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Cardiovascular System

Edward G. Lakatta

10.1002/cphy.cp110117

Source: Supplement 28: Handbook of Physiology, Aging

Originally published: 1995

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Cardiovascular Structure in Younger and Older Humans
1.1 Arterial Structure and Mechanical Properties
1.2 Cardiac Structure
1.3 Ventricular–Vascular Coupling
2 Myocardial and Cardiac Pump Function at Rest
2.1 Integrated Regulation of Cardiac Function
2.2 Cardiac Filling (Diastolic) Properties
2.3 Cardiac Volumes and Ejection Fraction
2.4 Myocardial Contractile Properties
2.5 Heart Rate and Rhythm
2.6 Cardiac Output
3 Cardiovascular Reserve
3.1 Postural Reflexes
3.2 Isometric Exercise
3.3 Dynamic Exercise
4 Sympathetic Modulation of Cardiovascular Function
4.1 Intact Organisms
4.2 Cardiovascular Target Organ Response to β‐Adrenergic Stimulation with Aging
4.3 Isolated Tissue or Cells
5 Parasympathetic Modulation of Cardiovascular Function
6 Cardiovascular Structure and Function in Younger and Older Animals
6.1 Cardiac Structure
6.2 Myocardial Stiffness
6.3 Regulation of the Cardiac Contraction
6.4 Similar Effects of Aging and Experimental Pressure Overload on Cardiac Regulatory Mechanisms and Gene Expression
6.5 Possible Mechanisms of Altered Cardiac Gene Regulation with Aging
6.6 Response of Older Rat Heart to Chronic Hemodynamic Overload
6.7 Coronary Blood Flow, Oxygen Consumption, and Oxidative Metabolism
7 Effect of Chronic Physical Conditioning on Cardiovascular Performance in Older Humans and Animals
7.1 Studies in Humans
7.2 Studies in Rodents
8 Summary
Figure 1. Figure 1.

A: Mean brachial arterial aortic pressure and aortic pulse wave velocity in two Chinese populations 25 selected without respect to arterial pressure (clinically hypertensive subjects included) and in a North American study population, the Baltimore Longitudinal Study of Aging (BLSA), in which hypertensive subjects (blood pressure greater than 140/90 mm Hg) were excluded from analysis 527. B: Augmentation index of the carotid artery pressure pulse in healthy individuals, measured in an applanation tonometry. The augmentation index is defined as the ratio of ΔP/PP%; ΔP is the pressure difference from the shoulder to peak; PP is pulse pressure. The ○ population included mildly hypertensive subjects.; the • population (BLSA) excluded clinically hypertensive subjects (blood pressure greater than 140/90 mm Hg). C: Hypothetical aortic input impedance spectra. Upper tracing, impedance modulus values decline from a high value at 0 Hz (the PVR) to a minimum at approximately 3.5 Hz. This is approximately the same frequency at which phase crosses zero (lower tracing). Negative phase values indicate that flow harmonics lead pressure harmonics; positive phase values indicate that flow harmonics lag pressure harmonics. Impedance moduli oscillate around a characteristic value (Z0 average of moduli > 2 Hz) because of wave reflections. A wave reflection index can be calculated as the difference between maximum and minimum impedance moduli. D: Aortic input impedance spectra and flow modulus vs. frequency in a young subject and an elderly subject. E: Characteristic aortic impedance increase with age.]

From Kelly et al. 250 with permission; From Vaitkevicius et al. 527 with permission; From Nichols et al. 365 with permission; From Nichols et al. 363 with permission; From Nichols et al. 363 with permission;
Figure 2. Figure 2.

A: Least‐squares linear regression of left ventricular end‐diastolic wall thickness (LVWT) on age (solid line = mean; dashed lines = ± 2 standard deviations of the mean) in healthy men and women as measured by echocardiography. Circles indicate LVWT in patients with aortic valve disease. B: LVWT at end‐diastole (top) and at end‐systole (lower) measured via M‐mode echocardiography in healthy men participating in the BLSA.

From Sjögren 471 with permission. From reference 172, with permission
Figure 3. Figure 3.

Arterial and cardiac changes that occur with aging in normotensive subjects and at any age in hypertensive subjects. One interpretation of the constellation (flow of arrows) is that vascular changes lead to cardiac structural and functional alterations that maintain cardiac function.

Modified from Lakatta 288 with permission
Figure 4. Figure 4.

Multiple interdependent factors regulate cardiac output.

From Lakatta 285 with permission
Figure 5. Figure 5.

A: Isovolumic relaxation time at rest measured from the closure of the aortic valve to the opening of the mitral valve in healthy male participants of the BLSA (Lakatta, E. G., and Fleg, J. L., unpublished results). B: Relationships between age and peak filling rate obtained at rest, at 50% of maximal workload, and at maximal workload. For each of these workloads, there was a significant inverse correlation between age and peak filling rate, r = −0.64 (rest), −0.53 (50% maximal workload), and −0.64 (maximal workload). The slopes of the three lines did not differ with a decrease in peak filling rate from 6% to 7% per decade 448.
Figure 6. Figure 6.

Linear regression on age of cardiac volume indices (A, at rest; B, during exercise) and ejection fraction (C), heart rate (D), cardiac index (E), systolic arterial pressure (F), and peripheral vascular resistance (G) at rest and during maximal cycle ergometry in the upright position. Study participants were healthy, sedentary male (n = 95, closed symbols) and female (n = 50, open symbols), community‐dwelling volunteers from the BLSA who had been rigorously screened to exclude clinical hypertension and occult coronary artery disease 147. Cardiac volumes were measured via gated blood‐pool scans 421. *Linear regression on age within sex is statistically significant. Age–gender interactions are described in Fleg et al. 147.
Figure 7. Figure 7.

Left ventricular SWI measured as the product of SVI and brachial systolic pressure at rest and during graded exercise in younger (< 40 yr) and older (> 60 yr) men (top), and women (bottom) of the study population depicted in Figure 7.

From Fleg et al. 147 with permission
Figure 8. Figure 8.

A: Left ventricular contractility index (LVCTI) measured as the ratio of end‐systolic arterial pressure and ESVI. Lines are the best fit, linear regressions at rest and during exercise in the presence and absence of β‐adrenergic blockade with propranolol. B: The effect of exercise on characteristic aortic impedance during graded treadmill exercise in the presence and absence of β‐adrenergic blockade (propranolol) in healthy adult □ and senescent ▪ beagle dogs. In the absence of β‐adrenergic blockade, exercise increased impedance in senescent but not in younger dogs. In contrast, during β‐blockade impedance was increased during exercise in dogs of both ages.

From Fleg et al. 150 with permission; From Yin et al. 567 with permission
Figure 9. Figure 9.

O2max as a function of age as measured in males of varying age, fitness, and body composition. Points are average O2max values for groups of men of different ages from reports in the literature for young athletes, master athletes, lean untrained, and overweight untrained men 14,23,33,39,52,92,96,102,184,350,392,416,417. Champion young athletes, ○, Heath et al. 208 and □ Dill et al. 102; ex‐champion athletes, Δ, Dill et al. 102 and Robinson et al. 417; cross‐country runners, ▴, Grimby and Saltin 184; runners ▪, Pollock et al. 392: groups of untrained men from 9 studies, • and X; master athletes ○ and •.

Modified from Heath et al. 208 with permission; From Heath et al. 208 and Fleg et al. 149, respectively, with permission
Figure 10. Figure 10.

A: The effect of a bolus I.V. isoproterenol infusion to increase heart rate in healthy young and older men at rest. B: Isoproterenol increases the LV ejection fraction in younger and older healthy men in the supine position prior to (pre) and following (post) chronic endurance training. Endurance training had no effect on this index of cardiac pump function or on its response to isoproterenol. C: Intraarterial isoproterenol (isoprenaline) infusions decrease the forearm vascular resistance in healthy younger and older men. D: I.V. arterial infusion of isoproterenol relaxes dorsal hand veins previously constricted by phenylephrine in men of varying ages. E: Top: Peak LV filling rates at rest and during exercise for young β‐blocked subjects and age‐matched non‐β‐blocked subjects. Peak filling rate was significantly less in those young subjects pretreated with propranolol at both relative and absolute workloads of 50% of maximal and maximal workloads (left) and 50 and 100 watts (right), respectively. Middle: Peak filling rates at rest and exercise for the older β‐blocked subjects and age‐matched non‐β‐blocked subjects. Peak filling rates were similar between the two groups both at relative workloads of 50% of maximal and maximal workloads (left) and absolute workloads of 50 and 100 watts (right). Lower: Peak filling rates at rest and exercise for young and old subjects pretreated with propranolol. Age differences noted during exercise in the absence of β‐blockade are no longer seen during exercise in the presence of β‐blockade.

From Yin et al. 564 with permission; From Stratton et al. 500 with permission; From van Brummelin et al. 528 with permission; From Pan et al. 383 with permission; From Schulman et al. 448 with permission
Figure 11. Figure 11.

A: The effect of norepinephrine on the maximum rate of isometric tension development in isolated trabeculae from hearts of varying ages. B: Velocity of cell shortening and C maximum rate of increase of the Indo‐1 fluorescence transient, an index of sarcoplasmic reticulum Ca2+ release into the cytosol, during electrically stimulated twitch in single cardiac myocytes isolated from the hearts of rats of varying ages and loaded with the fluorescent probe Indo‐1. D: Norepinephrine increases the L‐type sarcolemmal channel current (Ica) measured via whole‐cell patch clamp technique in single cells isolated as in B and C. E: Norepinephrine increases phosphorylation of troponin I (TNI) in suspensions of heart cells isolated from hearts of rats of varying ages as in above panels. In B–E norepinephrine stimulated β‐receptors, because prazosin and α1‐AR antagonist had no effect on the results.

From Lakatta et al. 295 with permission; From Xiao et al. 557 with permission; From Xiao et al. 557 with permission; From Sakai et al. 431 with permission
Figure 12. Figure 12.

Simplified schematic of excitation–contraction coupling mechanisms in cardiac muscle. Ca2+ influx (ICa) via L‐type sarcolemmal Ca2+ channels, activated by depolarization during an action potential, triggers the release of Ca2+ from the sarcoplasmic reticulum to increase the cytosolic [Ca2+]. The binding of Ca2+ to troponin (TROP) enables actomyosin (AM) interaction, resulting in myofilament force production and shortening. Cytoplasmic [Ca2+] is then lowered and relaxation ensues (Mito, mitochondria).
Figure 13. Figure 13.

Action potential (A), isometric twitch (B), and Cai transient (C) measured via aequorin luminescence in isometric right ventricular papillar muscles isolated form the hearts of young adult and senescent Wistar rats. Inset in C indicates the time course of the Cai transient (trace 1) relative to that of the contraction (trace 2). D: The force–pCa relationship in cardiac muscle in which membranes have been destroyed by detergent (Triton X) treatment does not vary with age. E: The ability of left ventricular trabeculae carneae to respond, via a detectable twitch contraction, to paired stimulation decreases with age as the coupling interval of the paired stimuli decreases. F: Left ventricular cell volume (single cells isolated via collagenase digestion of hearts), measured via Coulter counter technique, increases with age.

A and B from Wei et al. 545; C from Orchard and Lakatta 377 with permission.; D From Bhatnagar et al. 37 with permission; E From Lakatta et al. 296 with permission; F From Fraticelli et al. 159 with permission
Figure 14. Figure 14.

17.14. A: The effect of age on Ca2+ accumulation velocity by sarcoplasmic reticulum (SR) isolated from senescent and adult Wistar rat hearts. B: The effect of age on SR isolated from adult and senescent Fischer 344 rat hearts. Left, Vmax for Ca2+‐ATPase activity in isolated SR vesicles; middle, formation of phosphoenzyme product; right, concentration of SR Ca2+ pump protein. The effect of age on steady‐state mRNA levels for SR calsequestrin (D) Ca2+‐ATPase (C) in adult senescent Wistar rat hearts.

From Froehlich et al. 163 with permission; From Tate et al. 512 with permission; From Lompre et al. 321 with permission
Figure 15. Figure 15.

A: Average values for α and β myosin heavy chain (MHC) mRNA/mRNA18S of individual Wistar rat hearts measured by dot blot analysis (n = 11, 6, 10, and 10 for ages 6 wk, 6, 18, and 24 months, respectively). B: The α and β MHC proteins (V1 and V3 isoforms) of hearts of the same rat strain. C: Ca2+‐activated myosin ATPase activity of Wistar rat hearts decreases with age. D: The velocity of shortening during lightly loaded isotonic contractions in isolated cardiac muscle from younger and older rats decreases with aging. E: Left ventricular actin isoforms (cardiac or skeletal) do not change with aging as do the MHC isoforms in the Wistar rat.

From O'Neill et al. 376 with permission; From Effron et al. 118 with permission; From Effron et al. 118 with permission; From Capasso et al. 60 with permission; From Carrier et al. 63 with permission
Figure 16. Figure 16.

Chronic exercise training decreases the isometric contraction duration in isolated right ventricular papillary muscles of older Wistar rats (A) and the velocity of Ca2+ accumulation in sarcoplasmic reticulum isolated from Fischer 344 rats (B). In contrast, chronic exercise alters neither age‐associated decreases in the MHC isoform content (C) nor age‐associated changes in myosin ATPase activity (D).

A from Spurgeon et al. 486; B and D from Tate et al. 512; C from Farrar et al. 132 with permission


Figure 1.

A: Mean brachial arterial aortic pressure and aortic pulse wave velocity in two Chinese populations 25 selected without respect to arterial pressure (clinically hypertensive subjects included) and in a North American study population, the Baltimore Longitudinal Study of Aging (BLSA), in which hypertensive subjects (blood pressure greater than 140/90 mm Hg) were excluded from analysis 527. B: Augmentation index of the carotid artery pressure pulse in healthy individuals, measured in an applanation tonometry. The augmentation index is defined as the ratio of ΔP/PP%; ΔP is the pressure difference from the shoulder to peak; PP is pulse pressure. The ○ population included mildly hypertensive subjects.; the • population (BLSA) excluded clinically hypertensive subjects (blood pressure greater than 140/90 mm Hg). C: Hypothetical aortic input impedance spectra. Upper tracing, impedance modulus values decline from a high value at 0 Hz (the PVR) to a minimum at approximately 3.5 Hz. This is approximately the same frequency at which phase crosses zero (lower tracing). Negative phase values indicate that flow harmonics lead pressure harmonics; positive phase values indicate that flow harmonics lag pressure harmonics. Impedance moduli oscillate around a characteristic value (Z0 average of moduli > 2 Hz) because of wave reflections. A wave reflection index can be calculated as the difference between maximum and minimum impedance moduli. D: Aortic input impedance spectra and flow modulus vs. frequency in a young subject and an elderly subject. E: Characteristic aortic impedance increase with age.]

From Kelly et al. 250 with permission; From Vaitkevicius et al. 527 with permission; From Nichols et al. 365 with permission; From Nichols et al. 363 with permission; From Nichols et al. 363 with permission;


Figure 2.

A: Least‐squares linear regression of left ventricular end‐diastolic wall thickness (LVWT) on age (solid line = mean; dashed lines = ± 2 standard deviations of the mean) in healthy men and women as measured by echocardiography. Circles indicate LVWT in patients with aortic valve disease. B: LVWT at end‐diastole (top) and at end‐systole (lower) measured via M‐mode echocardiography in healthy men participating in the BLSA.

From Sjögren 471 with permission. From reference 172, with permission


Figure 3.

Arterial and cardiac changes that occur with aging in normotensive subjects and at any age in hypertensive subjects. One interpretation of the constellation (flow of arrows) is that vascular changes lead to cardiac structural and functional alterations that maintain cardiac function.

Modified from Lakatta 288 with permission


Figure 4.

Multiple interdependent factors regulate cardiac output.

From Lakatta 285 with permission


Figure 5.

A: Isovolumic relaxation time at rest measured from the closure of the aortic valve to the opening of the mitral valve in healthy male participants of the BLSA (Lakatta, E. G., and Fleg, J. L., unpublished results). B: Relationships between age and peak filling rate obtained at rest, at 50% of maximal workload, and at maximal workload. For each of these workloads, there was a significant inverse correlation between age and peak filling rate, r = −0.64 (rest), −0.53 (50% maximal workload), and −0.64 (maximal workload). The slopes of the three lines did not differ with a decrease in peak filling rate from 6% to 7% per decade 448.



Figure 6.

Linear regression on age of cardiac volume indices (A, at rest; B, during exercise) and ejection fraction (C), heart rate (D), cardiac index (E), systolic arterial pressure (F), and peripheral vascular resistance (G) at rest and during maximal cycle ergometry in the upright position. Study participants were healthy, sedentary male (n = 95, closed symbols) and female (n = 50, open symbols), community‐dwelling volunteers from the BLSA who had been rigorously screened to exclude clinical hypertension and occult coronary artery disease 147. Cardiac volumes were measured via gated blood‐pool scans 421. *Linear regression on age within sex is statistically significant. Age–gender interactions are described in Fleg et al. 147.



Figure 7.

Left ventricular SWI measured as the product of SVI and brachial systolic pressure at rest and during graded exercise in younger (< 40 yr) and older (> 60 yr) men (top), and women (bottom) of the study population depicted in Figure 7.

From Fleg et al. 147 with permission


Figure 8.

A: Left ventricular contractility index (LVCTI) measured as the ratio of end‐systolic arterial pressure and ESVI. Lines are the best fit, linear regressions at rest and during exercise in the presence and absence of β‐adrenergic blockade with propranolol. B: The effect of exercise on characteristic aortic impedance during graded treadmill exercise in the presence and absence of β‐adrenergic blockade (propranolol) in healthy adult □ and senescent ▪ beagle dogs. In the absence of β‐adrenergic blockade, exercise increased impedance in senescent but not in younger dogs. In contrast, during β‐blockade impedance was increased during exercise in dogs of both ages.

From Fleg et al. 150 with permission; From Yin et al. 567 with permission


Figure 9.

O2max as a function of age as measured in males of varying age, fitness, and body composition. Points are average O2max values for groups of men of different ages from reports in the literature for young athletes, master athletes, lean untrained, and overweight untrained men 14,23,33,39,52,92,96,102,184,350,392,416,417. Champion young athletes, ○, Heath et al. 208 and □ Dill et al. 102; ex‐champion athletes, Δ, Dill et al. 102 and Robinson et al. 417; cross‐country runners, ▴, Grimby and Saltin 184; runners ▪, Pollock et al. 392: groups of untrained men from 9 studies, • and X; master athletes ○ and •.

Modified from Heath et al. 208 with permission; From Heath et al. 208 and Fleg et al. 149, respectively, with permission


Figure 10.

A: The effect of a bolus I.V. isoproterenol infusion to increase heart rate in healthy young and older men at rest. B: Isoproterenol increases the LV ejection fraction in younger and older healthy men in the supine position prior to (pre) and following (post) chronic endurance training. Endurance training had no effect on this index of cardiac pump function or on its response to isoproterenol. C: Intraarterial isoproterenol (isoprenaline) infusions decrease the forearm vascular resistance in healthy younger and older men. D: I.V. arterial infusion of isoproterenol relaxes dorsal hand veins previously constricted by phenylephrine in men of varying ages. E: Top: Peak LV filling rates at rest and during exercise for young β‐blocked subjects and age‐matched non‐β‐blocked subjects. Peak filling rate was significantly less in those young subjects pretreated with propranolol at both relative and absolute workloads of 50% of maximal and maximal workloads (left) and 50 and 100 watts (right), respectively. Middle: Peak filling rates at rest and exercise for the older β‐blocked subjects and age‐matched non‐β‐blocked subjects. Peak filling rates were similar between the two groups both at relative workloads of 50% of maximal and maximal workloads (left) and absolute workloads of 50 and 100 watts (right). Lower: Peak filling rates at rest and exercise for young and old subjects pretreated with propranolol. Age differences noted during exercise in the absence of β‐blockade are no longer seen during exercise in the presence of β‐blockade.

From Yin et al. 564 with permission; From Stratton et al. 500 with permission; From van Brummelin et al. 528 with permission; From Pan et al. 383 with permission; From Schulman et al. 448 with permission


Figure 11.

A: The effect of norepinephrine on the maximum rate of isometric tension development in isolated trabeculae from hearts of varying ages. B: Velocity of cell shortening and C maximum rate of increase of the Indo‐1 fluorescence transient, an index of sarcoplasmic reticulum Ca2+ release into the cytosol, during electrically stimulated twitch in single cardiac myocytes isolated from the hearts of rats of varying ages and loaded with the fluorescent probe Indo‐1. D: Norepinephrine increases the L‐type sarcolemmal channel current (Ica) measured via whole‐cell patch clamp technique in single cells isolated as in B and C. E: Norepinephrine increases phosphorylation of troponin I (TNI) in suspensions of heart cells isolated from hearts of rats of varying ages as in above panels. In B–E norepinephrine stimulated β‐receptors, because prazosin and α1‐AR antagonist had no effect on the results.

From Lakatta et al. 295 with permission; From Xiao et al. 557 with permission; From Xiao et al. 557 with permission; From Sakai et al. 431 with permission


Figure 12.

Simplified schematic of excitation–contraction coupling mechanisms in cardiac muscle. Ca2+ influx (ICa) via L‐type sarcolemmal Ca2+ channels, activated by depolarization during an action potential, triggers the release of Ca2+ from the sarcoplasmic reticulum to increase the cytosolic [Ca2+]. The binding of Ca2+ to troponin (TROP) enables actomyosin (AM) interaction, resulting in myofilament force production and shortening. Cytoplasmic [Ca2+] is then lowered and relaxation ensues (Mito, mitochondria).



Figure 13.

Action potential (A), isometric twitch (B), and Cai transient (C) measured via aequorin luminescence in isometric right ventricular papillar muscles isolated form the hearts of young adult and senescent Wistar rats. Inset in C indicates the time course of the Cai transient (trace 1) relative to that of the contraction (trace 2). D: The force–pCa relationship in cardiac muscle in which membranes have been destroyed by detergent (Triton X) treatment does not vary with age. E: The ability of left ventricular trabeculae carneae to respond, via a detectable twitch contraction, to paired stimulation decreases with age as the coupling interval of the paired stimuli decreases. F: Left ventricular cell volume (single cells isolated via collagenase digestion of hearts), measured via Coulter counter technique, increases with age.

A and B from Wei et al. 545; C from Orchard and Lakatta 377 with permission.; D From Bhatnagar et al. 37 with permission; E From Lakatta et al. 296 with permission; F From Fraticelli et al. 159 with permission


Figure 14.

17.14. A: The effect of age on Ca2+ accumulation velocity by sarcoplasmic reticulum (SR) isolated from senescent and adult Wistar rat hearts. B: The effect of age on SR isolated from adult and senescent Fischer 344 rat hearts. Left, Vmax for Ca2+‐ATPase activity in isolated SR vesicles; middle, formation of phosphoenzyme product; right, concentration of SR Ca2+ pump protein. The effect of age on steady‐state mRNA levels for SR calsequestrin (D) Ca2+‐ATPase (C) in adult senescent Wistar rat hearts.

From Froehlich et al. 163 with permission; From Tate et al. 512 with permission; From Lompre et al. 321 with permission


Figure 15.

A: Average values for α and β myosin heavy chain (MHC) mRNA/mRNA18S of individual Wistar rat hearts measured by dot blot analysis (n = 11, 6, 10, and 10 for ages 6 wk, 6, 18, and 24 months, respectively). B: The α and β MHC proteins (V1 and V3 isoforms) of hearts of the same rat strain. C: Ca2+‐activated myosin ATPase activity of Wistar rat hearts decreases with age. D: The velocity of shortening during lightly loaded isotonic contractions in isolated cardiac muscle from younger and older rats decreases with aging. E: Left ventricular actin isoforms (cardiac or skeletal) do not change with aging as do the MHC isoforms in the Wistar rat.

From O'Neill et al. 376 with permission; From Effron et al. 118 with permission; From Effron et al. 118 with permission; From Capasso et al. 60 with permission; From Carrier et al. 63 with permission


Figure 16.

Chronic exercise training decreases the isometric contraction duration in isolated right ventricular papillary muscles of older Wistar rats (A) and the velocity of Ca2+ accumulation in sarcoplasmic reticulum isolated from Fischer 344 rats (B). In contrast, chronic exercise alters neither age‐associated decreases in the MHC isoform content (C) nor age‐associated changes in myosin ATPase activity (D).

A from Spurgeon et al. 486; B and D from Tate et al. 512; C from Farrar et al. 132 with permission
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Article Title: Cardiovascular System
 

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Edward G. Lakatta. Cardiovascular System. Compr Physiol 2011, Supplement 28: Handbook of Physiology, Aging: 413-474. First published in print 1995. doi: 10.1002/cphy.cp110117