The Effects of Age and Blood Pressure upon the Systolic Time Intervals in Males Aged Years

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1 Journal of Gerontology 1973, Vol. 28, No. 2, The Effects of Age and Blood Pressure upon the Systolic Time Intervals in Males Aged Years David J. Shaw, MD, Donald A. Rothbaum, MD, Charles S. Angell, MD, and Nathan W. Shock, PhD 1 The effects of age, activity status, and blood pressure on systolic time intervals (STI), including electromechanical systole (QS2), left ventricular ejection time (LVET), pre-ejection period (PEP), and their heart rate-corrected indices, QS2I, LEVTI, and PEPI, were analyzed in 315 male subjects aged years. An elevated diastolic blood pressure (> 90 mm Hg) was significantly correlated with prolongation of the PEP, PEPI and QS2I. An elevated systolic blood pressure (> 140 mm Hg) was significantly correlated with prolongation of the LVET, LVETI, QS2, and QS2I. Neither coronary heart disease, functional Class I (67 subjects), nor estimated daily physical activity (range cal/24 hours) were significantly related to STI. In 218 healthy normotensive subjects, a significant but small prolongation of the PEP and PEPI (4 msec/decade) and QS2I (5 msec/decade) was found from the 3rd through the 6th decade with a decline in these intervals in the 7th and 8th decades. An interpretation of these findings is offered.» A GING results in a deterioration of cardiac -^"*- performance (Harris, 1970). For example, the resting cardiac output decreased with age in subjects who were clinically free of cardiovascular disease (Brandfonbrener, Landowne, & Shock, 1955). However, the dye dilution technique used in these studies is inappropriate for use in surveys of normal subjects. The measurement of systolic time intervals (STI) is an easily performed, non-invasive technique for evaluating myocardial performance (Weissler, Harris, & Schoenfeld, 1968). The present study was designed to evaluate the usefulness of STI in detecting alterations in myocardial performance produced by aging, blood pressure elevation, and daily activity levels in a group of males participating in a study of aging. METHODS The subjects studied were 326 male participants in the Baltimore Longitudinal Study 1 Gerontology Research Center, National Institute of Child Health and Human Development, National Institutes of Health, PHS, US Dept. of Health, Education, & Welfare, Bethesda, and the Baltimore City Hospitals, Baltimore (Stone & Norris, 1966) and 10 staff members of the Gerontology Research Center. Their ages ranged from 20 to 89 years (mean 55.7). A detailed history, physical examination, chest x-ray, and resting 12-lead electrocardiogram were obtained on each subject. Immediately after recording the resting electrocardiogram, blood pressure and systolic time intervals were measured with the subject supine. The resting and Masters' electrocardiographs tests were interpreted according to the WHO modification of the Minnesota code (Rose & Blackburn, 1968). From a detailed activity questionnaire daily caloric expenditure was calculated for 282 of the subjects (McGandy, Barrows, Spanias, Meredith, Stone, & Norris, 1966). Simultaneous recordings of electrocardiogram, phonocardiogram, and carotid pulse tracing were made on a 12-channel oscillographic Honeywell Visicorder at a paper speed of 100 mm. per second with independent time lines at 10-msec. intervals. The electrocardiographic lead showing the earliest onset of ventricular depolarization (usually V 2 ) was used. The phonocardiogram was recorded from a Califor- 133

2 134 SHAW, ROTHBAUM, ANGELL, AND SHOCK nia Instruments piezoelectric crystal microphone or a Meico crystal microphone placed on the chest to record the aortic component of the second heart sound most clearly. The carotid pulse tracing was recorded from a funnel-shaped probe attached to a Statham P23Gb transducer or from an infant-size (1" X 2") blood pressure cuff inflated to 10 mm Hg, attached to a Statham PM5 transducer and placed directly over the right carotid artery. Figure 1 shows representative tracings. All recordings were made between 9:00 a.m. and 12:00 noon. Electromechanical systole (QS2) and left ventricular ejection time (LVET) were determined from the average of ten consecutive cardiac cycles. Pre-ejection period (PEP) was calculated from the above measurements (Weissler et al., 1968). Since QS2, LVET, and PEP were highly correlated with heart rate (Table 1), values for each subject were adjusted for heart rate by computations based on regression equations (Table 1) derived from data on 218 subjects with diastolic blood pressure less than 90 mm Hg and no evidence of coronary heart disease. CAROTID PULSE CUFF METHOD CAROTID PULSE i PROBE METHOD /\ PROBE M Fig. 1. Simultaneous recording of the carotid pulse tracing by blood pressure bladder [upper tracing and funnel shaped probe (second tracing from top)]. Note identity of left ventricular ejection time (LVET) by the two methods. Also shown are phonocardiogram (PCG) (third tracing) and electrocardiogram (ECG), lead V 2 (bottom tracing). Paper speed is 100 mm/sec, time lines are 10 msec. Pre-ejection period (PEP) = total electromechanical systole (QS2) LVET. Subjects with evidence of coronary heart disease by history or electrocardiogram were classified according to the New York Heart Association's functional classification system (1955). Eleven subjects with coronary heart disease, functional Class II, were excluded from data analysis; 8 of them were taking digitalis. Ten other subjects who were taking digitalis, reserpine, or thyroid hormones were also excluded. Observations obtained on the remaining 315 subjects, none of whom had evidence of valvular heart disease, were analyzed. For the analysis of the association between STI and blood pressure, subjects were divided into groups according to the blood pressure recorded at the time of testing. Group I consisted of 276 subjects with diastolic blood pressure less than 90 mm Hg. This group was subdivided into Group la, 232 subjects with systolic blood pressure less than 140 mm Hg; and Group Ib, 44 subjects with systolic blood pressure equal to or greater than 140 mm Hg. Group II consisted of 39 subjects with diastolic blood pressure equal to or greater than 90 mm Hg irrespective of systolic blood pressure. Data from 67 subjects with coronary heart disease, functional Class I, were included in the blood pressure analysis; 58 were in Group I and 9 were in Group II. Statistical analysis was performed using methods described by Snedecor and Cochran (1967). RESULTS Effect of heart rate on STI. The regression equations relating heart rate to STI in the 218 normal subjects are given in Table 1 and corn- Table 1. The Effect of Heart Rate on Systolic Time Intervals (msec) in the Present Study and from Weissler, Harris, and Schoenfeld (1968). 218 Subjects Aged Years Without Evidence of Arteriosclerotic Heart Disease or Hypertension Regression Equation Sy.x» rb P QS2 = (-2.27 x heart rate) -f <.001 PEP<i = (-0.56 x heart rate) <.001 LVET» = (-1.71 x heart rate) <.001 Normal Subjects from Weissler, Harris, and Schoenfeld (1968) QS2 = (-2.1 x heart rate) <.005 PEP = (-0.4 x heart rate) <.OO5 LVET = (-1.7 x heart rate) <.OO5 "Sy. x = standard error of estimate. b r = correlation coefficient. C QS2 = electromechanical systole (msec). d PEP = pre-ejection period (msec). e LVET = left ventricular ejection time (msec).

3 EFFECT OF AGE ON SYSTOLIC TIME INTERVALS 135 Group Normal Coronary heart disease, Class I DBP&90 mm Hg DBPS90 mm Hg and coronary heart disease, Class I N Table 2. Effect of Heart Disease on Systolic Time Intervals. Age 52±1» 66±2 54±3 HR 66±1 68±1 71±3 SBP 119±1 127±3 143±3<= DBP 71±1 73±1 95±1 QS2 396±2 394±4 386±6 PEP 99±1 99±2 103±3 LVET 297±2 295±3 283±5 QS2I 546±1 549±3 548±3 PEPI 136±1 138±2 143±3>> 9 63±3 68±3 141±4<= 97±2 399±9 107±7 293±5 554±8 145±7 N = Number of subjects; HR=heart rate; SBP=systolic blood pressure (mm Hg); DBP=diastolic blood pressure (mm Hg). QS2=Total electromechanical systole (msec). PEP=Pre-ejection period (msec). LVET=Left ventricular ejection time (msec). QS2I, PEPI, LVETI = The heart rate-corrected indices of the above systolic time intervals. SD B ±l SE (SE= ) "VN-1 h p<.05) ) Difference from normal group (DBP<90 mm Hg and no evidence of coronary heart disease). <=p<.01) pared with similar regression equations of Weissler et al. (1968). The previously reported negative correlations between heart rate and each of the three systolic time intervals, QS2, PEP, and LVET, were confirmed. Effect of coronary heart disease, functional Class I, on STI. The STI for 58 subjects with coronary heart disease, Class I, and diastolic blood pressure less than 90 mm Hg were not significantly different from the values for 218 normal subjects (Table 2). Although the PEP, pre-ejection period index (PEPI), and PEP/ LVET were slightly increased in the 9 subjects DIASTOLIC BLOOD PRESSURE (mm Hg) Fig. 2. Relationship between diastolic blood pressure and pre-ejection period (PEP) and its heart rate-corrected index (PEPI) for all 315 subjects. Values are mean for each 10 mm Hg diastolic blood pressure range (e.g., mm Hg) ± SE. N = number of subjects at each blood pressure level. LVETI 410±l 411±2 405±3 409±5 PEP/LVET.335db ± ± ±.O27 with coronary heart disease (Class I) and an elevated diastolic blood pressure, their STI were not significantly different from the STI of 30 subjects with an elevated diastolic blood pressure and no evidence of coronary heart disease (Table 2). Effect of blood pressure on STI. In subjects with diastolic blood pressure equal to or greater than 90 mm Hg, PEP and PEPI were increased (Fig. 2). For these subjects (Group II), diastolic blood pressure was significantly positively correlated with PEP (.44) and PEPI (.47) (p <.005). No significant relationship was demonstrated between diastolic blood pressure and PEP or PEPI for subjects in Group I (diastolic blood pressure < 90 mm Hg). A prolongation of LVET and left ventricular ejection time index (LVETI) with an increase in systolic blood pressure was shown for Group I but not for Group II subjects (Fig. 3). In group Ib (systolic blood pressure > 140 mm Hg) significant positive correlations were found between systolic blood pressure and LVET (p <.02), LVETI (p <.005), QS2 (p <.02), and electromechanical systolic index (QS2I) (p <.001). Effect of age on STI. For the group of 218 normal subjects no statistically significant relationship was found between age and the STL However, plots of the STI versus age by decades (Fig. 4) revealed an increase of PEP and QS2 and their respective indices, PEPI and QS2I, with age up to age 60 and a decline thereafter. Statistical analysis of the data on the 145 subjects under age 60 showed that PEP (p <.001), PEPI (p <.001), QS2, (p <.02), and QS2I

4 136 SHAW, ROTHBAUM, ANGELL, AND SHOCK (p <.005) and PEP/LVET (p <.01) increased significantly with age. Effect of daily activity on STL There was no significant relationship between any of the STI and daily activity in data including activity levels requiring 1623 to 5762 calories per 24 hours. DISCUSSION The measurement of STI is a non-invasive technique for evaluating left ventricular performance. The STIs are well correlated with isovolumic left ventricular dp/dt contraction, stroke volume, and ejection fraction as determined by invasive techniques (Harris, o GROUP I (DBPOOmm Hg) GROUP II (DBP>90mm Hg) n = SYSTOLIC BLOOD PRESSURE (mm Hg) Schoenfeld, & Weissler, 1967; Jones & Foster, 1964; Shaver, Kroetz, Leonard, & Paley, 1968; Stafford, Harris, & Weissler, 1970; Urschel, Co veil, Sonnenblick, Ross, & Braunwald, 1968; Wallace, Mitchell, Skinner, & Sarnoff, 1963). The significant inverse relationship between STIs and heart rate was confirmed (Montoye, Willis, Howard, & Keller, 1971; Weissler et al., 1968; Willems, Roelandt, De Geest, Kesteloot, & Joosens, 1970). Effect of diastolic blood pressure on the STI. Diastolic blood pressures below 90 mm Hg were not significantly related to any of the STIs. However, diastolic blood pressures greater than 90 mm Hg were significantly positively correlated with PEP, PEPI, QS2, and QS2I. Previous studies have shown the effect of diastolic blood pressure on the PEP. In healthy young subjects, Harris et al. (1967) found prolongation of the PEP as a result of hypertension induced by methoxamine infusion. In patients with congestive heart failure, Weissler et al. (1968) found the PEP was prolonged HEAR T RAT 50 n= O0S2I 430.»QS2 _ I 310 \-/ i, i, 0LVETI LVET x " T -Hi; z 1 3 V Fig. 3. Relationship between systolic blood pressure and left ventricular ejection time (LVET) (upper 290 panel) and its heart rate-corrected index (LVETI) 260 (lower panel) for 315 subjects. Group I = 276 subjects with diastolic blood pressure (DBP) < 90 mm Hg. Group II = 39 subjects with DBP > 90 mm Hg. For Fig. 4. Relationship between age by decade and heart Group I mean values are for each 10 mm Hg systolic rate, blood pressure and systolic time intervals for 218 blood pressure range (e.g., mm Hg) ± SE normal subjects (diastolic blood pressure < 90 mm Hg except for the last value which is 160 mm Hg or and no evidence of coronary heart disease). All values greater. For Group II mean values are for the following are mean for each decade (e.g., years) ± SE. blood pressure ranges: mm Hg, mm QS2 = total electromechanical systole; PEP = preejection period; LVET = left ventricular ejection time; Hg, mm Hg, and 160 mm Hg or greater. N and N' = number of subjects at each blood pressure QS2I, PEPI, LVETI = the heart rate-corrected indices level for Groups I and II, respectively. for the above systolic time intervals.

5 EFFECT OF AGE ON SYSTOLIC TIME INTERVALS 137 in subjects with an elevated diastolic or mean arterial pressure. Shah and Slodki (1964), studying 15 hypertensive subjects, attributed prolongation of the QS2 to prolongation of the PEP. On the other hand, Raab, de Paula e Silva, and Starcheska (1958) did not find an increase in the PEP as a result of hypertension induced by norepinephrine infusion after atropine blockade; however, they did not correct for the marked increase in heart rate which occurred in their subjects. Increased heart rate would shorten the PEP. Montoye et al. (1971) found no correlation between diastolic blood pressure and PEP in 602 normal subjects, but they did not specify the diastolic blood pressure range of their subjects. Effect of systolic blood pressure on STL In the absence of aortic valvular disease, LVET is positively correlated with stroke volume (Braunwald, Sarnoff, & Stainsby, 1958; Jones & Foster, 1964; Shaver et al., 1968; Weissler, Harris, & Schoenfeld, 1969; Weissler, Peeler, & Roehill, 1961) and negatively correlated with heart rate (Lombard & Cope, 1926; Weissler et al., 1961; Weissler & Schoenfeld, 1970). However, the effect of blood pressure on LVET has been a matter of controversy. In dog heart preparations with heart rate and stroke volume held constant, Braunwald et al. (1958) have reported an increase in LVET, and Wallace et al. (1963) a decrease in LVET in response to a marked increase in mean aortic pressure. In man, Weissler et al. (1961) found no significant relationship between elevated blood pressure and LVET uncorrected for heart rate and stroke volume. However, they did find a significant increase in LVET with an increase in the ratio of mean arterial blood pressure to stroke index (Weissler et al., 1968). Also in man, Shaver et al. (1968) produced acute increases in arterial blood pressure with methoxamine infusion while heart rate, stroke volume, and inotropic state were held constant. They demonstrated a highly significant correlation between increased systolic blood pressure and prolonged LVET. In an elderly population, Willems et al. (1970) found a small but significant positive correlation between systolic blood pressure and LVET after correction for heart rate and age by multiple regression analysis. On the other hand, Montoye et al. (1971) in the Tecumseh study failed to show any significant correlation between blood pressure and LVET. In our study, subjects with diastolic pressure less than 90 mm Hg demonstrated a significant correlation between systolic blood pressure and increased LVETI: For subjects with diastolic blood pressure > 90 mm Hg, there was no significant correlation between systolic blood pressure and LVETI. However, these latter subjects had a prolonged PEP and increased PEP/LVET. Weissler et al. (1969) reported that prolonged PEP, shortened LVET, and increased PEP/LVET are correlated with reduced stroke volume. Effect of age on the STL A number of investigators have studied age differences in ventricular performance by measurements of STL Harrison, Dixon, Russell, Bidwai, and Coleman (1964) found a slight increase in isovolumic contraction time and LVET with age which they attributed to the slower heart rate in their old subjects. Slodki, Hussain, & Luisada (1969) showed a prolongation of QS2 in elderly subjects; however, there was a wide range of PEP and LVET values. Friedman and Davison (1969) found a slight prolongation of the interval between the initial deflection of the QRS complex and the first major vibration of the first heart sound (QS1) in elderly subjects. Montoye et al. (1971) examining subjects without cardiac disease from the Tecumseh study found an increase in the PEP of approximately 4 msec/decade from the third to the seventh decade. The results from our subjects from the third to the sixth decade are similar; we also found increases in the PEP and PEPI of about 4 msec/decade. In our study PEP and QS2 declined after age 60 and in the Tecumseh study these intervals declined after age 70 (Montoye et al., 1971). In a cross-sectional study of healthy subjects, the improvement in ventricular performance with old age may be more apparent than real; in other words, it may be the result of selective mortality. If a marked prolongation of PEP and QS2 preceded the development of symptomatic coronary heart disease by years, such subjects would be classified as normal at middle age and as having symptomatic coronary heart disease at old age. The data from these subjects would be included in the calculations for PEP and QS2 in the middle age groups and excluded from similar calculations in the old age groups. Furthermore, the prolongation of PEP and QS2

6 138 SHAW, ROTHBAUM, ANGELL, AND SHOCK may be slight in normal subjects who do not develop coronary heart disease. Thus the impact of inclusion of subjects with the most marked deterioration of ventricular performance in the middle-age groups and their exclusion from the old age groups might exceed the impact of further slowly progressive decline in ventricular performance in the remainder of the healthy old group. Several investigators have found no prolongation of LVET with age (Friedman & Davison, 1969; Harrison et al., 1964; Lombard & Cope, 1926; Montoye et al., 1971). In contrast, Willems et al. (1970) reported a small increase of LVET with age (2 msec/decade) after correction for heart rate and systolic blood pressure by multiple regression analysis. We found slight but insignificant increase of LVETI with age which, after analysis by partial correlation coefficients, was attributable to the increase in systolic blood pressure with age. Effect of daily activity on STL No significant relationship between STI and estimated daily caloric expenditure was present in our subjects. Although Raab, de Paula e Silva, Marchet, Kimura, and Starcheska (1960) showed a shorter PEP in sedentary subjects than in active ones, they did not correct for the influence of heart rate on PEP. In their study the sedentary subjects had a higher resting heart rate than the active subjects and the higher heart rate would shorten the PEP. SUMMARY Systolic time intervals (STI) including electromechanical systole (QS2), left ventricular ejection time (LVET), pre-ejection period (PEP) and their heart rate-corrected indices QS2I, LVETI, and PEPI were analyzed in 315 male subjects aged years. An elevated diastolic blood pressure (> 90 mm Hg) was significantly positively correlated with prolongation of the PEP, PEPI, and QS2I. An elevated systolic blood pressure (> 140 mm Hg) was significantly positively correlated with prolongation of the LVET, LVETI, QS2, and QS2I. Neither coronary heart disease, functional Class I (67 subjects), nor estimated daily physical activity were significantly related to STI. In 218 healthy normotensive subjects, a significant prolongation of the PEP and PEPI (4 msec/decade) and QS2I (5 msec/decade) was found from the third through the sixth decade with a decline in these intervals in the seventh and eighth decades. If marked prolongation of the PEP and QS2 (reflecting diminished ventricular performance) in middleaged subjects preceded the development of symptomatic coronary heart disease, such subjects would be included in the middle-age groups and excluded from the old age groups. Thus, in a cross-sectional study of healthy subjects selective mortality may result in the apparent improvement in ventricular performance with age. 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