My task is to provide some general information

AJH 1998;11:41S 45S Aging, Changes in the Cardiovascular System, and Responses to Stress Myron Weisfeldt My task is to provide some general information about the cardiovascular changes associated with aging as a background for consideration of the management of hypertension in an elderly population. I like to use the aging of vision as a model. Clearly there are factors that change vision with age and factors that do not change it provided that disease is avoided. A change in near vision during the forties and fifties is almost universal. If the problem is corrected with glasses, cataracts in the seventies and eighties are a second nearly uniform aspect of aging. Again if that problem is corrected, and eye disease is avoided, then vision remains remarkably normal throughout the remaining life span. Similarly aging in the cardiovascular system results from factors that change with age. But, there is much in the heart and circulation that does not change with age if there is no heart or vascular disease. WELL MAINTAINED WITH AGE When rat cardiac muscle is stretched to optimal length, the tension that is developed by adult rats aged 11 to 13 months (comparable to 30-year-old human beings) is essentially the same as the tension that can be developed by 24 to 27-month-old rats (comparable in age to people 60 to 70 years old). 1 Likewise, when cardiac muscle is stimulated with extracellular calcium, the dose-response curve for the maximum contractile tension is the same in young adult and normalaged muscle. In humans, echocardiography 2 and gated blood pool scans 3 indicate a similar absence of age-related From the Department of Medicine, Columbia-Presbyterian Medical Center, New York, New York. Address correspondence and reprint requests to Myron Weisfeldt, MD, Department of Medicine, Columbia-Presbyterian Medical Center, 630 West 168th Street, New York, NY 10032. changes in contractile function. In individuals with no history of myocardial or valvular heart disease and normal exercise stress-tests to exclude ischemic heart disease, there was no change in end-diastolic or endsystolic volume or ejection fraction. Likewise there is no change in ejection fraction after -blockade. The ejection fraction was similar for 17 young (average age 30 years old) and 11 elderly (average age 66 years old) individuals who had received intravenous propranolol in a dose sufficient to block a 25 beat/min increase in heart rate stimulated by isoproterenol. 4 Although both end-diastolic and end-systolic volume were slightly greater after -blockade, there were no agerelated differences with or without -blockade. Likewise, the velocity of circumferential fiber shortening, an index of intrinsic contractility, was not different as a function of age before and after -blockade. There was some decreased contractility after blockade, but the effect was the same regardless of age. Again, this supports the idea that there is no age-related change in the intrinsic ability of cardiac muscle to develop force or exhibit contractility. Similarly, in both experimental animals 5 and in humans, 6 there is direct evidence that there is no ageassociated change in the maximum capacity of the coronary vascular bed. When myocardial blood flow was measured at rest in the catheterization laboratory using coronary sinus flow techniques and then was again measured at maximum vasodilatation with dipyridamole, no differences were observed in individual human subjects from age 20 to age 90. Aging produced a slight increase in total coronary blood flow, which most likely reflects the increase in systolic blood pressure and left ventricular mass with age. There is no age-associated change in maximal vasodilation of the coronary bed. Thus age does not decrease cardiac muscle function or the inotropic response to calcium; moreover, coronary perfusion and the maximum dilatory capacity of the coronary vascular bed 1998 by the American Journal of Hypertension, Ltd. 0895-7061/98/$19.00 Published by Elsevier Science, Inc. PII S0895-7061(98)00009-0

42S WEISFELDT AJH MARCH 1998 VOL. 11, NO. 3, PART 2 are not decreased with age. Also in the rat oxygen extraction is unchanged with age. CHANGES ASSOCIATED WITH AGE There are major changes in the cardiovascular system associated with aging. First, there is both cellular hypertrophy and modest chamber hypertrophy; the former is more marked than the latter. The cells themselves are larger in the senescent left ventricle because there is a drop out of individual cells with age, possibly in part as a result of apoptosis. 7,8 In humans between age 20 and 90, there is a 40% to 50% drop in the total number of nuclei and hence in the total number of cells in the myocardium. 9 This very strongly suggests an age-associated drop out of individual cells with a compensatory hypertrophy of the remaining cells. Left ventricular cell hypertrophy also results from the greater impedance to the left ventricular ejection. In almost every society, there is greater central arterial stiffness with age. In terms of left ventricular function load, this increased stiffness produces increased impedance to left ventricular ejection. As aging stiffens the central aorta, the left ventricle continues to eject the same amount of blood at the same rate into the aorta. As a result the velocity of movement of blood down the arterial system accelerates with age. This acceleration in pulse wave velocity extends down the entire arterial tree. When the pulse wave reaches the iliac bifurcation, it is reflected and transmitted back toward the aorta. Moreover, like the forward transmission, the backward transmission wave is also accelerated. In the young (20-year-old) aorta, the rate of transmission forward and backward is slow enough so that systole has been completed by the time the reflected wave returns to the heart. This has the effect of raising aortic diastolic pressure after the aortic valve has closed. This does not increase cardiac work and tends to maintain aortic blood pressure during diastole. Similarly, in middle age (40-year-old), there is little effect on blood pressure during systole, although the wave does return before the aortic valve closes. In the elderly (80-year-old), however, the reflected wave returns well before the aortic valve shuts. This elevates systolic left ventricular and arterial blood pressure increasing the work of the left ventricle in ejecting blood. This reflected wave has the additional effect in the elderly of decreasing the diastolic aortic pressure that supports coronary flow. Clearly this is a potentially important hemodynamic change and may have significant implications for the choice of antihypertensive strategy. It should be emphasized that these effects involve normal subjects. I have not addressed the situation where significant hypertension is present. This raises the issue of the difficulty in defining hypertension and normotension in the elderly. The fact remains, however, that there are appreciable changes in the nonhypertensives. Michael O Rourke and colleagues have examined noninvasive parameters of flow velocity and pulse wave transmission in populations of Asian and Australian societies. 10,11 In Chinese populations with very low incidences of atherosclerosis and atherosclerotic vascular disease, the same significant acceleration of pulse wave velocity from the central aorta to the brachial and the radial artery is observed across a wide age spectrum, including the elderly. Aortic stiffening and increased pulse wave velocity appears to be a uniform age change with superimposed disease change. Carroll et al 12 at the University of Chicago, demonstrated the same acceleration of pulse wave velocity invasively by flow and pressure catheters in the central aorta of patients undergoing catheterization. He examined subjects from age 20 to 80 years with noncoronary artery disease chest pain associated with varying severity of cardiomyopathy and clinical heart failure. In these subjects, the same very marked age-related increase in pulse wave velocity was observed for those without heart failure as for those with heart failure. This study went on to show that in both cardiomyopathic patients and in normals, an arterial vasodilating drug, nitroprusside, decreased aortic pulse wave velocity. Thus, even though the aorta and the large vessels are almost uniformly stiff in elderly subjects, pulse wave velocity can be decreased by administration of arterial vasodilating drugs. This suggests that the changes with age in the aorta are not due to collagen fibrosis or atherosclerosis, but mainly to alterations in smooth muscle compliance, neurohormonal tone, or muscle thickness. As mentioned, there is increased left ventricular wall thickness in elderly subjects who have no evidence of coronary disease on stress testing, and this increased thickness is primarily due to cellular hypertrophy. In addition, however, there is cell hypertrophy due to some chamber cell drop out with age. This overload hypertrophy is characterized by prolongation of cardiac muscle contraction. Thus, although the ability of the muscle to develop force is unchanged with age, there is an age-associated prolongation of contraction. 13 The modest pressure overload hypertrophy would seem to be an adaptive response to increased impedance to ejection. The rapid transmission of the reflected wave back to the aorta superimposes it on the direct systolic ejection wave, and puts a greater load on the left ventricle. The resultant increased blood pressure leads to left ventricle hypertrophy. Cellular hypertrophy consequent to myocardial cell drop out would result in overload as well. There is one major change in the cardiovascular system with age. This is the marked decrease in the

AJH MARCH 1998 VOL. 11, NO. 3, PART 2 AGING, STRESS, AND THE CARDIOVASCULAR SYSTEM 43S response of the entire circulatory system to -adrenergic stimulation. There is no concomitant change in response to -stimulation and, as far as has been tested, little change in the parasympathetic system. There is only a specific selective decrease in -sympathetic response with age. Circulating blood levels of norepinephrine and epinephrine are unchanged or even higher in the elderly than in their younger counterparts. 14 The decrease in response is probably partly due to this increased stimulation, resulting in desensitization as occurs in heart failure. The mechanism of this age-associated change is also partly due to a decrease in sympathetic response at the receptor level and finally is due specifically to decreased intracellular calcium mobilization from the intracellular calcium stores of the cardiac muscle cell. In using twitches from isolated muscle preparations to compare old and young rats, the former had some prolongation of contraction, but the tension developed was the same in both. Following stimulation with norepinephrine, however, young adult muscle had markedly greater contractility than aged muscle. 15 19 Human cardiac muscle from organ donors shows a very similar pattern of reduction in isoproterenol response with age; 20 however, young and old had similar responses to calcium, analogous to what was seen in rat muscle. In addition to the age-associated decrease in myocardial contractility after -sympathetic stimulation, there is also an age-associated decrease in the response of the heart rate to -stimulation with isoproterenol. 21 This is seen strikingly during exercise in humans. Finally, there is also a decrease in the arterial vasodilating response to sympathetic stimulation. This makes the systolic load on the left ventricle even greater during exercise, since the aorta is stiffer at rest and will not dilate with epinephrine during exercise to accommodate the increased stroke volume. Toda and Miyazaki 22 exposed vascular ring preparations of coronary artery or aortic strips of 2-year-old and 12-year-old dogs to increasing concentrations of epinephrine. The epinephrine produced considerable response in young dogs and no response in old dogs. This difference is not the result of an age-associated arterial stiffness resulting from vessel collagen that prevents any response, because stimulation with nitroglycerin demonstrated an equal response in old and young rings. Thus like the inotropic response, where the inotropic response to calcium is normal but the inotropic response to sympathetic stimulation is markedly diminished, there is a selective age-associated alteration in the ability of the aorta and coronary vessels to dilate with physiologic epinephrine stimulation, although the arteries are still able to dilate to other nonsympathetic vasodilators. All that is stated above with regard to exercise response and age has been confirmed in awake chronically instrumented dogs. 23 Aortic impedance in young dogs during treadmill exercise decreased following epinephrine stimulation. In contrast, in older dogs there is an increase in impedance to ejection into a stiff aorta that does not dilate. If this difference in impedance during exercise results from sympathetic activity, it should be eliminated by administration of a -blocking drug. In both young and old dogs, heart rate and impedance change were the same after -blockade. There was no significant age-related difference; the young dog s response is turned into an old dog s response by -blockage. To summarize, when older individuals are compared to younger individuals, exercise induces a smaller increase in heart rate and contractility and a larger increase in impedance. Thus the changes in heart rate, contractility, and impedance would tend to decrease cardiac function during exercise in the elderly. The critical question is whether the intrinsic cardiac muscle reserve is adequate to compensate for these limitations in exercise response if there is no cardiac disease. To study this question in humans, 61 volunteers ranging from 20 to 80 years old and without cardiac disease based on normal electrocardiogram (ECG) stress tests and normal thallium scans (in subjects over 40 years) were studied. 3 The subjects came from the Baltimore Longitudinal Study on Aging at the National Institute on Aging. They were active but not well conditioned individuals. They were studied noninvasively with gaited blood pool scans and upright bicycle exercise, increasing from rest by 25 W increments every 3 min. All were able to exercise to a level of 125 W. At rest the cardiac output was about 6 L/min; at 125 W of exercise cardiac output was 16 L in both young and old. As expected, the heart rate response to exercise was less in the older than in the younger individuals; older individuals had a larger end-systolic volume because of the decreased contractility. This was likely because of both less inotropic response and increase in impedance to left ventricular ejection in the elderly. But, in the elderly, as exercise progressed the intrinsic cardiac muscle function was called on with acute increased end-diastolic volume, leading to increased stroke volume via Starling s law. This effect was far greater in the older individuals than in the younger ones. The slower heart rate in the elderly and less inotrophy and greater load was compensated for by the increased stroke volume so that cardiac output was unchanged with age. Thus the question of whether in the normal individual cardiac muscle func-

44S WEISFELDT AJH MARCH 1998 VOL. 11, NO. 3, PART 2 tion can compensate for the decrease in sympathetic tone can clearly be answered in the affirmative. In the presence of disease, probably including hypertension, or other superimposed factors, the cardiac reserve will be invaded earlier. Older individuals who are victims of acute myocardial infarction, heart failure, or other conditions that might affect intrinsic myocardial function would have higher mortality and morbidity than their younger counterparts with acute myocardial infarction. LONG-TERM RESPONSE TO STRESS Two additional points that have relevance to hypertension are an age-associated decrease in the ability of the heart to respond to interventions that induce hypertrophy and perhaps less regression to left ventricular hypertrophy in elderly human subjects. Following aortic banding that produced an acute increase of 25 mm Hg in blood pressure, the hearts of 9 month old rats hypertrophied significantly; with the same increase in arterial pressure due to banding, 18 and 22 month old rats showed no hypertrophy. 24,25 This pattern was observed with volume overload hypertrophy associated with heart block 26 or aortic regurgitation. 27 In humans, to determine whether regression of hypertrophy occurred with treatment of hypertension and if so, whether it was beneficial for the older hypertensive individuals, we randomized a group of patients with a mean age of 68 years to a -blocker (atenolol) or a calcium antagonist (verapamil). 28 Before treatment the systolic blood pressure ranged from 171 to 179 mm Hg and the diastolic blood pressure from 93 to 98 mm Hg. Their mean left ventricular mass was somewhat above normal for their age. The answer to the question of whether hypertrophy regresses in the elderly was yes with verapamil and no with atenolol, at least during the 60 day follow-up period of the study. The study showed a decrease in thickness of the posterior left ventricular wall and of the septum by echocardiography. Moreover, left ventricular filling was improved in conjunction with regression of left ventricular hypertrophy. Thus after 6 months of treatment and then 2 weeks without verapamil, there was a further increase in filling rate. The ejection fraction at rest was unchanged, so that there was no evidence of deterioration in left ventricular function as a result of regression in hypertrophy. Exercise data during the verapamil regression experiment showed no differences between treated and untreated heart rate responses at baseline, during treatment, and after 6 months of treatment. Mean arterial pressure, as expected, decreased during verapamil treatment but rose back toward the original level once the verapamil had been stopped for 2 weeks. The end-diastolic volume, as estimated by the gated blood pool scans, and the left ventricular ejection fraction during maximum exercise were unchanged throughout the verapamil intervention. It could be argued that the reduction in blood pressure allowed the ejection fraction to remain the same even though the intrinsic contractility of the heart was diminished. In fact, however, when the ejection fraction was measured 2 weeks after discontinuation of verapamil, with blood pressure almost back to pretreatment levels, there was no significant decrease in the ejection fraction at maximum exercise. SUMMARY I have presented a picture of cardiovascular aging that resembles the situation with vision, where in the absence of actual disease, near vision changes with age and cataracts appear with age but after these are corrected, vision remains markedly unchanged with age. For the undiseased heart, intrinsic cardiac muscle function and the inotropic response to nonsympathetic mediators, along with coronary perfusion, are well maintained with age. There are, however, some changes that do occur with age. Cellular hypertrophy occurs, both because of cell drop out and because of some chamber hypertrophy secondary to increased impedance to left ventricular ejection. As a result of the hypertrophy, there is some prolongation of systole secondary to delayed relaxation. This is typical of what occurs in hypertension induced hypertrophy as well. 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