Aging-associated cardiovascular changes and their relationship to heart failure

Abstract

Aging represents a convergence of declining cardioprotective systems and increasing disease processes that is fertile ground for the development of heart failure. Fifty percent of all heart failure diagnoses and 90% of all heart failure deaths occur in individuals older than 70. This article discusses the microscopic and macroscopic changes in cardiovascular structure, function, protective systems, and disease associated with aging. In addition to outlining important clinical considerations and conditions in older persons, the link between normal aging and the elevated risk for development of stage B heart failure is explained and potential therapeutic pathways are highlighted.

Figure 1

Average prevalence of heart failure according to age and sex: Framingham Heart Study, 16-year follow-up. (Modified from McKee et al “The natural history of congestive heart failure: the Framingham study.” NEJM, 1971; 285: 7796).

Figure 2

Pathways linking aging to heart failure. (Modified from Lakatta, EG. Age-associated cardiovascular changes in health: impact on cardiovascular disease in older persons. Heart Failure Rev.:2002 p1480).

FIGURE 3

Arterial and cardiac changes that occur with aging in healthy humans. (Modified from Lakatta, EG: Cardiovascular regulatory mechanisms in advanced age. Physiol. Rev 73: 413–465, 1993).

FIGURE 4

Longitudinal changes in peak VO₂ by gender, predicted from the mixed-effects model, and separated by gender in panel A with the percent change by decade represented in panel B. A. Peak VO₂ declines progressively more steeply with advancing age, with similar declines in men and women. Note that peak VO₂ is only slightly higher in men than women at younger ages, converging by old age. B. Per-decade longitudinal changes in peak VO₂ by gender and age decade, derived from the mixed-effects model. Note that longitudinal declines in peak VO₂ steepen with age and that men decompensate at an accelerated, though similar rate after age 60. (With permission from Strait JS, Lakatta EG Cardiac Aging: Aging from human to molecules” Muscle, 2011. Modified by Ferrucci, L from Fleg JL, Morrell CH, Bos AG, et al. Accelerated longitudinal decline of aerobic capacity in healthy older adults. Circulation 2005;112:674–682).

Figure 5

Diastolic Function at Rest and with Exercise A. The Doppler diastolic time-flow-velocity profile, showing the E and A waves from which the indexes of diastolic filling performance are derived. Time is represented on the horizontal axis. A simultaneous electrocardiogram (ECG) is shown as a timing reference to indicate atrial and ventricular activation. LV indicates left ventricular. B. The ratio of early left ventricular diastolic filling rate (E) to the atrial filling component (A) declines with aging, and the extent of this E/A decline with aging in healthy BLSA volunteers is identical to that in participants of the Framingham Study. (With permission from Strait JS, Lakatta EG Cardiac Aging: Aging from human to molecules” Muscle, 2011.) C. Maximum left ventricular (LV) filling rate at rest and during vigorous cycle exercise assessed via equilibrium gated blood-pool scans in healthy volunteers from the BLSA. EDV, end-diastolic volume. (With permission from Strait JS, Lakatta EG Cardiac Aging: Aging from human to molecules” Muscle, 2011).

FIGURE 6

An overview of change in the aging heart that predispose to a reduced threshold for abnormal Ca2+ handling during acute stress. See text for details. (With permission from Strait JS, Lakatta EG Cardiac Aging: Aging from human to molecules” Muscle, 2011. Modified from Lakatta, E. G., Sollott, S. J., & Pepe, S. (2001). The old heart: operating on the edge Novartis Foundation symposium, 235, 172-96).

FIGURE 7

(A) Stroke volume index (SVI) as a function of end-diastolic volume index (EDVI) at rest (R) and during graded cycle workloads in the upright seated position in healthy Baltimore Longitudinal Study of Aging (BLSA ) men in the presence and absence (dashed lines) of β-adrenergic blockade. R, seated rest; 1–4 or 5, graded submaximal workloads on cycle ergometer; max, maximum effort. Stroke volume vs end-diastolic functions with symbols are those measured in the presence of propranolol; dashed line functions without symbols are the stroke volume as vs end-diastolic functions measured in the absence of propranolol. Note that in the absence of propranolol the SVI vs EDVI relation in older persons (dashed lines) is shifted rightward from that in younger ones (dashed lines with points). This indicates that the left ventricle (LV) of older persons in the sitting position compared to that of younger ones operates from a greater preload both at rest and during sub-maximal and max exercise. Propranolol markedly shifts the SV-EDVI relationship in younger persons (▲ without points) rightward, but does not markedly offset the curve in older persons (●). Thus, with respect to this assessment of ventricular function curve, β-adrenergic blockade with propranolol makes younger men appear like older ones. The abolition of the age-associated differences in the LV function curve after propranolol are accompanied by a reduction in heart rate, which at max, is shown in (B) Peak exercise heart rate in the same subjects as in A in the presence and absence of acute β-adrenergic blockade by propranolol. (C) The age associated reduction in peak LV diastolic filling rate at max exercise in healthy BLSA subjects is abolished during exercise in the presence of β-adrenergic blockade with propranolol. Y, <40 years; 0, >60 years (14). (With permission from Strait JS, Lakatta EG Cardiac Aging: Aging from human to molecules” Muscle, 2011)

Figure 8

Age associated changes in arterial structure and function in men (stars) and women (squares) in the Baltimore Longitudinal Study of Aging (BLSA). Best fit regression lines (quadratic or linear) are shown for men (solid lines) and women (dotted lines). (A) Aortic root size (measured by M-mode Echocardiography) indexed to body surface area. (B) Common carotid-intima-medial thickness (measured by B-mode ultrasonography). (C) Carotid-femoral pulse wave velocity (an index of central arterial stiffness). (With permission from: Najjar SS, Lakatta EG, Gerstenblith G. Cardiovascular Aging: The Next Frontier in Cardiovascular Prevention. In Prevention of Cardiovascular Disease: Companion to Braunwald’s Heart Disease Blumenthal R, Foody J, Wong NA (editors). 2011. Saunders, Philadelphia, 2011:415–432).

FIGURE 9

Ventricular pressure-volume diagram from which effective arterial elastance (EA) and left ventricular (LV) end-systolic elastance (ELV) are derived. EA represents the negative slope of the line joining the end-diastolic volume (EDV) and the end-systolic pressure (ESP) points. ELV represents the slope of the end-systolic pressure-volume relationship passing through the volume intercept (V0). The shaded area represents the cardiac stroke work (SW), and the hatched area represents the potential energy (PE). LV ESP is the LV pressure at the end of systole. EDV is the LV volume at the end of diastole. End-systolic volume (ESV) is the LV volume at the end of systole. Stroke volume (SV) is the volume of blood ejected by the LV with each beat and is obtained from subtracting ESV from EDV. BP, blood pressure; EF, ejection fraction; PVA, pressure-volume area. (With permission from Chantler, Lakatta, Najjar. Arterial-ventricular coupling: mechanistic insights into cardiovascular performance at rest and during exercise, J Appl Physiol 105:1342–1351, 2008, and based on Sunagawa et al. 1983. Left ventricular interaction with arterial load studied in isolated canine ventricle. The Am J of Phys, 245 (5 Pt 1), H773-80).

FIGURE 10

(A) Arterial ventricular coupling indexed for body surface area (E_aI/E_LVI), (B)Effective arterial elastance indexed to body surface area (E_aI), and (C) Effective left ventricular elastance indexed to body surface area (E_LVI) in men (dashed lines) <40 yr of age (triangle) and >60 yr of age (circle) as well as women (solid lines) <40 yr of age (diamond) and >60 yr of age (star) in the supine and seated positions, at 50% of maximal workload, and at peak exercise. E_aI/E_LVI decreases during exercise in both young and older men and women (P < 0.0001). However, older men and women have a blunted decline in E_aI/E_LVI (P < 0.001). E_aI increases during exercise in both young and older men and women (P < 0.0001). At maximal exercise, E_aI is greater in older vs. younger women (P < 0.002). In contrast, E_aI does not differ between young and older men. E_LVI increases during exercise in both young and older men and women (P < 0.0001). At maximal exercise, E_LVI is greater in younger vs. older men (P < 0.001) and tended to be greater in younger than older women (P < 0.07). (With permission from Strait JS, Lakatta EG Cardiac Aging: Aging from human to molecules” Muscle, 2011. Modifed from Najjar SS, Schulman SP, Fleg JL, et al. Relationship of age and sex on ventricular-vascular coupling at rest and exercise. Circulation 2000(Suppl);102:II-602).

FIGURE 11

Changes in the injury and protection thresholds in aging heart. (A) Aging diminishes the hearts threshold to sustain injury (e.g., from ischemia/reperfusion, etc.). Lifestyle modifications, including exercise and possibly caloric restriction, may partially diminish the aging effect. Comorbidities (such as diabetes) have negative influence. (B) Aging increases the hearts threshold to activate protection-signaling mechanisms. Various pharmacologic agents (e.g., sulfonylureas, antioxidants, partial fatty acid oxidation (PFAO) inhibitors, and COX-2 inhibitors) that can interfere with cardioprotective signaling-pathways can exacerbate this trend and further increase the protection threshold. Exercise and caloric restriction might attenuate the age-dependent trends (Modified from Juhaszova M, Rabuel C, Zorov DB, et al: 2005. Protection in the aged heart: preventing the heart-break of old age? Cardiovasc Res 66: 233–244).