The Clinical Reality

It is estimated that by the year 2035, nearly one in four individuals will be 65 years of age or older. Cardiovascular diseases, such as coronary artery atherosclerosis and hypertension, and resultant chronic heart failure (CHF) reach epidemic proportions among older persons and are the leading cause of mortality in the United States, accounting for over 40 percent of deaths in those aged 65 years and above. The incidence of CHF increases 9-fold in men and 11-fold in women annually between the sixth and ninth decades of life, and in persons aged 80-89 years the annual incidence of CHF is 27 per 1000 in men and 22 per 1000 in women. Prevalence rates are similar to those of incidence. Thus, age, per se, is a major risk factor, if not the major risk factor, for chronic heart failure. The clinical manifestations and prognosis of heart failure also worsen with increasing age. Heart failure accounts for more hospital admissions in the older population, than any other single condition: about 50% are readmitted within 6 months. Long-term survival is very poor with a minority surviving 5 years after diagnosis. The changing population demographic in the US virtually ensures that these numbers will become more remarkable in the coming years. In fact, CHF is the only major cardiovascular syndrome that is increasing, and it is considered the cardiovascular epidemic of the new millennium, and as a result, has been designated a national research priority.

Interactions of the Cardiovascular Aging Process and the Pathophysiology of Cardiovascular Diseases

Alterations in Cardiovascular Structure and Function in Otherwise Healthy Older Persons

Clinical manifestations and prognosis of cardiovascular diseases are exaggerated in older persons of advanced age, in part, because of interactions that occur between age-associated cardiovascular changes in health and specific pathophysiologic mechanisms that underlie a given disease. In other words, the specific pathophysiological mechanisms that cause clinical disorders in older persons become superimposed on heart and vascular substrates that have been modified by aging per se. A fundamental understanding of age-associated changes in cardiovascular structure and function, ranging in scope from humans to molecules, is tantamount to unraveling age-disease interactions, but this is what is required for effective and efficient prevention and treatment of cardiovascular disease and resultant CHF in older persons. Differences in cardiovascular function between older and younger individuals have been extensively described in the literature. However, confusion often arises in the interpretation of these differences because of a failure to acknowledge, or to control for, interactions among age, disease, and life-style. Genetic components of aging, disease and lifestyle that presently remain largely unknown probably complicate the picture further. Based on studies that have attempted to address these interactions, a mosaic of multiple specific age-associated changes in cardiovascular structure and function has emerged.

Cardiovascular structure and function at rest
Generally, a significant loss of cardiac myocytes occurs during the normal aging process in both humans and animals. Still, left ventricular wall thickness (LV) increases with age, due largely to an increase in the size of remaining cardiac myocytes. Focal increases in LV collagen also occur with aging. There is considerable evidence to indicate that multiple components of the vascular load on the LV increases with age, due, in part, to an age-associated increase in arterial stiffening. These vascular changes, and an associated increase in systolic blood pressure at rest with aging, are likely causes of the age-associated increase in LV diastolic wall thickness. However, in older persons free of disease, the exquisite cardiac and vascular load matching characteristic of younger persons is preserved at least at rest, because the increased resting vascular stiffness with aging is accompanied by an increased total ventricular systolic stiffness. The fraction of LV end-diastolic volume ejected with each beat (ejection fraction, EF) at rest is approximately 65% and does not decline with age. However, the stiffer arterial system and adaptive changes in the heart, while maintaining normal ventricular vascular coupling at rest, has several implications which include: 1) an enhanced lability of cardiovascular function; 2) limited reserve capacity; 3) a greater pressure sensitivity to vasodilators or blood volume alterations; 4) compromised coronary flow and exacerbated responses to myocardial ischemia; and 5) a greater likelihood of more severe heart-vascular mismatching when heart failure occurs. Thus, from the standpoint of coupling optimization, the normal aged heart appears to be far less adaptive and more vulnerable to disease than a younger one.

Cardiovascular reserve capacity
When cardiovascular reserve function in healthy, adult volunteer community-dwelling subjects ranging in age from 20 to 85 years is compared, impaired LV ejection reserve capacity, due to failure of older persons to regulate ESV as effectively as younger ones, is among the most dramatic cardiac changes noted. Impaired ESV regulation in older healthy persons is accompanied by LV dilation at end diastole and an altered diastolic filling pattern, and by diminished acceleration of the heart rate. However, while the failure to reduce ESV in older healthy persons impairs the EF reserve, these persons utilize the Frank Starling mechanism to maintain an SV of a similar magnitude to that in younger persons. However, the Frank Starling mechanism is deficient in older persons, due to impaired LV ejection, and their SV in the context of an augmented EDV is not greater than in younger persons, as would be anticipated if the Frank Starling mechanism remained intact. The deficiency in end systolic volume regulation and reduction in LV ejection fraction reserve in older persons result from deficient intrinsic myocardial performance, and from an augmented afterload, due, in part, to a deficiency in beta-adrenergic stimulation to enhance myocardial contractility or to reduce the pulsatile components of vascular afterload. These changes result in sub-optimal ventricular vascular coupling during stress in otherwise healthy older persons and limit cardiovascular reserve with advancing age. The net result is that persons at the older end of the age range (e.g. 90 years) can augment their cardiac index 2.5 fold over that at seated rest, while those at the younger end of the spectrum can increase their cardiac index 3.5 fold. A decrease in the maximum capacity for physical work with aging is due to both diminished cardiac reserve and to alterations in the peripheral circulation that limit oxygen delivery and utilization. It is noteworthy that in both older men and women there is substantial inter-individual variation in exercise capacity, LV ejection characteristics, heart rate, and maximum cardiac output. Physical conditioning can retard some of the cardiovascular deficits that accompany aging in health.

Altered Cell Function and Reduced the Cellular Response to Stress with Aging

Cellular mechanisms of age-associated changes in cardiac function, largely studied in rodents, include cardiac myocyte enlargement and coordinated changes in gene expression or changes in encoded protein levels or function. These changes modify several key steps of cardiac muscle excitation-Ca2þ release-contraction-relaxation coupling, resulting in a prolonged action potential (AP), a prolonged cytosolic Ca2þ (Cai) transient and a prolonged contraction and delayed relaxation. The altered cellular profile, which results in a contraction that exhibits a reduced velocity and a prolonged time course, can be considered to be adaptive rather than degenerative, because reduced shortening velocity is energy efficient and a prolonged contraction permits continued ejection for a longer period into the stiffened vasculature that accompanies advancing age. There is also a richly documented age-associated reduction in the postsynaptic response of myocardial cells to beta-AR stimulation, which appears to be due to multiple changes in molecular and biochemical mechanisms that couple the receptor to post-receptor effectors. The major limiting modification of this signaling pathway with advancing age appears to be at the coupling of the beta-adrenergic receptor to adenyl cyclase via the Gs protein, leading to a reduction in the ability to sufficiently augment cell cAMP to drive the phosphorylation of key proteins that are required to alter protein function and augment cardiac function.

Aggregate, age-associated alterations to the regulation cytosolic Caþþ concentration predispose the senescent myocardium to altered cell Caþþ homeostasis. Cardiocytes of senescent hearts exhibit a reduced threshold for pathologic manifestations of excess Ca2þ loading during stimulation (physiologic or pharmacologic) or in response to disease scenarios that increases Ca2þ influx, e.g., in response to neurotransmitters, post-ischemic reperfusion, or oxidative stress. Cell remodeling noted above is one cause of the relative Ca2þ intolerance of cardiocytes in the senescent heart; another cause is changes in the composition of membranes in which Ca2þ regulatory proteins reside, and a third cause is an enhanced likelihood for intracellular generation of reactive oxygen species. The net result is that the aged myocardium demonstrates an increase in the Ca2þ dependent component of diastolic tone, particularly at higher heart rates and reduced Caþþ threshold for diastolic after-depolarizations and for ventricular fibrillation. The multiple changes in cardiac excitation, myofilament activation, contraction mechanisms, and gene expression that occur with aging are interrelated. Many of these have been interpreted as adaptive in nature because they also occur in the hypertrophied myocardium of younger animals adapted to experimentally induced chronic hypertension. These adaptations underlie the maintenance of normal resting ventricular vascular coupling with aging, in spite of a stiffer vasculature. However, there is some evidence to suggest that the adaptive response to chronic pressure loading is reduced in older animals, possibly in part, because some of the adaptive capacity of the heart is used as a response to the aging process, per se. Specifically, the capacity for molecular adaptation to hemodynamic overload and/or ischemia is diminished in the aged hearts.

Chronic Heart Failure in Animals of Advanced Age

The difficulty in obtaining mechanistic information on heart failure in older humans provides a strong rationale to study animal models of heart failure associated with aging. Animal models with a predictable clinico-pathologic course such as the hypertensive rat provide an important resource for advancing our understanding of the genesis of heart failure in the aging hypertrophied heart. Hypertensive rats develop cardiac dysfunction and heart failure between 18-24 months of age, manifest by recognized clinical, pathological, and hemodynamic findings, as well as myocardial fibrosis, myocyte loss, and impairment of intrinsic myocardial function. Impaired calcium cycling in association with increased heart rates appears to contribute to systolic and diastolic dysfunction observed in the failing hypertensive rat myocardium. Virtually all manifestations of failure and associated changes in gene expression can be prevented by inhibition of production or blocking the effects of angiotensin II, a component of the neurohormonal system well-recognized to be activated in association with heart failure. Treatment with an angiotensin converting enzyme inhibitor or an angiotensin I receptor blocker prior to heart failure is able to prevent not only failure but also intrinsic myocardial tissue dysfunction in the old SHR rat. However, while treatment after failure demonstrates clinical improvement, as seen in humans, impairment of intrinsic myocardial function is not reversed.

Chronic Heart Failure in Older Humans

There is a substantial disparity between the importance of CHF in the older patient and our knowledge regarding it. This is due, in part, to significant variability in the effects of aging and to age/disease interactions. In older persons with CHF in whom myocardial contractility declines due to ischemic damage or other etiologies, adaptive ventricular-vascular matching that is preserved at rest in healthy older persons becomes sub-optimal, and further deteriorates during stress.

CHF in community-dwelling older persons is very often thought to occur with ''normal'' systolic LV function, particularly among women regardless of age. However, a resting ejection fraction of 65% (as occurs in men and women rigorously screened to exclude disease) ought to be the standard against which to gauge whether systolic function is ''normal''. In contrast to healthy older persons, many older persons who have symptoms of CHF with ejection fractions greater than 50% have an inability to increase end diastolic volume and stroke volume via the Frank-Starling mechanism despite severely increased LV filling pressure, indicative of diastolic dysfunction. These individuals often have an exaggerated increase in aortic stiffness beyond that of normal aging and this may contribute to their exercise intolerance; they can also have a systolic arterial pressure that exceeds that of older persons without CHF, i.e., they have systemic (specifically systolic) hypertension.

Abnormalities in diastolic chamber stiffening and relaxation probably contribute to the syndrome of CHF with an ejection fraction of 50% or more. The combined effect of exaggerated diastolic stiffening, and impaired left ventricular contractile reserve and reduced maximum ventricular vascular systolic stiffening, results in impaired vascular-ventricular coupling, which limits the LV to eject blood. In instances when venous, right heart, and pulmonary capacitance remain more normal than that of the left circulation, as is often the case in older persons, the sudden appearance of acute pulmonary edema often ensues. In the stressful scenario of acute pulmonary edema, surely an EF as low as 50% does not reflect ''normal'' systolic reserve function. Rather, both an inability of the left heart to fill and to increase its ejection capacity prevail. Thus, this scenario is one of mixed diastolic and systolic dysfunction.

Management of the Older Patient with Heart Failure

Chronic heart failure management in older patients is often complicated by the presence of multiple co-morbid conditions, financial or psychosocial issues, and non-compliance with complex medication and dietary regimens. Observational studies and randomized trial programs utilizing a semi-structured approach to chronic illness care have reported substantial reductions in hospital readmission rates for CHF associated with significant cost savings, improved quality of life and satisfaction with care, and enhanced compliance with medications and diet. Optimal management requires a systematic approach requiring coordination across caregiver disciplines, education of the patient, enhancement of self-management skills, the judicious use of medications, and effective follow-up. Most successful CHF management programs have utilized a case coordinator, typically responsible for 50-100 patients, usually a qualified nurse clinician or nurse practitioner, who provides appropriate educational materials, solicits the expertise of other team members and ensures proper follow-up. A distinctive feature of disease management from traditional care is the emphasis on developing self-management skills.

Since few of the ''old old'', i.e. those over 75 years of age, have been enrolled in clinical trials, the efficacy of current heart failure therapies remains uncertain in this age group. Exaggerated ventricular-vascular stiffening in older patients may also affect the therapeutic response to standard heart failure management strategies. In such patients, there is higher blood pressure sensitivity to diuretics, and thus a greater difficulty in titrating therapy due to pressure lability. Vasodilators will likely have a greater impact on systemic blood pressure than on cardiac output in the context of increased ventricular and vascular stiffness. Agents targeted to reduce the stiffness of both the heart and vasculature are good candidates for therapy in older patients with CHF. For example, drugs that counter aldosterone-induced fibrosis, such as spironolactone or angiotensin-II mediated changes (ACE-inhibitors and angiotensin receptor blockers) or new experimental medications that act by breaking non-enzymatic advanced glycation crosslinks, appear to be promising for reducing both ventricular and vascular stiffening in the aged cardiovascular system. Despite the fact that numerous clinical trials have convincingly documented the beneficial effects of ACE inhibitors and beta adrenergic receptor antagonists in treating CHF, these agents are largely underutilized in the elderly. As novel pharmacologic treatments are developed to improve heart and vascular stiffening, we will be better able to test the benefits of maintaining optimal coupling in restoring cardiovascular adaptability and resilience to disease insults.

Considerable evidence has accrued over the last two decades that cardiac rehabilitation programs can also benefit individuals with CHF. Improvements in functional capacity and quality of life have consistently been observed in CHF patients participating in these programs. Despite demonstrated benefits, a lack of Medicare reimbursement for these programs in CHF patients has stifled their widespread application to CHF patients.

As improvements in the treatment of CHF reduce mortality, the prevalence of CHF is expected to increase. Thus, changes in medical therapy of CHF and associated cardiovascular diseases may also contribute to a secular increase in the prevalence of CHF unless a dramatic advance in its prevention is realized. Given that the prevalence of CHF in older persons will increase markedly even if the incidence of the condition is stable, efforts aimed at the prevention of coronary events and prevention of hypertension will be critical in reducing the further burden of disease. However, even in the ''best'' case interventions scenario, the prognosis for established CHF in older patients remains poor. The main thrust of research must therefore be aimed at more effective strategies for heart failure prevention in our aging population. Finally, specific measures should be undertaken to plan for and facilitate end-of-life care in older patients.

The full Table of Contents of the special Heart Failure Reviews edition is as follows:

Introduction
Edward G. Lakatta, M.D.

The Burden of Chronic Congestive Heart Failure in Older Persons: Magnitude and Implications for Policy and Research
Frederick A. Masoudi, M.D., Edward P. Havranek, M.D. ,Harlan Krumholtz

Diastolic Heart Failure in the Elderly
Dalane Kitzman, M.D.

Cardiovascular Aging Without a Clinical Diagnosis
Edward G. Lakatta, M.D.

Concepts of Vascular-Ventricular Coupling in Advanced Age in Health and Their Implications for Heart Failure Therapies
David A. Kass

Acute and Chronic Adaptation to Hemodynamic Overload and Ischemia in the Aged Heart
Shogen Isoyama, M.D. and Yuko Komatsubara-Nitta, M.D.

Studies of Prevention, Treatment and Mechanism of Heart Failure in the Aging Spontaneously Hypertensive Rat
Oscar H. L. Bing, M.D., Chester H. Conrad, Marvin O. Boluyt, Kathleen G. Robinson, Wesley W. Brooks

Management of Heart Failure in the Elderly
Michael W. Rich, M.D.

Can Exercise Conditioning Be Effective in the Older Heart Failure Patient?
Jerome Fleg, M.D.

The abstracts of these articles can be accessed, online, free at:
http://www.kluweronline.com/issn/1382-4147. In addition, full texts in PDF format can be purchased.