end diastole and end systole still occurs during vigorous exercise in older men (see Flti. 33-M). This dilatation is more pronounced in elderly persons who have silent ischemia (ie, who have no symptoms or signs of coronary disease at rest but have an abnormal ECG and thallium scan during exercise). Thus, end-diastolic volume is not compromised by ;\ “stiff heart,” either at res! or during exercise. However, end-diastolic pressure, which has not been measured in healthy older and younger persons during exercise, may be expected to increase with age. During vigorous exercise, the left ventricular stroke volume, which depends upon the end-diastolic and end-systolic volumes, is not reduced in healthy elderly persons (see FIG. 33-Wi). Thus, ihc cardiac dilatation at end diastole outweighs Ihe concomitant age-associated deficiency in end-systolic volume {see Fifi. 33-5 A).
The maximum cardiac index is only slightly decreased wilh age in healthy men (sec Flu. 33-6C). Stroke volume in older women is not as well maintained because women have a relatively smaller end-diastolie volume during exercise. Thus, the maximum cardiac output during vigorous cycle exercise decreases more in older women than in men because older women have a reduced heart rate and stroke volume.
Because neither men nor women can reduce left ventricular end-systolic volume sufficiently during vigorous exercise, ejection fraction increases less compared wilh that in younger persons (see Fin. 33—5iJ). The failure lo increase ihe left ventricular ejection fraction during exercise is more severe in older persons who have silent ischemia. An age-associated decrease in myocardial conlraetile reserve or a failure of ventricular afterload to sufficiently decrease can cause left ventricular end-systolic volume lo be insufficiently reduced during exercise in healthy older persons. The peripheral vascular resistance declines to about the same extent during vigorous exercise in healthy older and younger persons (see FiG. 33-60). The ratio of systolic blood pressure to end-systolic volume, an index of myocardial contractility, decreases with age during vigorous exercise but not at rest. The apparent decrease in left veniricular contractility is more severe in older persons with silent ischemia than in those who are healthy (sec FiG. 33-5C).
(1-Adrenergic Modulationp-Adrenergic stimulation has iwo effects on myocardial contraction: The strength is enhanced and the duration is decreased. Because heart rate increases dramatically in response to ^-adrenergic stimulalion, the contraction must be briefer to permit myocardial relaxation and proper filling of the ventricle during a shorter diastole.
p-Adrenergic modulation of pacemaker cells accounts in part for an increased hearl rate during exercise. Rapid infusions of β-adrenergic agonists (eg. isoproterenol) have been used to demonstrate a diminished heart rate response with age (see FIG. 33-7A). Ejection fraction is increased to a lesser extent in older than in younger men (see FiG. 33-1B). Forearm vascular dilatation in response to intra-arterial infusion of isoproterenol is less in older than younger men (sec FiG. 33-7C). Catecholamines also modulate venous lone and Ihus its capacitance during stress, cx-Adrcnergic-mediated venoconstrietion during exercise is nol impaired with atiing and is a major factor facilitating the return of blood to the heart. The effect of ^-adrenergic stimulation in relaxing veins decreases wilh age (see FIG. 33-7/)).
The hemodynamic pattern observed in many healthy older persons during exercise (ie, reduced heart rate and greater cardiac dilatation at end diastole and end syslole with maintenance or augmentation of stroke volume) occurs in younger persons who exercise while receiving β-blocker therapy. p-Adrenergic blockade also abolishes the age-associated decrease in the peak left ventricular filling rate in the sitting position, both at rest and during vigorous exercise.

Overall cardiovascular performance is maintained within a narrow range by adjustments in interrelated factors. These homeostatic adjustments enhance both the heart’s pumping action and peripheral blood flow. Basic cellular and extracellular biophysical mechanisms, each subject to autonomic modulation, determine the functional level of each factor. For example, when changing from supine to upright position or when performing daily activities or exercise, cholinergic modulation decreases while adrenergic modulation increases as documented by increased levels of plasma catecholamines.
The regulation of cardiovascular function is efficient. In healthy persons, cardiac output is matched to the demand for peripheral blood flow. Maximal aerobic capacity, ie. whole-body oxygen consumption al exhaustion (V0;max), and cardiac output vary considerably in exercise stress tests, depending on whether cardiovascular or noncardiovascular (eg. psychologic, musculoskeletal) factors limit exercise. Age-associated decreases in cardiac output at exhaustion (ie, the maximal measured cardiac output) do not necessarily equate with reduced cardiovascular reserve, as in younger persons.
The maximum exercise capacity and maximal oxygen consumption decline with age but to a variable extent among individuals. Elderly persons in good physical condition can match or exceed Ihe aerobic capacity of unconditioned younger persons. This indicates cither lhal physical deconditioning causes the decline in some older persons or lhal physical conditioning can retard aging’s effect on cardiorespiratory function.
Maximal cardiac output and stroke performance are often extrapolated from measurements of Voanax and heart rate using the Fick principle. However, specific but variable age-related changes in stroke volume and arteriovenous oxygen difference essentially preclude extrapolation of maxima! cardiac outpul from measurements of Vo^max and maximal heart rate. An assumption that arteriovenous oxygen remains constant with aging attributes a measured decline in Vt^max to central rather than peripheral factors. This assumption may not be valid, because during vigorous exercise stress lesls, 90% of cardiac output is directed lo working muscles. In sedentary persons, lean body mass can decrease 10% k> 12% with aging, which could cause a reduction in arteriovenous oxygen difference that could thereby account for reduced Vo2inax. Another factor is the efficiency by which blood flow is redistributed to muscles and oxygen is extracted by working muscles. Improved oxygen consumpiion with physical conditioning is achieved by enhanced arteriovenous oxygen rather than by improvements in maximal cardiac output.
In summary, the aerobic capacity of both middle-aged and older men can increase with endurance training and is mediated by adaptations in peripheral and cardiac mechanisms (depending upon the intensity of exercise and Ihc amount of whole-body oxygen consumpiion before training). Hnduranee training in older women augments VO2max nearly exclusively by increasing arteriovenous oxygen. These adaptations also explain, in part at least, differences in Vo?max measured in cross-sectional studies of younger and older sedentary persons and of older athletes and their sedentary counterparts.

The interplay of stroke volume factors (preload, afterload, myocardial contractility, and coronary flow) and heart rate delermines cardiac output (see FIG. 33-1). The resting, sitting cardiac index is no! reduced in healthy older men (see Piei. 33-6C). In women, neither end-diastolic nor stroke volume increases with age to compensate for the modest reduction in heart rate, so cardiac output al res! decreases slightly. These sex differences appear to be due in part to differences in fitness, even between sedentary men and women. A decline in cardiac output at rest may be due to cardiac or noncardiac factors (eg, severe coronary artery disease, hypertension, or a reduced demand for flow because less lean body mass results in decreased basal metabolism).

The heart rate at rest is modulated by relative sympathetic and, more important, parasympathetic tone. In healthy men, the supine basal heart rate does not change with aging; in the sitting position, the heart rate decreases slightly. Spontaneous variations in heart rale over a 24-h period occur less often with age in men without coronary artery disease. Variations in the sinus rate wilh respiration also diminish. In contrast to resting heart rate, intrinsic sinus rate (ie. that measured wilh both sympathetic and parasympathetic blockade) declines significantly with age. For example, al 20 yrofage, the average intrinsic heart rate is 104 beats/min compared with 92 beats/min between ages 45 and 55 yr. Studies in older persons are lacking.

The resting ejection fraction is not reduced in older men and women whose resting end-diastolic and end-systolic volumes are comparable to those o\’ younger persons (see HlG. 33-5).
Stroke volume is calculated from steady-stale measurements of cardiac output and heart rate. Stroke volume remains constant with age, even in persons whose systolic blood pressure has increased within the normal range (see FIG. 33-5), although some studies contradict this. A modest decline in stroke volume at rest occurs in some elderly hypertensive patients.

Another determinant of myocardial function at rest is the adequacy of coronary flow. Although coronary flow measurements in persons without coronary artery disease are not available, there is no indication that coronary flow is reduced in such persons. This factor probably does not limit myocardial function in healthy elderly persons.

In addition to preload and afterload, myocardial and left ventricular pump performance depends on the myocardial contractile state (also referred to as intrinsic myocardial cell performance, contractility, inotropic state, or excitation-contraction coupling). The extent to which myofilaments become Ca++ activated during systole is determined by the extent ol diastolic stretch (preload). Myofilament shortening during contraction (afterload) affects how long Ca ‘ remains bound to the myofilaments throughout systole. Myocardial fiber length both before and during shortening is a modulatory factor of the strength of the heartbeat The effects of preload and afterload in altering myofilament Ca,* activation mimic those of inotropic stimulants, which also alter Ca ‘ - activation before or during contraction.
Because many factors interact to regulate cardiac performance (see FIG. 33-1). the intrinsic contractile behavior of myocardial fibers cannot be determined in situ. One index of myocardial contractility that is generally considered superior to others is (he trajectory of end-systolic volume vs. mean arterial pressure (sometimes referred to as Emax) derived from a series of pressure-volume loops measured over a range of cardiac volumes. In noninvasive studies, a crude index of this Irajec-tory (ie, the ratio of end-systolic arterial pressure to end-systolic vul-ume) is not reduced at rest with age in either healthy men or women.
Age-associated changes in the mechanisms that govern excitation-contraction coupling in cardiac muscle have been demonstrated in animal models. Some of these changes are related in part to alterations in gene expression. Studies in rats show that contractile force production, at least at low stimulation, is preserved in old age. While (here is no clear indication that passive stiffness in isolated cardiac muscle increases with age, stiffness during contraction does increase. The affinity of (he myofibrils for Ca'’ is preserved in senescent muscle, and the increase in myoplasmic Ca+’ aflcr excitation is not age related.
Contraction is prolonged in senescent cardiac muscle, probably because Ca+ ■ is released more slowly into the myoplasm during systole. This most likely occurs because the sarcoplasmic reticulum sequesters less calcium. While the action-potential duration is also longer in senescent cardiac muscle, its role in prolonged contraction is unclear. Action-potential changes could reflect age-related changes in sarcolemmal ionic conductance or could result from the prolonged myoplasmic Cal+ transient elicited by excitation. In the older heart, myosin isoenzymes shift to slower forms, and adenosine triphosphatase activity declines; these changes appear to underlie the decline in shortening velocity observed when isolated senescent cardiac muscle contracts iso-ton ical ly.
These interrelated changes in excitation-contraction mechanisms and myofibrillar biochemistry are adaptive rather than degenerative, in that they serve to maintain the contractile function of the senescent heart. Regular exercise can reverse some of these changes (eg. the prolonged contraction due to the diminished rate at which the sarcoplasmic reticulum pumps Ca,”"1″). Inotropic responses to cardiac glycosides and to ^-adrenergic stimulation (see below) are also reduced in old age.

The exlenl to which muscle shortens during contraction varies inversely with the load borne by individual fibers. Forces that resist myocardial fiber shortening after Ihe onset of myofilament Ca ‘ activation (ie, during systole) are collectively referred to as afterload. There are two major components of afterload: cardiac and vascular.
The cardiac component of afterload is determined by the ventricular radius, both at the onset and during the Ca1 ‘-activated slate (ie. at end diastole and throughout the ejection period). The ventricular radius is an afterload as well as a preload factor because of Laplace’s law, which states that at a constant ventricular pressure, vascular wall stress increases as ventricular radius increases. Myocardial wall stress is the force generated by Ihe myofilaments and cross-sectional area of the myocardial wall. Thus, wall thickness is also related to afterload.
The vascular component of afterload is determined by vascular input impedance. Vascular impedance has steady and pulsatile components: the steady component is commonly referred to as peripheral vascular resistance, while the pulsatile component is referred Io as characteristic vascular impedance. An additional pulsatile component of vascular afterload is the reflected pulse wave. Thus, the total arterial load placed upon the left ventricle can be characterized by peripheral vascular resistance, characteristic vascular impedance, and pulse wave reflection. The extent to which each of these factors changes with age varies dramatically among individuals.
The average total peripheral vascular resistance is calculated indirectly from steady-slate measurements of cardiac output or flow. Mean arterial pressure is calculated by Ohm’s law:
mean pressure Steady flow   =
mean resistance
Some studies report that basal peripheral vascular resistance increases with age; others have not found this to be so.
Characteristic aortic impedance is usually < 10% of total vascular impedance. Calculated from instantaneous measurements of pressure and flow harmonics, it is determined in part by aortic stiffness, aorlic wall thickness and diameter, and aortic pressure.
One index of vascular stiffness is pulse wave velocity, which increases with age, owing to the changes in arterial structure noted above. Age-associated increases in pulse wave velocity and late augmentation of carotid pressure pulse are blunted in older athletes. Although aortic stiffness is a well-known concomitant of aging, an increase in characteristic aortic impedance has recently been demonstrated via probes Ihat simultaneously measure blood flow and pressure.
Because of increased aortic pulse wave velocity, pressure waves from peripheral sites are returned to the heart sooner in older persons. Pressure in the aorlic root continues to rise and peaks later in systole, thereby altering the pressure pulse contour (see FIG. 33-3). Arterial stiffening and the associated increase in pulse wave velocity appear to cause the increase in systolic blood pressure within ihc clinically normal range that is associated with aging. Some physiologists suggest that this increase in systolic blood pressure reflects a resetting of the baroreceptor reflex to a higher level in the elderly. The same structural changes that render Ihe aorta siiffer and cause pulse wave velocity to increase could be responsible for less baroreceptor stimulation for a given change in aortic pressure. Alternatively, afferent nerve impulses may vary with age and explain the blunted baroreceptor response, as may changes in efferent signals to the arterial system.
The increase in systolic pressure affects left ventricular afterload. The lelt ventricle may empty incompletely during each cardiac cycle leading to a reduced ejection fraction and ventricular dilatation. Left ventricular wall thickness may increase sufficiently to normalize wall stress (see above), thus maintaining normal cavity siz.c and ejection Iraetion: this occurs in healthy older persons whose increase in systolic blood pressure is clinically normal. Resting end-diaslo!ic volume in the seated position increases with age in men but nol in women. Fnd-syslohc volumes al rest do nol differ substantially with age in otherwise healthy persons.
Current medical practice is not to treat patients whose age-associated increased systolic blood pressure falls within Ihe clinically normal range. However, epidemiologic studies show lhat these untreated elderly persons arc at higher risk for cardiovascular events: how much the risk is increased depends on how high systolic blood pressure rises. An increase that is greater than what has been defined as normal is referred k> as isolated systolic hypertension (see Ch. 35).
How the heart and vasculature adapt to age-associated changes is summarized m FIG. .13-4. Strikingly similar changes occur in patients in whom the heart has adapted to hypertension by an increase in mass. In addition, in patients with systolic plus diastolic hypertension, peripheral vascular resistance also increases substantially.

Factors that determine ventricular volume (ie. fiber stretch, end-diastolic blood volume, and filling pressure) are sometimes referred to FIG. 33-1. Factors that govern cardiac output. Trie overlap at the center indicates the interdependence of these determinants ol lunction. The bidirectional arrows indicate that each function not only is modulated by autonomic tone but also is governed by a negative as preload. Preload is related to the filling volume and degree of myocardial stretch before excitation; hence, it is one determinant of myocardial function and pump performance. Left ventricular compliance (inverse of stiffness) affects ihe atrioventricular pressure gradient, which determines left ventricular filling rate. A reduction in ventricular compliance with age remains unproved because its measurement requires Ihe simultaneous determination of pressure and volume.
The early diastolic filling rate progressively slows after the aye of 20 yr, so that by 80 yr. the rate is reduced up to 50% (see FIG. 33-2). This reduction in filling rate (demonstrated by echocardiography, radionuclide angiography, and Doppler ultrasonography) is attributed either to structural (fibrous) changes within the left ventricular myocardium or to residual myofilament Ca”1 ‘ activation from Ihe preceding systole (ie, prolonged isometric relaxation), which is discussed in grealer detail below.
Despite Ihe slowing of left ventricular filling early in diastole, end-diastolic volume is not usually reduced in healihy elderly persons. Because stroke volume at rest does not decline appreciably with age, the at-rest filling volume during each cardiac cycle is roughly the same regardless of age. Thus, in healthy persons, more filling occurs later in diastole to compensate for ihe slowed early filling. This later filling response is due to atrial enlargement and a more vigorous atrial contraction (see FlG. 33-2) and is manifested on auscultation as a fourth heart sound (atrial yallop). Loss of this atrial kick occurring with acute atrial fibrillation can be clinically significant in elderly persons whose ventricular function is compromised for other reasons. The end result may be heart failure, particularly if the ventricular rale is rapid.

Cardiovascular function and cardiac output are determined by the interaction of several variables, each of which is ultimately dependent on biophysical mechanisms that regulate cardiac muscle and ventricular function (see FIG. 33-1).