Ventricular performance in human hearts aged 61 to 73 years

MISCELLANEOUS

TOPICS

Ventricular

J.V. NIXON,

Performance in Human Hearts Aged 61 to 73 Years MD, HUGH HALLMARK,

MD, KIM PAGE, MS,

PETER R. RAVEN, PhD, and JERE H. MITCHELL,

MD

The effects of increasing and decreasing cardiac preload by 15 % on the left ventricular (LV) performance of 11 carefully screened normal subjects aged 61 to 73 years were examined. Comparisons were made with 11 subjects aged 21 to 26 years. Two-dimensional echocardiograms were obtained before and at the termination of 5 degrees of headdown tilt for 90 minutes and at the termination of graded lower body negative pressure to -40 mm Hg. Heart rates and blood pressures were unchanged after physiologic interventions. Changes in LV end-diastolic and stroke volumes were similar but of a smaller magnitude in the older subjects compared with changes in younger subjects. When

LV end-diastolic volumes obtained at each extreme of preload variation were compared, the range of mean change was less in the older (23 ml, 26%) than in the younger subjects (31 ml, 41%). Control LV end-diastolic and end-systolic volumes were greater in the older subjects. This study shows that despite larger control LV volumes, alterations in preload produce changes in the LV end-diastolic and stroke volumes of these older subjects that conform to the normal LV function curve, but that these responses are diminished compared with changes in younger subjects, suggesting an age-related change in diastolic stiffness. (Am J Cardiol 1985;56:932-937)

Both experimental and human studies have shown that aging of the heart produces characteristic changes in different parts of the cardiac cycle.l-s Experimental studies of senescent myocardium have shown differing findings regarding both systolic and diastolic stiffness,r4 although prolonged contraction durations and attenuated inotropic responses to catecholamines6-8 are consistent findings. Human studies have also produced differing conclusions in older subjects both at rest and during dynamic exercise. g-11 These differences may be partially attributed to the difficulty in identifying an elderly population that is free of significant intrinsic cardiac disease and, in particular, coronary artery disease.rr Recent noninvasive studies in our laboratory have defined the extreme ranges of the relation between left

ventricular (LV) end-diastolic and stroke volumes (i.e., the Frank-Starling curve) in normal young subjects and in certain subsets of patients.r2J3 This study examines the effects of large variations in cardiac filling volume on the LV performance of a group of elderly subjects screened to exclude as comprehensively as possible the presence of intrinsic cardiac disease and, in particular, coronary artery disease. Comparisons were made with normal young subjects to define the differences, if any, in the response of the aging left ventricle to large variations in preload.

Methods Subjects: Studieswerecarried out in 11volunteer subjects, aged 61 to ‘73years, who were screenedto exclude as comprehensively as possible intrinsic cardiac disease. The screeningprocedure wasas follows: Asymptomatic persons from area-agedprogramswere recruited. Thosewith a negative history, normal results on physical examination, and normal electrocardiographicfindings at rest underwent serial test evaluations to exclude the existence of coronary artery diseaseby Bayesian analysis.I4 The reported prevalence of coronary artery diseasein this asymptomaticagegroupranges from 11to 81%.15Data from our laboratory and other laboratories showmaximal stresstesting to have a sensitivity of 71%and a specificity of 92%for the diagnosisof coronary ar-

From the Cardiovascular Service, Veterans Administration Medical Center, and the Division of Cardiology, Southwestern Medical School, University of Texas Health Science Center, Dallas, Texas. This study was supporbd by the Research Service of the Veterans Administration, Dallas, Texas. Manuscript received November 17, 1984; revised manuscript received May 24, 1985, accepted May 25, 1985.’ Address for reprints: J. V. Nixon, MD, Cardiovascular Service, Veterans Medical Center, 4500 South Lancaster Road, Dallas, Texas 75216. 932

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TABLE I

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Rest Heart Rates, Arterial Pressures, End-Systolic Stress/Length Ratios in Young and Old Subjects

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Subjects Young Heart rate (beats/min) Blood pressure (mm Hg) Systolic Mean Diastolic Wall stress (dynes/cm2) Stress/length ratio All values are exoressed NS = not signifidkt.

Old

56 f 3 108f3 79 f 65 f 68 f 22f as mean

f standard

59f 126 94 75 78 24

2 2 5 1 error

tery disease.16J7 After a stresstest showingnegative results in thesesubjects,the probability of the existenceof coronary diseasedecreasesto 4 to 57%. Bartel et al18reported that fluoroscopically detected coronary artery calcification has a sensitivity of 56%and a specificity of 97%for the diagnosisof coronary artery disease.In subjectswith a negative result on fluoroscopy after a negative stresstest result, the likelihood of the existenceof coronary artery diseasedecreasesagainto 2 to 37%.While not eliminating the likelihood of the existence of coronary disease,this is an acceptable minimal range of prevalence for the disease.Furthermore, evaluation by Zdimensionalechocardiographyof LV segmentalwall motion asreported by our laboratory wasalsocarried out.lg The 11 subjectshad no echocardiographicevidenceof segmentalwall motion abnormalities at rest or during the interventions of head-downtilt and lower body negative pressure. Eleven subjects,aged21 to 28 years, werestudied for comparison. Details of the study were explained to each of the elderly and young subjectsand they gave informed written consent. Echocardiograms: The echocardiographictechniquesand the methodsand accuracy of measurementsusedin our laboratory have been described in detail.13Other echocardiographic measurementsusedin this study weremeridional LV wall stress,wherewall stress= systolicpressureX end-systolic diameter (ESD)/4 X wall thickness(1 -t wall thickness/ESD) dynes/cm2fz0and systolic stress-dimensionratio, expressed asmeridional wall stress/ESD ratio.sl The heart rate was determined from simultaneouselectrocardiographic recordings.Blood pressurewasrecorded at l-minute intervals throughout each intervention by Narco Bio-Systems programmed electrosphygmomanometerand recorded on a strip-chart recorder. Previous studies have demonstrated good agreement between these studies and Mean arterial pressurewas calauscultatory readings.12az2 culated as diastolic pressure + one-third of the pulse pressure. Experimental protocol: The protocol of head-down tilt and gradedlower body negativepressureusedto increaseand decreaseLV preload has been described in detail.ls Measurementsfrom echocardiogramsobtained before and at the termination of each preload variation were compared. Five degreeshead-down tilt for 90 minutes producesa transient increasein central venouspressureof 2.5 cm HsO, with a return to baselinewhen the left ventricle reachesits maximal size.22Graded lower body negative pressureto -40 mm Hg produces venous pooling with a progressiveincreasein leg volume of 500 to 700 ml and a transient decreasein central venouspressureof 5 cm HZ0.22 On a separateoccasion,6 of the older subjectsunderwent 5 degreesof head-downtilt for 6 hours to determine whether the time sequenceof the responseof the older left ventricle

f f f + f

P 1

NS

4 3 3 6 2

<0.005 <0.005 <0.02 NS NS

of the mean.

to prolongedhead-downtilt wasdifferent in younger subjects. Leg volumes were estimated before and after 6 hours of tilt and calculated by Simpson’srule from measurementsof leg circumferencesat 12 well-defined pointsz2 Values determined before and at the termination of each intervention were comparedand significant differenceswere determined by analysisof variance for single factor experiments having repeated measures.23 When significant differences(p <0.05) between groups were found, within-group differenceswere determined by the Student-Newman-Keuls multiple rangetest and values <0.05 were consideredsignificant. Power curves and linear regressionequationsweredetermined from individual values of stroke volumes and enddiastolic volumesto obtain LV function curves.

Results Rest heart rates, systemic arterial pressures, end-systolic wall stress and end-systolic stress/length ratios are listed in Table I. The anticipated differences in arterial pressures associatedwith age were found. No significant differences were found between the young and the older subjects in rest heart rate, end-systolic wall stress and end-systolic stress/length ratio. Changes in LV dimensions, shortening fraction, mean velocity of circumferential fiber shortening, heart rate and blood pressure are summarized in Table II. There were no significant differences between control data in either subject group before head-down tilt and before lower body negative pressure. In the young subjects, the changes after both headdown tilt and lower body negative pressure were identical to those found previously in our laboratory (Table II, Fig. 1). Significant cha.nges included an 18% increase in end-diastolic volume and a 31% increase in stroke volume during bead-down tilt, and a 16% decrease in end-diastolic volume and 22% decrease in stroke volume during lower body negative pressure (Fig. 2). In the older subjects during bead-down tilt, mean end-diastolic volume increased 8%, from 104 f 9 to 112 f 9 ml (p
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In the older subjects, during lower body negative pressure, mean end-diastolic’ volume decreased 15%, from 104 f 9 to 89 f 8 ml (p
i

Discussion This study shows that in normal older subjects, the response of the left ventricle to increases and decreases in preload of 15% produces changes that conform to a normal ascending LV function curve, but which are diminished when compared with changes in normal young subjects. When end-diastolic volumes obtained at each extreme of preload variation were compared, the elderly subjects had an increase of only 26% of their lowest end-diastolic volume during lower body negative pressure, whereas the young subjects had an increase

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FIGURE 1. Changes in left ventricular systolic and stroke volumes, and ejection velocity of circumferential fiber shortening values (C) during head-down tilt (T) and pressure (L) in young and old subjects. significant changes in mean values. ence.

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end-diastolic, endfraction and mean (VCF) from control lower body negative Asterisks represent Circ = circumfer-

EJECTION FRACTION

0.57

0.61

0.57

0.53

MEAN VCF (circ/sec)

0.86

0.91

0.83

0.82

0.83

0.84

0.81

0.78

C

T

C

L

c

T

c

L

END-DIASTOLIC VOLUME YOUNG

END-SYSTOLIC VOLUME

OLD

YOUNG

STROKE VOLUME YOUNG

OLD

OLD

+30-

FIGURE 2. Percent changes in left ventricular end-diastolic, end-systolic and stroke volumes from control values during head-down tilt (T) and lower body negative pressure (L) in young and old subjects.

$ 5

+20-

+ ,.

3

O-

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of 41%. Furthermore, the end-diastolic and stroke volumes of the older subjects ranged over a series of higher points on the normal Frank-Starling curve, despite body weights equivalent to those of the young subjects. Previous studies carried out to determine the effect of age on the hemodynamic responses to various physiologic interventions have shown an attenuated heart rate and blood pressure response to head-up tilt, the Valsalva maneuver, the cold pressor test and static exercise.24 A possible exp lanation for these altered responses was a reduction in baroreceptor activity with age as previously shown by Gribbin et al? However, in

OJ

0

I

I

I

I

20

40

60

80

END-DIASTOLIC FIGURE volumes negative

I

100

4

I

120 140

VOLUME

I

I

160

180

(mls)

3. Relations between left ventricular end-diastolic and stroke at supine rest and during both head-down tilt and lower body pressure in young and old subjects.

TL

TL

TL

TL

TL

our studies, no significant changes in heart rate or blood pressure occurred during either head-down tilt or lower body negative pressure. These findings concur with those of Ebert et al,26 who showed no changes in heart rate or blood pressure in subjects aged 50 to 59 years during graded lower body negative pressure to -40 mm Hg. Furthermore, they demonstrated a significant reduction in stroke volume during lower body negative pressure in their subjects compared with those of a young group of subjects. These z

160-

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140.

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120.

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TIME (hours)

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4

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FIGURE 4. Changes in left ventricular end-diastolic, end-systolic and stroke volume from control values (time 0) during 6 hours of head-down tilt in 6 of the elderly subjects.

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findings, obtained by impedance cardiography, concur with our echocardiographically estimated changes in stroke volume. The findings in our study have several possible explanations, although some questions remain. Although it has been suggested that older subjects have less venous compliance changes during physiologic interventions,s4 the magnitude of central fluid shift demonstrated by a reduction in leg volume of a mean of 800 ml is identical to the magnitude found in younger subjects. This would appear to confirm that no comparative difference in magnitude of central fluid shift was a factor. It has been suggested that a greater central blood volume may exist in the older subjects.27 Higher LV end-diastolic volumes at rest in our older subjects would comparative measurements of transthoracic impedance in young and older subjects by Ebert et al26 showed no differences, suggesting that increased central blood volume is unlikely. The older human left ventricle may operate near its maximal volume, as suggested by Parker and Case.2s They summarized several of their studies during various interventions with changes in blood volume and filling pressures and concluded that the human LV function curve reaches a plateau rapidly after relatively small increases in end-diastolic volume. Previous studies in normal young subjects in our laboratory do not support this concept having findings similar to those of the young subjects in this study.i2 Apparently, our findings in older subjects do not concur with this concept either. Figure 3 shows that while the range of changes in end-diastolic and stroke volumes is less than in the young subjects, the proportional changes in stroke volume with changes in enddiastolic volume are identical, without movement off the normal Frank-Starling curve. Furthermore, there is no evidence that the plateau phase of the curve has been reached in these older subjects. The value of echocardiography in serially evaluating changes in LV performance during acute interventions is well accepted. The calculation of LV volumes is based on the assumption that the left ventricle is always ellipsoid in shape and the minor diameter is always half the major diameter.i2 At the extremes of ventricular volumes encountered in our subjects, the ventricle may have altered its shape, becoming more ellipsoid at small volumes and more spherical at higher volumes. The regression equation of Teichholz et a12g was derived from a series of angiographically normal ventricles over a wide range of volumes than those encountered in our patients during the various interventions. Furthermore, estimations of ventricular volumes in all types of cardiac disease by 2-dimensional echocardiography have shown a better correlation with angiography.30 However, the linear dimensional changes are identical to the volume changes, the regression equation used is valid over the ranges of ventricular volumes of our subjects, and evidence of the existence of coronary disease excluded subjects from the study. Thus, an intrinsic error in volume estimation would apply consistently to comparative values. Considerable effort was made in this study to select older subjects for study who were free of significant

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intrinsic cardiac disease and, in particular, coronary artery disease. The use of serial test evaluations to determine prevalence of disease and, in particular, coronary artery disease, has been advocated as acceptable in a’normal population, in which cardiac catheterization cannot be justified. l4 The screening procedure used for providing the subjects in our study was more thorough than somelo and less thorough than others.ll Without cardiac catheterization, however, the presence of coronary artery disease cannot be ruled out. Nevertheless, the selection of 11 subjects older than age 60 years, with a less than 2 to 37% likelihood of having coronary artery disease, and who had no echocardiographic evidence of segmental wall motion abnormalities at rest or during the interventions, appear to make up a suitable subset of subjects for study. The differences in mean arterial pressures between the young and older subjects may serve to explain the differences in ventricular dimensions in the 2 groups. Should this be the case, one would expect significant differences in both end-systolic wall stress and the stress/length ratio between the 2 groups. Furthermore, there were no differences in mean heart rate between the 2 groups of subjects, either at rest or during the interventions of head-down tilt and lower body negative pressure. Acknowledgment: We are grateful to Arvella Peters for her technical assistance and to Reba Beaty for her secretarial help.

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17. Nixon JV, Lipscomb K, Blomqvist CG, Shapiro y;tg, significant left main coronary disease.

W. Exercise testing in men Br Heart J 1979;42:410-

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Bartel AG, Chen JT, Peter RH, Behar VS, Kong Y, Lester RG. The significance of coronary calcification detected by fluoroscopy: a report of 360 patients. Circulation 1974;49:1247-1253. Nixon JV, Brown CN, Smitherman TC. Identification of transient and persistent segmental wall motion abnormalities in patients with unstable angina by two-dimensional echocardiography. Circulation 1982;65:1497-1500. Grossman W, Jones D, McLaurin LP. Wall stress and patterns of hvoer.’ trophy in the human left ventricle. J Clin Invest 1975;56:56-64. Marsh JDr Green LH, Wynne J, Cohn PF, Grossman W. Left ventricular end-systokc pressuredimension and stress-length relations in normal human subjects. Am J Cardiol 1979;44:1311-1317. Nixon JV, Murray RG, Bryant C, Johnson RL Jr, Mitchell JH, Holland 06, Gomez-Sanchez C. Verne-Marine P. Blomavist CG. Earlv cardiovascular adaptation to simulated zero gravity.‘J Appl’Physiol 1979;46:541-548. Winer BJ. Statistical Principles in Experimental Design. 2nd ed. New York: McGraw-Hill, 1971:261-368. Smith JJ, Ebert TJ, Tristani FE, Porth CJ, Stekiel WJ, Barney JA. Effect

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of age and coronary artery disease on autonomic responses to circulatory stress. Adv Physiol Sci 1981;9 (Cardiovasc Physiol):357-365. Gribbin B, Pickering TC, Sleight P, Peto R. Effect of age and high blood pressure on baroreflex sensitivity in man. Circ Res 1971;29:424-431. 28. Ebert T, Hughes CV, Tristani FE, Birney JA, Smith JJ. Effect of age and coronary heart disease on circulatory responses to graded lower body negative pressure. Cardiovasc Res: 1982;16:663-669. 27. Wilkinson PL, Stowe DF, Tybert JV, Parmley WW. Effects of blood volume on responses to Valsalva-like maneuvers in dogs (abstr). Physiologist 1975;18:450. 28. Parker JD, Case RB. Normal left ventricular function. Circulation 1979; 60:4-12. 29. Teichholz LE, Kreulen T, Herman MV, Gorlin R. Problems in echocardiographic volume determinations: echocardiographic-angiographic correlations in the presence and absence of asynergy. Am J Cardiol 1976;27:7-11. 30. Folland ED, Parisi AF, Moynihan PB, Jones DR, Feldman CL, low DE. Assessment of left ventricular eiection fraction and volumes bv real-time. twodimensional echocardiography: a comparison by cineangiographic and radionuclide techniques. Circulation 1979;62:760-768. 25.

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