The isovolumic index: A new noninvasive approach to the assessment of left ventricular function in man

The Isovolumic Index : A New Noninvasive Approach to the Assessment of Left Ventricular Function in Man G. B. JOHN MANCINI, MD, FRCP(C), DENNIS COSTELLO, MD, VALMIK BHARGAVA, PhD, WILBUR LEW, MD, MARTIN LeWINTER, MD, and JOEL S. KARLINER, MD

Both a high ratio of preejection period (PEP) to left ventricular ejection time (LVET) and a prolonged isovolumic relaxation time are associated with left ventricular dysfunction . In pilot studies in instrumented dogs, we measured a combined isovolumic index, defined as (isovolumic contraction + isovolumic relaxation time)/LVET and found an inverse correlation with changes in fractional shortening . To test the utility of this index in human subjects, we used the electrocardiogram, mitral valve (MV) echogram, and indirect carotid arterial tracing to calculate isovolumic index as (time from R wave to MV opening - LVET)/LVET X 100% . Normal subjects had isovolumic index values that averaged 24 + 7% (standard deviation), in contrast to patients with cardiomyopathy who averaged 65 + 14% (p <0 .001 versus normal values) and patients with coronary artery disease who averaged 40 + 15 % (p <0 .001 versus normal values and patients with cardiomyopathy) . All normal subjects had an

isovolumic index of 532% and all patients with cardiomyopathy had values >32% . Of patients with coronary artery disease, 72% (21 of 29) had an isovolumic index >32% . An isovolumic index >32% identified 20 of 22 patients (91%) with a reduced ejection fraction and 12 of 14 (86 %) with a segmental wall motion abnormality, and it was a more sensitive marker of these abnormalities than abnormal E point-septal separation . In 6 patients with coronary artery disease who had simultaneous echocardiograms and measurements of left ventricular pressure by micromanometer tip catheter, the time constants of isovolumic pressure decrease were uniformly increased in association with an isovolumic index >32% . In contrast, all had normal PEP/LVET ratios . The isovolumic index is thus a sensitive, potentially useful noninvasive marker of left ventricular dysfunction that is easily obtained from the routine echocardiogram .

It has long been appreciated that in patients with left ventricular myocardial disease the period of isovolumic contraction is often lengthened whereas the ejection time is diminished .' When the preejection period is used as an estimate of the isovolumic contraction time, the ratio of preejection period to left ventricular ejection time can provide a useful index of abnormal left ventricular performance which has been correlated inversely with cardiac output, stroke volume, and fractional shortening. 2 4 More recently a number of studies

have demonstrated that indexes of myocardial relaxation are frequently abnormal in patients with left ventricular myocardial disease .5-14 We therefore postulated that a ratio of the sum of isovolumic contraction and relaxation times to left ventricular ejection time might be a sensitive index for the identification of left ventricular dysfunction . In pilot studies in dogs, described subsequently, this ratio did show an inverse correlation with fractional shortening . Accordingly, we then used a simple echocardiographic technique to derive the ratio and tested whether it would detect differences among a population of normal subjects, patients with coronary artery disease, and patients with congestive cardiomyopathy . We also assessed the sensitivity, specificity, and predictive accuracy of this ratio in detecting familiar markers of left ventricular dysfunction (wall motion disorder, depression of the ejection fraction, and abnormalities of myocardial relaxation) and compared the ratio to 2 other noninvasive indexes of left ventricular

From the Cardiology Division, Department of Medicine, San Diego Veterans Administration Medical Center and University Hospital, University of California, San Diego, California . Manuscript received March 1, 1982 ; revised manuscript received June 23, 1982, accepted June 25, 1982 . Address for reprints : Martin LeWinter, MD (111 A), San Diego Veterans Administration Medical Center, 3350 La Jolla Village Drive, San Diego, California 92161 .

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dysfunction, echocardiographic E point-septal separation and the preejection period/left ventricular ejecLion time ratio (PEP/LVET) .

Methods Animal studies: Six adult mongrel dogs were anesthetized with intravenous morphine sulfate (3 mg/kg) and alpha chloralose (90 mg/kg) . The dogs were intubated and respiration was maintained with a Harvard respirator . The heart was exposed through a median sternotomy and suspended in a pericardial cradle . Pacing electrodes were sutured to the left, atrium, and propranolol (1 mg/kg) was administered intravenously . Elk id-filled catheters were placed in the left atrium through a pulmonary vein and in the left ventricle through a femoral artery . These catheters were connected to Statham P23Db transducers with zero reference at the level of the right atrium . A Konigsberg P20 micromanometer was then inserted through the left atrial appendage into the left ventricle . The pressure obtained from the micro manometer was matched to that from the fluid-filled catheter . The latter was then withdrawn to a position just above the aortic valve to provide a recording of central aortic pressure. The micromanometer was frequently checked for drift by comparing peak left ventricular systolic pressure to peak aortic pressure . An inflatable occlusion cuff was then placed about the inferior versa cava . Finally, a pair of 5 MHz piezoelectric crystals (1 .5 min in diam iter) were inserted through stab wounds in the left ventricular myocardium to the mid-wall depth approximately I cm apart . The crystals were placed at the midpoint, perpendicular to the ventricular long axis, and connected to a sonomicrometer-amplifier system for measurement of the shortening of a segment of myocardium oriented with the hoop axis fibers . The sonomicrometer was calibrated with a signal of known delay after the completion of each study . Atrial pacing at rates of approximately 10 beats/min greater than the basal rate was then initiated to maintain heart rate constant during the rest of the experimental protocol . To vary left ventricular preload and fractional shortening, the caval occlusion cuff was first inflated until end-diastolic pressure was 5 mm Hg or less . The cuff was then deflated in small increments with a data point obtained after each deflation . Once the cuff was completely deflated, an intravenous infusion of dextran in saline solution was begun to increase end-diastolic pressure to the 15 to 20 mm Hg range . Data were obtained at 3 to 7 points as left ventricular end-diastolic pressure was increased to this level . All data were recorded on a polygraph (Brush Clevite, model 2000) and analyzed at a paper speed of 200 mm/s with, respiration suspended at end-expiration . Five cardiac cycles were averaged for each measurement . Four discrete timing events were measured . Left ventricular end-diastole was defined as the nadir of the pressure tracing after the a wave of the high gain left ventricular pressure tracing . Aortic valve opening and closure were defined by the aortic pressure recordings from the upstroke and dicrotic notch and transposed to the micromanometer tracing . Mitral valve opening was determined by the pressure cross-over points of the left atrial and left ventricular pressures . Fractional segment shortening was calculated as the difference between segment length at aortic valve opening and closure divided by segment length at aortic valve opening . The isovolumic index (IVI) in these animals was defined as the sum of the duration of isovolumic contraction (IVC, from end-diastole to aortic valve opening) and isovolumic relaxation (IVR, from aortic valve closure to mitral valve

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opening) divided by the left ventricular ejection time (LVET) and expressed as a percentage ; IVI [(IVC + IVR)/

LVEq'j x 100. Clinical studies : Patient population : The normal group consisted of 14 subjects ; 6 were volunteers, 7 had been referred for the evaluation of innocent murmurs, and I had an echocardiogram performed before cardiac catheterization for the evaluation of atypical chest pain . Catheterization subsequently revealed no hemodynamic, left ventricular, or coronary angiographic abnormalities . All subjects had normal results on physical examination . None was taking any medication at. the time of study and all had normal M-mode arid 2-dimensional echocardiographic examinations . The mean age of this group was 31 + 13 (SD) years (range 17 to 61) . Resting heart rates ranged between 51 and 90 beats/min (mean 66 ± 10) and the blood pressure was 120/77 ± 18/9 mm Hg . The card iomyopathy group included 12 patients ranging in age from 34 to 70 years (mean 54 + 10) . All had dilated forms of cardiomyopathy with chronic, stable symptoms of congestive heart failure . The cause was ischemic in 10 and idiopathic in 2 . One patient was not receiving medication at the time of the study . All others were taking digoxin and diuretics . Six of the 12 were receiving prazosin, 3 were ingesting nitrates, and 1 was also taking hydralazine . Two patients were receiving concomitant oral amrinone therapy . All 12 patients were in sinus rhythm with rates ranging between 58 and 99 heats/min (mean 79 + 14), while the blood pressure was 113/72 1 14/13 mm Hg . No patient had clinical evidence of valvular disease. Resting equilibrium radionuclide angiography was performed in all of these patients for measurement of ejection fraction . The group with coronary artery disease included 29 patients . of whom 8 had undergone diagnostic cardiac catheterization within 2 weeks of the echocardiographic study . Seven patients were studied within 48 hours of catheterization, and 6 patients underwent echocardiography at the time of cardiac catheterization . All 21 catheterized patients had evidence of significant coronary artery disease as defined by angiographic l urinal narrowing of 70% or more in at least I major vessel . The other 8 patients with coronary artery disease had either a history of a myocardial infarction (as evidenced by a typical history, diagnostic changes in creatine kinase levels, and evolution of persistent electrocardiographic signs) or a history of chronic, stable angina with diagnostic electrocardiographic or reversible thalliun-201 scintigraphic abnormalities, or both, during exercise . Six of these 8 patients also had resting gated radionuclide ejection fraction determinations. Echocardiographic and radionuclide examinations were carried out at least 6 months after acute infarction in this group, and in all cases ischemic symptoms were stable . One patient with coronary artery disease was receiving digoxin at the time of study arid 18 were taking beta-blocking drugs . Ages ranged from 24 to 69 years (mean 53 + 12) . During echocardiographic study the blood pressure was 131 /79 ± 27/16 mm Hg and the heart rate was 66 ± 13 beats/min (range 46 to 90) . No patient had evidence of valvular disease . The :3 groups were not different with respect to blood pressure, but both groups of patients had a higher mean age than that of normal subjects (p <0 .001) and the mean heart rate in the cardiomyopathy group was higher than that in the other two groups (p <0 .025) . Methods : All patients underwent M-mode echocardiography using a Toshiba SSH-10A sonolayergraph with a Toshiba strip chart recorder . Each normal patient and all patients with cardiomyopathy also had 2-dimensional echocardiographic

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ISOVOLUMIC INDEX-MANCINI ET AL

FIGURE 1 . Calculation of the isovolumic index (WI) from the simultaneous carotid arterial pulse tracing and mitral valve echocardiogram is demonstrated in a normal patient . LVET = left ventricular ejection time ; R-MVO = the time from the peak of the R wave to mitral valve opening . Dotted time markers are at intervals of 500 ms .

examination using a 78° electronic phased array transducer to exclude unsuspected segmental wall motion abnormalities or valvular disease such as mitral valve prolapse . Simultaneous carotid arterial pulse tracings were recorded using a Fukuda model TY-303 transducer . In the 6 patients with coronary artery disease who had echocardiographic examinations during cardiac catheterization, simultaneous left ventricular pressure was measured with a micromanometer tip high-fidelity catheter (Miller) . Pressures were acquired on-line onto computer tape . Left ventricular pressure was also displayed on the echocardiographic strip chart paper and by using calibration signals, the specific high fidelity pressure tracing corresponding to simultaneous echocardiography events could be identified . This approach eliminated the need to hand-digitize the left ventricular pressure recording from high speed recordings so that the Toshiba strip chart recorder could be run at 50 mm/s . At this speed the mitral valve echocardiogram was not excessively expanded . The mitral valve echocardiogram was obtained with the transducer in the second to fifth intercostal spaces and within 3 to 4 cm of the left sternal border such that maximal excursion of the mitral valve leaflets was recorded . The onset of mitral valve opening was taken from the onset of the most rapid anterior motion of the anterior mitral valve leaflet 15 (Fig . 1) .

A suitable limb electrocardiographic lead was selected which showed a sharp R wave and this was recorded simultaneously on the strip chart . No patient had evidence of bundle branch block . The isovolumic index was determined as follows . The left ventricular ejection time was taken from the onset of the most rapid upstroke of the catorid arterial pulse tracing to the dierotic notch . The period from the peak of the R wave to the mitral valve opening (R-MVO) was then determined . We chose the peak of the R wave from which to measure the interval of total electromechanical systole and isovolumic relaxation (R-MVO) because in our experience it was more easily reproducible than the onset of the Q wave, particularly in tracings recorded from the echocardiographic strip chart, in which gain and lead selection are limited . Subtracting left ventricular ejection time from R-MVO gives an interval that includes isovolumic contraction, isovolumic relaxation, and a small interval of electromechanical delay . Therefore, this measure provides an estimation of the time during which the left ventricle is in an isovolumic state and is termed the isouolumic tinge (lv i ). Thus, the echocardiographie isovolumic index was defined as follows : IVI (`%) = [(R-MVO - LVET)/ LVET] x 100 = (IVT/LVET) x 100 . Recordings were made during quiet respiration and 5 suitable cycles were averaged to determine the isovolumic index . Because we did not calculate the delay in the carotid pulse tracing, the actual preejection period (time for electromechanical delay plus isovolumic contraction) and the precise duration of isovolumic relaxation could not he determined separately by this method . The E point-septal separation was determined in all suitable M-mode recordings (51 of 55 patients) and considered abnormal when ?5 .5 mm . 1 ° PEP/LVET was calculated from the simultaneous electrocardiogram and micromanometer ascending aortic pressure tracing in the 6 patients studied at the time of catheterization .t 7 The preejection period was measured from the onset of the Q wave to the onset of the most rapid upstroke of the ascending aortic pressure tracing . In 7 of the 12 patients with cardiomyopathy PEP/LVET was de-„ termined noninvasively in standard fashion' nn the same day as the echocardiographie study . High fidelity left ventricular pressure tracings were digitized at 200 samples/s and the first derivative of the left ventricular pressure was computed . End-diastolic pressure was defined as the pressure at which dP/dt reached 200 mm Hg/s and the pressure increased monotonically thereafter . The interval of isovolumic relaxation was defined from the time of peak negative dP/dt to a point at which the left ventricular pressure was at least 10 mm Hg above end-diastolic pressure of that beat . Left ventricular isovolumicc pressure (P) with respect to time (t) was then fitted to an exponential curve's of the form : P = P O exp (-t/T), where P t, is the pressure at peak negative dP/dt and T is the time constant . In each patient T was measured from the same 5 beats from which the isovolumic index was calculated . Tt 10 was calculated in the same fashion using only the first 40 ms of the isovolumic pressure decline . Biplane left ventricular cineangiograms were examined independently by 2 observers without knowledge of the isovolumic index for identification of areas of hypokinesia, akinesia, or dyskinesia . Gated equilibrium radionuclide angiograms at rest were obtained by a protocol validated in our laboratory and described previously .' 9 The difference in counts/cycle in studies repeated at least I month apart was 11% and the interobserver variation was also ±1% counts/cycle . The radionuclide ejection

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ISOVOLUMIC INDEX-MANCINI ET AL

P < D .DO1 -P

90 - P

EO

'0

C

0001-

< 0 001 -

-

00

SO

U

40

3D

PO

10 3

0 IS FRADT7ONA . SHORTENING (N)

27

Correlation between fractional shortening and isovolumic index is demonstrated in 2 dogs .

NORMAL SUBJECTS

FIGURE 2 .

fraction was determined without knowledge of the isovolumic index . Statistics : All data are given as mean 1 1 standard deviation. The chi-square test with Yate's correction and the paired and unpaired Student's t tests were used when appropriate to assess statistical significance . Correlations were tested using linear regression analysis . "Sensitivity" was defined as the number of true-positive test results divided by the total number of subjects with the clinical abnormality being analyzed . "Specificity" was defined as the number of true-negative test results divided by the total number of subjects without the clinical abnormality being analyzed . "Predictive accuracy" was defined as the number of true-positive test results divided by the total number of positive test results . Results Animal studies : Figure 2 demonstrates the correlations in 2 dogs between the isovolumic index and fractional shortening during 7 stepwise increases in the left ventricular filling pressure . Note that the isovolumic index decreased as fractional shortening improved . In 3 of the remaining 4 dogs, the correlations were also high (r = -0 .94, -0.97, and -0 .99), whereas the last correlation was -0.75. Clinical studies : The isovolumic index did not correlate significantly with age, heart rate, systolic blood pressure, or mean blood pressure . As shown in Figure 3, normal subjects had the lowest isovolumic index (24 t 7%) in contrast to patients with cardiomyopathy (65 f 14%, p <0.001 versus normal subjects) and those with coronary artery disease (40 ± 15%, p <0 .001 versus normal subjects and patients with cardiomyopathy) . All normal patients had an isovolumic index :532% whereas all patients with cardiomyopathy had values >32% . The coronary group showed some overlap with the normal subjects, but the majority (21 of 29, 72%) had an isovolumic index >32% . Analysis of the coronary patients alone (Table 1) showed no significant difference in the absolute value of the IVI in those who (1) were or were not taking

ISOVOLUMIC INDEX-MANCINI ET AL

CORONARY ARTERY CARDIOMYOPATHY PATIENTS DISEASE PAIIEN'S

FIGURE 3 . Isovolumic index in the study population . Means ± deviation are shown .

1

standard

beta-blocking drugs, (2) did or did not have a wall motion abnormality, (3) had a normal or reduced ejection fraction, and (4) had an elevated or normal left ventricular end-diastolic pressure . Table II demonstrates the sensitivity, specificity, and predictive accuracy of an elevated isovolumic index (>32%) and an abnormal E point-septal separation (?5.5 mm) 16 for (1) the presence of disease in the entire study group ; (2) the presence of coronary disease (excluding coronary patients in the cardiomyopathy group) ; (3) the presence of wall motion abnormalities whether segmental or diffuse (including patients with cardiomyopathy) ; and (4) the presence of an abnormal ejection fraction . A radionuclide ejection fraction <50% or an angiographic ejection fraction <55% was consid-

TABLE I

Class I

Subclassification of Patients With Coronary Artery Disease Patient Data On beta-blocking drugs (n = 18)

Isovolumic Index 1 ) 44 1 15 p = NS

II

Off beta-blocking drugs (n = 11) Wall motion abnormality (n = 14)

35 1 12

wall motion abnormality (n = 7) Subnormal ejection fraction (n = 10)

46 1

Normal ejection fraction (n = 17) Left ventricular end-diastolic pressure > 12 mm Hg (n=9)

40 1 17

Left ventricular end-diastolic pressure :512 mm Hg (n = 12)

47 ± 16

43 1 11 p=NS

No III

19

42 1 12 p=NS

IV

41 1 11

p=NS



ISOVOLUMIC INDEX-MANCINI ET AL

ered abnormal . Note that the isovolumic index was a more sensitive indicator than an abnormal E pointseptal separation for the presence of these commonly employed markers of left ventricular dysfunction . However, the specificity and predictive accuracy tended to be lower. Because the E point-septal separation was always normal when the isovolumic index was normal whereas the isovolumic index was sometimes increased despite a normal E point-septal separation, it follows that the sensitivity, specificity, and predictive accuracy of the presence of abnormalities of either of these measures or both merely reflected the behavior of the isovolumic index alone . For purposes of comparison with E point-septal separation, an abnormal isovolumic index was defined as any value greater than the highest found in our normal group (that is, 32%), because this is the way an abnormal F point .-septal separation has been defined previously. 16 Using >38% (2 standard deviations above the normal group mean) as the definition of an abnormal isovolumic index, the sensitivity decreased modestly . However, sensitivity improved when either or both of these measures were abnormal (Table III) .

TABLE II

Simultaneous hemodynamic and echocardiographic data from the 6 coronary patients so studied are shown in Table IV . All patients had significant wall motion abnormalities . Despite the occurrence of both normal and abnormal ejection fractions and end-diastolic pressures and the wide range of peak positive and negative dP/dt values, all patients had abnormal time constants of relaxation . 9 . 10 Note that the isovolumic index was >38% in 5 of the 6 and >32% in all, whereas all had a normal PEP/LVET (<0 .42) . 20. 21 In contrast, in the 7 patients with cardiomyopathy in whom these determinations were made, both PEP/L VET and the isovolumic index were abnormal . As indicated, the PEP/L VET and the isovolumic index could be compared in a total of 13 patients (6 with coronary artery disease and 7 with cardiomyopathy) . In this subgroup, the PEP/L VET (expressed as a percentage) averaged 45 ± 14 and was invariably smaller than the isovolumic index, which averaged 60 ± 17 (p <0 .01) . In a random subgroup of 10 patients the isovolumic index as measured independently by 2 observers varied by ±8% . In a separate subgroup of 7 subjects, the re-

Sensitivity, Specificity, and Predictive Accuracy of an Increased lsovolumic Index (tIVI) or Abnormal E Point-Septal Separation (tEPSS) for the Presence of Disease and Left Ventricular Dysfunction Sensitivity

Presence of disease Presence of coronary disease (excluding patients with ischemic cardiomyopathy) Abnormal rest ejection fraction Segmental wall motion abnormality Segmental or diffuse wall motion abnormality

Predictive Accuracy

ChiSquare'

Value

P

IVI EPSS IVI EPSS

80% 54% 72% 32%

(33/41) (20/37) (21/29) (8/25)

100% 100% 100% 100%

(14/14) (14/14) (14/14) (14/14)

100% 100% 100% 100%

(33/33) (20/20) (21/21) (8/8)

24 .92 10 .29 17 .02 3 .84

<0 .001 <0.01 <0.001 <0.05

IVI EPSS IVI EPSS tlVl tEPSS

91% 74% 86% 58% 92% 79%

(20/22) (14/19) (12/14) (7/12) (24/26) (19/24)

61% 80% 76% 95% 76% 95%

(19/31) (24/30) (16/21) (19/20) (16/21) (19/20)

63% 70% 71% 88% 83% 95%

(20/32) (14/20) (12/17) (7/8) (24/29) (19/20)

12 .56 11 .74 10 .53 8 .71 20 .26 21 .30

<0.001 <0.001 <0 .01 <0 .01 <0.001 <0 .001

I

definition all normal patients had a normal ' Chi-square analysis with Yates' correction .

By

TABLE III

Specificity

IVI (<32%) .

Numbers in parentheses refer to actual number of patients .

Sensitivity, Specificity, and Predictive Accuracy of an Increased Isovolumic Index (TIVI)' and an tiVi + Abnormal E Point-Septal Separation (tEPSS) for the Presence of Disease and Left Ventricular Dysfunction

Presence of disease Presence of coronary disease (excluding patients with ischemic cardiomyopathy) Abnormal rest ejection fraction Segmental wall motion abnormality Segmental or diffuse wall motion abnormality

IVI IVI+ tEPSS tlVl TIVI+ tEPSS IVI IVI+ tEPSS tlVI ilVI+ tEPSS 'IVI tiVl+ fEPSS

Sensitivity

Specificity

Predictive Accuracy

ChiSquarer

p Value

66% (27/41) 76% (31/41)

100% (14/14) 100% (14/14)

100% (27/27) 100% (31/31)

14.53 21 .28

<0.001 <0.001

52% (15/29) 66% (19/29)

100% (14/14) 100% (14/14)

100% (15/15) 100% (19/19)

8 .96 13 .88

<0 .01 <0 .001

91% (20/22) 91% (20/22)

81% (25/31) 71% (22/31)

77% (20/26) 69% (20/29)

23 .58 17 .47

<0 .001 <0 .001

64% (9/14) 79% (11/14)

81% (17/21) 81% (17/21)

69% (9/13) 73% (11/15)

5 .55 9 .84

<0 .02 <0 .01

77% (20/26) 88% (23/26)

81% (17/21)

83% (20/24) 85% (23/27)

12 .27 20 .15

<0 .001 <0 .001

81% (17/24)

' Greater than 38 % (that is, 2 standard deviations above the mean VI of normal subjects) . Chi-square analysis with Yates' correction . Number in parentheses refer to actual number of patients . I

t

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ISOVOLUMIC INDEX--MANCINI ET AL

TABLE IV

Simultaneous Hemodynamic and Echocardiographic Data in Subgroup of Patients With Coronary Artery Disease Studied With Micromanometer Tip High Fidelity Pressure Transducers

Ejection Fraction

Systolic Blood Pressure (mm Hg)

0 .57 0 .50 0 .53 0 .52 0 .70 0 .48

130 165 130 170 160 120

LVEDP (mm Hg)

Peak Positive dP/dt (mm Hg/s)

Peak Negative dP/dt (mm Hg/s)

9 25 7 13 11 15

1,630 ± 89 1,508 ± 19 1,529 ± 43 1,638+238 1,426 ± 308 1,213 f 23

1,531 ± 66 1,630 1 130 1,665 + 154 2,040 ± 250 1,765±213 1,469 f 55

T (ms) 57 .2 54 .5 50 .5 53 .3 50 .1 51 .5

± ± 1 1 ± ±

2 .6 8 .1 1 .3 2 .3 5 .4 2 .0

T, (ms) 53 .1 68 .0 61 .2 64 .7 54 .8 55 .0

± h ± ± ± f

6 .5 3 .0 1 .6 8 .8 9 .9 1 .7

PEP/LVET

IVI I%)

0 .38 0 .24 0 .38 0 .26 0 .28 0 .35

48 46 45 61 34 53

Data are given as mean f 1 standard deviation . See text for definition of T and T, . IVI = isovolumicc index ; LVEDP = left ventricular end-diastolic pressure ; LVET = left ventricular ejection time ; PEP = preejection period .

producibility of the measurement from 2 different echocardiograms performed on 2 separate occasions (at least 24 hours apart) when there had been no interval change in clinical status or drug therapy was ±5% . Discussion The isovolumic index as we have defined it is an easily obtainable echocardiographic measurement that requires only the recording of an electrocardiographic R wave, a carotid arterial pulse tracing, and the echocardiogram of the anterior leaflet of the mitral valve . These recordings are well within the capabilities of any echocardiographic laboratory and do not require special equipment or a change in the usual routine of echocardiographic examination . Furthermore, the noninvasive nature of this procedure lends itself to widespread application and repeated measurements over the course of a patient's illness or perhaps during interventions and specific therapy . Although the use of single-channel dual echocardiography allows for the direct measurement of isovolumic contraction and relaxation, 22 it is often difficult to obtain consistent, clear, simultaneous echograms of aortic and mitral valve opening and closure, and it is virtually impossible with only I operator . The isovolumic index can be recorded in virtually any patient and without the need for split-screen capabilities or added personnel . The rationale for this measurement stems from 2 lines of reasoning . First, abnormalities of left ventricular relaxation have been noted in patients with coronary artery disease even in the absence of wall motion abnormalities, subnormal values for ejection fraction at rest, or acute ischemia . 5-7,9,10 These abnormalities have been detected by measurement of peak negative dP/dt or the time constant or isovolumic pressure decrease using invasive techniques, or both . Although the isovolumic index gives no information about the rate of pressure decrease during relaxation, an abnormally slow rate of decline can obviously influence the isovolumic index by increasing the total isovolumic period . Indeed, others have shown that the isovolumic relaxation period as measured echocardiographically or by apexcardiography is prolonged at rest in many patients with cor-

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onary artery disease when compared with normal subjects.' 1-14 .23 The second line of reasoning providing a rationale for measurement of the isovolumic index stems from previous work describing systolic time intervals . Initial observations demonstrated that nonvalvular heart disease tended to lengthen the preejection period while the ejection time became shortened . The PEP/LVET ratio provided a useful index which correlated with cardiac output and stroke volume .' - „ Others showed similar correlations of PEP/LVET with fractional shortening . 1 Stack et a1 21 .21 demonstrated its apparent utility in coronary disease . In addition, Lewis et a1 25 demonstrated that the PEP/NET ratio was somewhat sensitive to the presence of wall motion abnormalities in patients with coronary disease . Although their patients with wall motion disorders had statistically lower angiographic ejection fractions than did those without segmental abnormalities, the average ejection fraction in both groups remained normal . Even so, PEP/LVET was significantly greater in the presence of segmental contraction disorders . On the basis of these observations, we hypothesized that an index combining isovolumic contraction, relaxation, and left ventricular ejection times might be a sensitive marker for the presence of cardiac disease . We also anticipated that abnormalities in such an index might occur in the absence of commonly accepted indicators of left ventricular dysfunction, because abnormalities in the components of this index have been noted even without the presence of wall motion abnormalities or a depressed ejection fraction . The results shown in Table II appear to bear out these predictions . Thus, the isovolumic index is a sensitive indicator of the presence of disease even in the absence of wall motion abnormalities or a depressed ejection fraction, or both, and it is more sensitive than increased E point-septal separation in this regard . Perhaps not surprisingly, the specificity and predictive accuracy of the isovolumic index for the presence of these abnormalities are less impressive than its sensitivity. This Finding could reflect the possibility that very subtle aberrations of the relation between isovolumic contraction and relaxation and ejection may result from the presence of coronary artery

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disease even when the disease is uncomplicated by abnormalities of left ventricular function detected by other techniques . The use of a higher value to define an abnormal isovolumic index (>38%) enhanced specificity . Furthermore, the sensitivities of the isovolumic index and abnormal E point-septal separation were each improved when either or both of these abnormalities were present (Table III) . Although the isovolumic index is highly sensitive and compares favorably with E pointseptal separation, the overlap between patients with coronary artery disease and normal subjects (Fig. 3) demonstrates that it does not completely identify all such patients . As indicated previously, although patients with coronary disease may have abnormalities of the components of the isovolumic index without other indicators of abnormal ventricular function, it is not always the case . Hence, some degree of overlap is to be anticipated, and like all other noninvasive indexes, the isovolumic index is not completely sensitive in this regard . Although we initially hoped that the isovolumic index would correlate in a linear fashion with ejection fraction in the entire clinical population as it did with fractional shortening in the experimental animals, this did not turn out to be the case . Similar problems have been noted by some with respect to the use of PEP/LVET or E point-septal separation for the prediction of ejection fraction in coronary patients . 16,26-1s Nevertheless, our experimental preparation demonstrated a high negative correlation of the isovolumic index with improved fractional shortening when each dog was considered individually . This finding underscores 2 points . First, as the animal studies demonstrate, the isovolumic index may be influenced by differences in loading conditions, variables that were not manipulated in our clinical population and that require further investigation . Second, although we showed the usefulness of an isolated determination of the isovolumic index in the clinical subjects the animal data suggest that serial measurements in an individual during changes in clinical status or therapy or during acute interventions may also be a useful application . Although modest, age-dependent prolongation of systolic time intervals and relaxation have been observed,9, '2 . 29 others have failed to confirm this finding ." We found no age-dependence of the isovolumic index either in the entire study group or within each group . Similarly, the isovolumic index did not appear to be related to heart rate within the range of our study (46 to 99 beats/min), although it might vary as a function of heart rate in individual subjects . This study does not specifically compare the isovolumic index with PEP/LVET as a predictor of coronary disease, wall motion abnormalities, or reduced ejection fraction . However, although PEP/LVET was calculated in only a minority of our coronary patients, it is of note thatt in each of these cases the isovolumic index was abnormal despite the presence of a normal PEP/LVET . This finding is consistent with the work of several other investigators who have demonstrated that PEP/LVET is not always sensitive in patients with coronary disease and left ventricular dysfunction 26-2s

It is important to stress certain methodologic features of measurement of the isovolumic index, particularly as they relate to comparisons between the isovolumic index and routinely obtained PEP/LVET ratios . We chose the peak of the R. wave from which to measure the interval of total electromechanical systole and isovolumic relaxation (R-MVO) because in our experience it is more easily reproducible than the onset of the Q wave, particularly in tracings recorded on the echocardiographic strip chart . As a consequence, a substantial portion of the true electromechanical delay is not included in the R-MVO interval. In subjects with a normal PEP/LVET, the time for electromechanical delay accounts for a much greater portion of the PEP/LVET ratio than it does in individuals with an increased YEP/LVET, assuming a QRS complex of normal duration . This disproportionate contribution of electromechanical delay in normal compared with abnormal subjects is further exaggerated in determining the isovolumic index because of the addition in the numerator of the isovolumic relaxation time, which is also shorter in normal subjects. The standard technique for measuring PEP/LVET employs the onset of the Q wave as the beginning of PEP. If PEP/LVET were defined from the peak of the R wave, however, values for PEP/LVET in normal subjects would be systematically much shorter than those calculated in the usual fashion . This explains the fact that our isovolumic index value of 24 t 7% in normal subjects apears surprisingly small in comparison with standard PEP/LVET ratios . Furthermore, in the abnormal subjects in whom PEP/ LVET and the isovolumic index could be compared, the index was appropriately longer than PEP/LVET, as would be anticipated in a group in which electromechanical delay is a less important determinantt of both ratios . Moreover, methodologic differences in the recording of timing intervals can also produce substantially different results . 1 .15 . '- 13:1 It is therefore important to employ strict methodologic techniques in calculating the isovolumic index, particularly in timing the beginning of electromechanical systole and mitral valve opening. We conclude that the isovolumic index is a sensitive indicator of left ventricular dysfunction and of the presence of coronary disease in some patients without abnormalities of other measures of systolic function . Furthermore, because the isovolumic index is easily determined during routine echocardiography, it may also be useful in serial measurements in individual patients during various phases of disease or therapy, an application that will require future validation . References 1 . Weissler AM, Harris WS, Schoenfeld CD . Systolic time intervals in heart failure in man . Circulation 1968 ;37 :149-159 . 2 . Welsider AM, Harris VIS, Schoenfeld CO . Bedside technique fw the evaluation of ventricular function in man . Am J Cardiol 1969;23:577-583 . 3 . Lewis RP, Rillgers SE, Forester WF, Boudoulas H . A critical review of the systolic time intervals . Circulation 1977 ;56 :146-158 . 4 . McDonald IG, Hobson ER . A comparison of the relative value of noninvasive techniques-echocardiography, systolic lime intervals, and apexcardio graphy-in the diagnosis of primary myocardial disease . Am Heart J 1974 ;88:454-462 . 5 . Grossman W, McLaurin LP. Diastolic properties of the left ventricle . Ann Intern Mad 1976 ;84 :316 326.

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6 . Grossman W, Barry H . Diastolic pressure-volume relations in the diseased he ap . Fed Proc 19 80 ;39 :148-155, 7 . Gibson DG, Prewm TA, Brown DJ . Analysis of left ventricular wall movement during isovolumic relaxation and its relation to coronary artery disease . Br Heart J 1976 ;38 :1010-1019 . 8 . Lewis BS, Grtsman MS . Current concepts of left ventricular relaxation and compliance . Am Heart J 1980 ;99:101-112 . 9 . Hiroto Y . A clinical study of left ventricular relaxation. Circulation 1980; 62 :756-763. 10. Rousseau MF, Veriter C, Detry JMR, Brasseur L, Poulev H . Impaired early left ventricular relaxation in coronary artery disease : effects of intracoronary nifedipine . Circulation 1980;62 :764-772 . 11 . Rubenstein JJ, Pohosl GM, Foster JR . The echocardiographic determination of isovolumic relaxation period in patients with normal and diseased coronary arteries (abstr) . Clin Res 1973 ;21 :446 . 12. D'Angelo R, Shah N, Rubler S . Diastolic time intervals in ischemic and hypertensive heart disease : a comparison of isovolumic relaxation time and rapid filling time with systolic time intervals . Chest 1975 ;68 :56-61 . 13. Benchimol A, Ellis JG . A study of the period of isovolumic relaxation in normal subjects and in patients with heart disease . Am J Cardiol 1967 ; 19 :196-206 . 14. Lewis 8S, Lewis N, Sapoznikov D, Gelman MS . Isovolumic relaxation period in man . Am Heart J 1980 ;100:490-499 . 15. Rubenstein JJ, Pohost GM, Dinsmore RE, Harthorne JW . The echocardiographic determination of mural valve opening and closure : correlation and hemodynamic studies in man . Circulation 1975 ;51 :98-103 . 16. Lew W, Henning H, Schelbert H, Karliner JS. Assessment of mitral valve E point-septal separation as an index of left ventricular performance in patients with acute and previous myocardial infarction . Am J Cardiol 1978 ;41 :836--845 . 17. Martin CE, Shaver JA, Thompson ME, Reddy PS, Leonard JJ . Direct correlation of external systolic time intervals with internal indices of left ventricular function in man . Circulation 1971 ;44 :419-431 . 18. Weiss JL, Frederiksen JW, Weisfeldt ML . Hemodynamic determinants of

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the time-course of tall in canine left ventricular pressure . J Clin Invest 1976;58 :751-760 . 19 . Slutsky R, Karllner J, Ricci 0, of al. Left ventricular volumes by gated equilibrium radionuclide angiography : a new method . Circulation 1979; 60 :556-564 . 20 . Tavel MF. Clinical Phonocardiography and External Pulse Recording . 2nd ad . Chicago : Year Book Medical, 1973 :167-169 . 21 . Stack RS, Sohn YH, Welssler AM . Accuracy of systolic time intervals in detecting abnormal left ventricular performance in coronary artery disease. Am J Cardiol 1981 ; 47 :603-609 . 22 . Arditti A, Rosenzwelg B, Kronzan I, Sharaz J, Laniado $ . Single channel dual echocardiography . Am J Cardiol 1980 ;46 :277-280 . 23 . Araoye MA, Rubler S, Holford FD . Isovolumic relaxation time in normal subjects and patients with cardiac disease : comparison of determinations made with echocardiographic techniques and apex cardiography . Angiology 1978 ;29 :7-16 . 24 . Stack RS, Lee CC, Reddy BP, Taylor ML, Welssler AM . Left ventricular performance in coronary artery disease evaluated with systolic time intervals and echocardiography . Am J Cordial 1976;37 :331-339 . 25 . Lewis RP, Boudoutas H, Welch TO, Forester WF . Usefulness of systolic time intervals in coronary artery disease. Am J Cardiol 1976 ;37 787796 . 26 . Eddleman EE Jr, Swatzell RH Jr, Bancroft WH Jr, Baldone JC Jr, Tucker MS . The use of the systolic time intervals for predicting left ventricular ejection traction in ischemlc heart disease . Am Heart J 1977 ;93 :450454, 27 . Parker ME, Just HG. Systolic time intervals in coronary artery disease as indices of left ventricular function : fact or fancy? Br Heart J 1974 ;36 : 368-376. 28 . Rater 0, Pugh D, Gray W . Practical significance of systolic time intervals in coronary artery disease . Chest 1973 ;64 :186-188 . 29. Harrison TR, Dixon K, Russel RO Jr, Bldwai PS, Coleman FIN . The relation of age to the duration of contraction, ejection and relaxation of the normal human heart . Am Heart J 1964 ;67:189-199,

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