(Circulation. 1996;93:1608-1612.)
© 1996 American Heart Association, Inc.
Articles |
Aging and Cardiovascular Disease
A Summary of the Eighth Münster International Arteriosclerosis Symposium
From the University of Chicago (Ill) Medical Center and the Laboratoire de Biologie Cellulaire, Equipe de Tissu Conjonctif, Université Paris VII.
Correspondence to R.W. Wissler, PhD, MD, Distinguished Service Professor of Pathology, The University of Chicago Medical Center, Department of Pathology, MC 3083, 5841 S Maryland Ave, Chicago, IL 60637.
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Introduction |
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 Top Introduction |
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This unique symposium focused on the remarkable increase in the older population that is occurring in many countries of the world. The international experts spoke on the effects of aging on cardiovascular disease, which is by far the most prominent cause of morbidity and mortality in the elderly. The program highlighted some of the most prominent changes that occur in the elderly and influence the toll that cardiovascular disease takes. The program was divided into four sessions: (1) the effects of aging on some of the cardiovascular risk factors; (2) the effects of aging on the heart muscle; (3) reports on recent studies of the effects of aging on morphology and function of the conduction system; and (4) a session featuring outstanding authorities on aging and the elastin, collagen, and calcium of the vessel wall, all of which are frequently added to the artery wall during aging. The speakers were carefully selected from top scholars in England, Germany, Finland, France, Italy, Japan, and the United States.
Professor W.H. Hauss, who pioneered the development of the Institute for Arteriosclerosis Research at the University of Münster, Germany, and is now in his 80s, opened the symposium and introduced four prominent officials in health, education, and other German government posts, who added their words of welcome.
The first session was chaired by Professor G. Assmann, who is the current director of the Arteriosclerosis Research Institute in Münster, Germany. He gave the opening presentation on genetic determinants of life expectancy, a subject on which he is a world authority. He began his presentation with a brief description of the very large PROCAM study of more than 35 000 individuals, two thirds of whom are male, being carried out at the University of Münster Arteriosclerosis Institute in Westphalia. This long-term study of the natural history of stroke, cancer, and myocardial infarction in this population has already produced many significant results concerning risk factor effects on the susceptibility of individuals to heart attacks and stroke.
The PROCAM study to date indicates that HDL cholesterol is the most decisive factor in the myocardial infarction attack rate after age 75 years. These and other statistics have led Professor Assmann to study the genetic defects affecting LDL and HDL, which may not be recognized by the usual laboratory tests of levels in the serum but may be very important factors affecting cardiovascular mortality.
To perfect our ability to recognize genetic abnormalities in LDL and HDL, the Münster Institute laboratory has developed a pool screening technique that can detect DNA abnormalities in more than 5000 PROCAM individuals very quickly. The results of this type of screening have led to the discovery of a number of genetic defects in the LDL apolipoproteins (apo) B and E. Professor Assmann emphasized the importance of apo A-I in removing cholesterol from the cell after the transfer proteins have brought it to the inner layer of the plasma membrane, and he noted that the E4, E4 polymorphism increases cholesterol cellular uptake in aging arteries and also leads to marked decreases in serum HDL cholesterol. A recent report indicates that 10% of the polymorphism of apo A-IV is characterized by a metabolic defect in which dietary cholesterol intake becomes very important and minor differences in LDL apo B receptors may influence the life expectancy of the individual.
Professor Assmann then turned to some of his most recent areas of investigation. Genetic defects of lipase formation and function influence triglyceride levels, frequently coupled with low HDL cholesterol, both contributing to progression of atherosclerosis. He summarized Lp(a) genetic variations, which also seem to influence ischemic heart disease frequency, as do some of the genetic variations of the plasma level of fibrinogen.
Professor M.J. Tikkanen of the first Department of Medicine at Helsinki University Hospital was the second speaker. He spoke on cardiovascular risks in women, with special emphasis on the effects of age and menopause. At about age 50 years, according to the Framingham study, the serum cholesterol of women begins to be higher, on average, than that of men. This trend starts much earlier in female heavy smokers. But if estrogen treatment is initiated at this time, the LDL cholesterol increment is decreased, and it remains lower than that found in men of the same age. The most critical data indicate that the serum estrogen level is directly related to the ultimate HDL cholesterol level as well as to the LDL cholesterol level.
Professor Tikkanen emphasized the close association of the depression of HDL cholesterol in the blood and the combination of menopause and cigarette smoking, depending to some extent on how many cigarettes are smoked per day. He also quoted a number of studies indicating that one can definitely change the risk of clinical cardiovascular events with estrogen therapy.
Professor S. Grundy, director and chairman of the Center of Human Nutrition and the Department of Clinical Nutrition at the University of Texas Southwestern Medical Center in Dallas, Tex, spoke next. He pointed out that in general, serum cholesterol values increase with age in both men and women and that most of this is due to increases in LDL cholesterol, because LDL cholesterol clearance is decreased in older individuals. He also presented habitual diet data indicating a trend toward increased cholesterol intake by the elderly. Dr Grundy pointed out that body mass also increases with age, which parallels the increase in serum cholesterol. He related this to the recently discovered triad of insulin resistance, obesity, and lipoprotein disturbances as well as the trend toward a concomitant decrease in HDL cholesterol. The increase in LDL cholesterol with age frequently seems to be associated with a triglyceride increase and insulin resistance. Unfortunately, this is often related to an increase in blood pressure and a decrease in HDL cholesterol.
As another example of lipoprotein changes related to aging, he mentioned the apo E4 association with Alzheimer's disease, which is receiving so much attention at present.
He also covered the important relationship between diet and triglycerides and the important association of these with lipids coming into the portal circulation and the development of abdominal obesity. He indicated that this is more frequent in elderly women and may be augmented by the loss of estrogen activity and the associated insulin resistance that is frequently observed.
The fourth speaker on this part of the program, dealing with risk factors as influenced by aging, was Professor W. Palinski from the Department of Medicine at the University of California at San Diego, La Jolla. His studies have dealt particularly with the development and the effects of autoantigenic epitopes of oxidized lipoproteins as a result of the changes that occur during oxidation and the similar effects of advanced glycosylation of lipoproteins. He reports that oxidation of lipoproteins results in the formation of lipoperoxides, which can be found in atherosclerotic lesions. Furthermore, he and his coworkers have demonstrated that circulating antibodies to these epitopes are made and that immune complexes can be demonstrated in the serum. He showed immunohistochemical preparations demonstrating that IgG is found in these arterial lesions and that these are specific for the epitopes of oxidized LDL.
Then he reviewed the mechanisms by which glycosylation changes the lipoprotein molecules and summarized the data indicating that these products collect in the arteries of diabetic subjects and in the arteries of animal models of diabetes, including the arteries of diabetic Watanabe rabbits that are developing atherosclerosis. In this animal model, both oxidized LDL and glycosylated LDL have been demonstrated in the same arterial lesions.
He gave a summary of some of the many experimental attempts at intervention to counteract these reactions to altered LDL that lead to augmented atherogenesis. Aminoguanidine is a good example of an antioxidant that seems to be highly effective, especially when administered with vitamin E. It has been amazingly effective when used in apo E gene knockout transgenic mice, which are particularly prone to atherosclerosis.
In the final presentation of this part of the program, Professor A. Postiglione and his coauthor Professor M. Mancini of Naples, Italy, presented evidence supporting the treatment of cardiovascular risk factors in the elderly. Life expectancy is increasing all over the world, and women are not necessarily always the favored half of the population in this respect. In fact, in Italy, older women consistently have higher cholesterol values than older men at almost every part of the upper age range. Unfortunately, hypercholesterolemia is common in older people even when they remain active and consume a Mediterranean diet, which is relatively low in fat and high in monounsaturated oil and contains relatively little animal protein and abundant complex carbohydrates.
Professor Postiglione stated that the evidence at present indicates that individuals with elevated cholesterol should continue treatment even at a very old age. It is particularly important for those individuals who are in relatively good functional, cognitive, and emotional states to practice this kind of preventive cardiology. These individuals need to be supported and protected in every way possible, and they deserve careful medical management to avoid any tendency toward depression or chronic cardiovascular illness.
He pointed out that cerebral strokes seem to have different risk factors and emphasized that it is particularly important in this respect to diagnose and treat hypertension and to do everything possible to overcome the addiction to smoking and to include aspirin, at least 75 mg/d, as a part of the preventive measures. One needs to support the attempts to continue moderate and regular physical activity. In his experience, the level of LDL in the serum did not seem to be nearly as relevant in preventing cerebrovascular disease as it is in preventing coronary disease.
This session provided an excellent overview of the numerous risk factors that need to be modified or counteracted by skillful medical and public health management if the elderly are to have the pleasant and active years that are desirable. Furthermore, society will benefit greatly if the octogenarians are able to avoid the debilitation of strokes and chronic heart failure so that their children and grandchildren will be better able to enjoy their company and to benefit from their wisdom.
The second session was chaired by Professor G. Breithardt, the head of Cardiology and the associate director of the Arteriosclerosis Institute at the University of Münster. It dealt with the effects of aging on the myocardium.
The first speaker was P. Anversa from Valhalla, NY. He reported the results of studies of myocardial hypertrophy in the aging rat, pointing out that there is a remarkable increase in collagen and a decrease in functional myocardial cells by as much as 38%. He emphasized the need for a more complete study of apoptosis and bionecrosis, which probably increases by 10-fold. The changes in coronary blood flow with aging also need additional definitive study.
The second speaker of the second session was Dr. E.G. Lakatta from the Laboratory of Cardiovascular Science at the Gerontology Research Center of the National Institute of Aging in Baltimore, Md. He spoke on the decrease in cardiovascular reserve during aging accompanied by chronic heart failure, which increases remarkably after the age of 60 years. He has been studying a constant group of older individuals in an effort to relate their cardiovascular status to aging, various disease processes, and lifestyle. He finds that their blood pressure increases with age and that in older individuals, the heart dilates with exercise and stays dilated for longer periods, even though the stroke volume remains constant. The ejection fraction is also maintained with exercise, but the reserve capacity of the heart decreases substantially. The other changes that are observed in these individuals during exercise are a decrease in the maximum heart rate, an increase in cardiac size, and a decrease in cardiac emptying.
Dr Lakatta then considered the vascular changes that have been observed during aging. He emphasized the increase in arterial stiffness that occurs with age, even though vascular tone does not change after sodium nitroprusside has induced smooth muscle cell relaxation. Thus, relatively stiff arteries are of some value because they help maintain blood pressure in older people.
Dr Lakatta discussed myocardial cell contraction and how it is influenced by aging, which depends on the changing function of the Ca2+ channels on the surface of myocardial cells. This is a fruitful area for further research.
The third presentation of the second session was given by Drs M. Böhm and E. Erdmann of the Internal Medicine Clinic at the University of Cologne in Germany. Their subject was inotropism and adrenergic signal transduction in the aging myocardium, which followed naturally from the previous two presentations. These workers described their studies of the effects of mechanical load, contractile dysfunction, sympathetic nerve activation, and ß-adrenergic desensitization on the function of the aging rodent heart. They have determined that the ejection fraction of the aging heart is usually not altered and have observed a decrease in myocytes accompanied by a definite increase in interstitial tissue.
In discussing how these aging hearts react to exercise, they pointed out that the relationships between cell length and tension, systolic force, diastolic fraction, and response to adrenergic stimuli all change. They also noted that there is an increase in wall motion and end-diastolic volume and a decrease in cardiac output without a similar increase in heart rate. The cardiac response to norepinephrine is altered, and the release of calcium is no longer adequate. The cyclases are decreased, and there seems to be a defect in the clearing of norepinephrine from the system. In fact, their studies indicate that serum norepinephrine rises to much higher levels in older individuals because of a defect in norepinephrine uptake and extraction.
Accompanying these altered reactions, they found that signal
transduction decreases with aging in SpragueDawley rats
and that the ß-receptors as well as the 
-receptors and the
ß-adrenergic receptors in the myocardium are also
decreased. In their summary, they emphasized that because of these
changes, the aging heart responds much more poorly to training and the
myocardium is much more sensitive to the toxic effects of
digitalis, isoproterenol, and other powerful stimulatory drugs.
The fourth presentation of the second session was given by Dr B. Swynghedauw and his coworkers of Hôpital Lariboisière of Paris, France. He reported on the senescent rat heart, with special emphasis on the phenotypic changes that are related to arrhythmias and heart rate regulation. This group has been working on aging of the cardiovascular system in Wistar rats and in spontaneously hypertensive rats (SHRs). Their studies emphasize the yang and yin effects as applied to the fibrosis and the independent endocrine vascular changes that occur simultaneously during senescence. They have concentrated especially on the senescent changes in the renin-angiotensin system in the rat at 18 months. The renin concentration goes up, but angiotensin II levels decline, and these are contrasting changes that occur in the left ventricle but not in the right ventricular myocardium. In their animal models, heart rate variability (HRV) is studied in relation to hemodynamic overload. The expression of the gene that encodes the membrane proteins responsible for myocardial calcium metabolism changes when the hypertrophied myocyte loses some of its capacity to buffer calcium changes. They are defining the biological parameters that characterize the muscarinic and adrenergic systems. These, too, are modified in relation to the impaired HRV control. Transgenic manipulation of these rodents results in an overexpression of atrial ß1-arrhythmias and ß-blockers.
They have obtained definite evidence that the degree of fibrosis in the aging heart can be reversed in both the older SHRs and older Wistar rats, with reduction of the collagen density and of the premature beats that were evident in the SHRs.
The fifth presentation of the second session was given by
Dr W. Haverkamp and Professor G. Breidthardt from the Institute of
Arteriosclerosis Research at the University of
Münster in Germany. They discussed the effects of aging on the
ECG and on arrhythmias in the clinical setting. They pointed
out that there have been few studies evaluating the various types of
arrhythmias in the elderly. One of these is the
Cardiovascular Health Study at four centers in the
United States involving 5201 men and women 
65 years old. AV block is
the most frequent defect in men of all ages up to 85 years. In women,
one of the main defects with aging is a prolonged QT interval. In their
presentation, they point out that 24-lead monitoring
provides a useful predictor of impending problems, and they conclude
that ventricular tachycardia is the major
forerunner of serious heart attacks or impending
ventricular fibrillation.
They called attention to a 1992 study that showed a marked difference in the heart rhythm disturbances in older patients. They demonstrated that propranolol treatment reduced mortality when it was administered after a heart attack, especially in patients between 60 and 69 years of age.
The third session was chaired jointly by Professors R.W. Wissler of the University of Chicago, Ill, and L. Robert of the Laboratoire de Biologie Cellulaire at the University of Paris VII, France. It was opened with a presentation by Professor S. Bharati. Dr Bharati, a world-renowned authority on the diseased conduction system, serves as a professor of pathology at Rush Medical College in Chicago and at the Maurice Lev Congenital Heart and Conduction Center of the Heart Institute for Children at Christ Hospital in Palos Heights, Ill. She pointed out that with advancing age, there is an increase in ß-elastic and collagenous tissues in all parts of the conduction system and an increase in fat tissue around the sinoatrial node as well as in the atrial septum, the AV node, and the bundle of His. These changes are usually associated with fibrosis near the summit of the ventricular system and are most common in hearts from hypertensive individuals or individuals who have had severe coronary heart disease or severe and widespread sclerosis of the small arteries in the myocardium as well as patients with amyloidosis of the heart.
Occasionally, calcification of the diseased parts of the conduction system is also present. This appears to be associated with calcification of the base of the aortic valve, the membranous septum, and the mitral valve base. Arrhythmias such as sick sinus syndrome, atrial fibrillation, bundle-branch block, or complete AV block are the most frequent associated clinical states, depending on the site of the most severe involvement of the conduction system. Unfortunately, these changes may also be one of the causes of sudden death in the elderly. However, atrial fibrillation is the most common of these arrhythmias and among the most easily treated, so that the elderly subject can lead a useful and relatively symptom-free life.
One of the challenges for future research is to investigate the varying influences of both genetic and environmental factors that affect the cause and pathogenesis of these conduction defects.
Professor A.J. Camm of London then presented additional data on age-dependent alterations of the conduction system, emphasizing the clinical arrhythmias associated with various pathological changes. For example, he noted that the frequency of fibrotic modifications of the conduction system, which increases from 17% at <50 years of age to 36% in individuals >60 years of age, while the percentage of myocytes in the sinoatrial node drops from 46% to 27% and the percentage of fatty change in the conduction system increases substantially. These changes result in a steady decrease in maximal heart rate and a progressive decrease in heart rate relative to blood pressure, both of which appear to be associated with vagal neuropathy and a loss of ß-adrenergic receptors.
Treatment with theophylline, low-activity isoprenalin, and pacemakers was discussed by Professor Camm, who noted that age-related myocardial incompetence continues to progress even in paced patients, but longevity frequently appears to be restored.
Professor J.L. Fleg from the Laboratory of Cardiovascular Sciences at the Gerontology Research Center at the NIH in Baltimore, Md, then spoke about the age-dependent prevalence of conduction defects as well as their prognostic significance. Prevalence is estimated from the Baltimore Longitudinal Study as being about 4%, with an increase in the PR interval from about 160 to about 170 ms, with a resulting atrial fibrillation prevalence of about 13% of total observed cases in the absence of any current disease. The frequency of right bundle-branch block increases steadily with age to reach about 4 per 1000 of the studied population >50 years of age.
Professor R. Okada of Tokyo then gave an overview of the most frequently observed conduction defects in the Japanese aging population. He gave a figure of atrial fibrillation of 3% of the over-65 population and right bundle-branch block of about 4% in men >70 years old. He noted a rather high frequency of sick sinus syndrome and AV block in elderly women in Japan.
His pathological study of 207 autopsy hearts from patients with conduction defects confirms the prevalence of fibrotic changes and fatty changes accompanying loss of myocytes. In cases of AV block, the fibrofatty degeneration interrupted the distal end of the His bundle in women and the proximal bundle branch in men.
Professor Okada also described the potential pathogenetic role of ischemia, inflammation, or metabolic disorders in conduction defects. He indicated that in the young as well as in the old population, mechanical stress and autonomic nerve stimuli may well play a crucial role.
The afternoon of the second day of the symposium was devoted to the age-dependent changes in the vessel wall and their relationship to atherogenesis. This meeting was chaired by Professor Robert.
The first presentation was by Professor Robert, who emphasized cellular and molecular mechanisms of vascular aging, including the interactions between arteriosclerosis and atherosclerosis, ie, that although arteriosclerosis frequently increases in severe atherosclerosis, they are independent processes. He has studied elastin peptides in the circulating blood of several thousand people and found levels that would saturate elastin-laminin receptors on the endothelial cells. This receptor, which mediates the NO-dependent vasorelaxation, is inhibited by laminin and lactose. This receptor, present on monocytes, also mediates chemotactic movements and triggers the release of superoxide and lytic enzymes. During aging, the receptor loses its coupling to its transmission pathway but still mediates release of free radicals.
Out of his wealth of work, Professor Robert proposes a hypothesis to account for the age-dependent modification of the vascular wall, which indicates that the simultaneous release of NO and O2- results in peroxynitrite formation (ONOO-), with known toxic effects. The resulting decrease in NO available for vasodilatation increases the need for reduced glutathione, so that antioxidant defenses decline with age. The progressive endothelial damage may lead to loss of the calcium homeostatic regulations and an increase in the entry of oxidized LDL into the artery. This process could be the basis for the progressive increase of lipids and calcium in elastic tissues, the degradation of the tissues by elastases, and the progressive cross-linking of collagen fibers by nonenzymatic glycation.
Dr G. Fleckenstein-Grün from the Physiology Institute at the Albert Ludwigs University in Freiburg, Germany, continued the consideration of calcium and the aging of coronary arteries. She described several processes, such as the accumulation of free radical metabolites, lipid peroxidation of proteins and lipids, and damage to arterial DNA, that along with the accumulation of free and total cholesterol are notable between the first and ninth decades of life. Calcium ions may be critical in mediating age-dependent modification by (1) binding to elastin, (2) decreasing reactions that increase intracellular calcium and elastase release, and (3) decreasing myocardial calcium overload, which may be responsible for progressive myocardial cell death. She emphasized the notable, conspicuous increase of calcium in coronary artery plaques, which may be as much as 12-fold in fatty streaks, 24-fold in fibrous plaques, and 80-fold in complicated advanced plaques.
Dr Fleckenstein-Grün indicated that calcium is a neglected key factor in hypertension, and the clinical trials being conducted may in time indicate the best therapeutic approaches for preventing many of the effects of hypertension.
Dr J.B. Michel of INSERM in Paris, France, discussed induced arterial wall enlargement during aging. Her studies in Wa-Rij rats indicate that wall rigidity and enlargement of the aorta are responses to pressure and shear stress and may be associated with large biosynthetic activities of arterial smooth muscle cells. ACE inhibitors do not modify elastin calcification in the rat. Histamine-induced vasodilatation appears to be progressively decreased with age as well.
Professor J. Atkinson from the Department of Pharmacology at the University of Nancy, France, spoke further about calcium and aging in the compliance and resistance of arteries. He, too, has been using 2-year-old normotensive rat arteries compared with young rat arteries as well as those with induced elastocalcinosis. He emphasized that the calcinosis concerns primarily the elastic elements and leads to stiffening of the vessel wall as well as arterial enlargement. He finds that the increase in calcium deposition involves mainly elastic fibers near the intima and can be responsible for some of the increased cross-linking involving desmosine and isodesmosine. His measurements include changes in impedance, compliance, and pulse velocity. Detailed studies of the carotid artery have involved intracellular calcium monitoring with fura-2. He has studied the effects of norepinephrine and ionomycin and found a strong modification of the rheological properties of the artery wall produced by calcium deposition in elastic fibers.
Similar mechanisms may be involved in left ventricular mass enlargement and in the age-dependent increase of the lower pressure limit of cerebral blood flow, which may increase the probability of ischemic cerebral damage. Professor Atkinson has found that long-term treatment with ACE inhibitors reduces the aortic calcium overload and its structural and functional consequences. He suggests a possible role of adrenergic receptors against age-dependent sympathetic hyperactivation in preventing age-linked uncoupling of intracellular transduction amplification pathways. Further use of these two models may lead to new pharmacological approaches to counteract extracellular elastocalcinosis and intracellular G protein–mediated coupling mechanisms.
Professor K. Sames of the University of Hamburg, Germany, then spoke on age-related changes in vascular proteoglycans. He pointed out that the composition of glycosaminoglycan chains of vascular proteoglycans are altered with age, so that chondroitin sulfate and keratan sulfate are relatively increased. He indicated that these may be important in relation to lipid retention in the artery wall. He has studied the aging process of artery cells in vitro by means of increasing passage numbers and has found a relative increase in heparan sulfate chains and modifications of size and distribution of proteoglycans.
Professor Robert concluded the meeting by summarizing many of the new concepts that have been developed concerning uncoupling of receptors active in the regulation of vascular and myocardial functions. He emphasized that free radical damage may be one of the underlying mechanisms in the aging process.
He recommends the detailed study of suitable animal models of vascular aging, which are leading to new targets and novel mechanisms to counteract age-dependent vascular modifications such as arteriosclerosis and atherosclerosis. In conclusion, he stated that the rapid increase in the proportion of the aging population worldwide renders imperative the intensification of pharmacological research on this relatively neglected area of vascular pathology.
Professor Hauss thanked the speakers and coorganizers for their presentations and for their emphasis on the role of the altered mesenchyme in the development of cardiovascular disease.
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