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Evaluation of myocardial contractility in man
Evaluation
of myocardial
contractility
in man
Hector J. Hermann, X.0.* Rrxjindnr Singla, M.D. J. Francis Dammann, M.D. Charlottesville, Til.
Methods
W
ith the analysis of the isometric contraction of isolated papillar) muscle and intact left ventricle, an assesstnent of myocardial contractility can I)e made independent of fiber length or its function as a pump.’ Experimental studies suggest that the ratios between the first derivative and end-diastolic pressure2 and integrated isometric tension’ are constant for a given inotropic state. If so, these ratios should give better indices of contractility than the paratneters routineI!evaluated in most clinical laboratories. Furthermore, clinical and experimental observations indicate that the ratio of stroke volume to end-diastolic volume, enddiastolic pressure, estimation of stroke \\,ork, and determination of the first and second derivative of the left ventricular pressure are of value used serially in the individual patient, but are of uncertain diagnostic significance in comparing one patient to another. In the present study, the isovolumetric phase of the left ventricular contraction 11as been analyzed in 53 patients with sevrral tJ.pes of heart disease in order to assess the significance and relative value of those caxperitnental findings.
*.\ddress correspondence to: IIector riat IIospital, 250 East Superior
I ‘01. Ti. No.
6. pp. 75576/j
JWIC, 1969
J. Herman. St., Chicago,
Fifty-three patients were selected for this study and divided into three different groups. Only those in whom the diagnosis had been established by detailed cardiac catheterization were included. Group I. The control group of 13 patients consisted of 6 patients without evidence of valvular or myocardial disease who underwent cardiac catheterization because of the presence of functional murmurs, and 7 patients with pure mitral stenosis. The existence of mitral insufliciency was ruled out by cineangiography and the patients were considered to have no abnormalities involving the left ventricle. Group 11. This group included 15 patients with unequivocal myocardial disease of different etiology. Eight fulfill the criteria for idiopathic primary myocardiopathy, and 7 had evidence of advanced arteriosclerotic heart disease. Except for 3 patients (Nos. 15, 16, and 20), the patients in this group had no evidence of valvular disease. Grolip 111. This group n-as comprised oi 25 patients ~vith a single valvulnr lesion causing either severe degrees of tttitral or aortic insufficiency or aortic stenosis. Left ventricular angiograms were 01,.
hI.tI., IXrector. Ill. 60611,
Cardiovascular
American
laboratory,
Heart
Chicago
Jnurnal
Wesley
hlrmo-
755
756
Hermmn,
Sing-h, and Dtrmmnnn
tained with the injection of 40 to 60 ml. of a 7.5 per cent solution of sodium and methylglucamine diatrizoate (Renovist, Squil)l)) into the left ventricle (L\:) or left atrium (LA), and biplane films (Elema-Schonander, Stockholm, Sweden) or single plane tine exposed at 6 or 30 frames per second, respectively. Volumes were calculated using the ellipsoid reference figure and the area length method of Dodge and associates” and corrected 11). the regression equation : I-,, = IrC . .936 - 3.6. (‘ineangiograms I\-ere obtained with the patients in the RAO
Mean
overestimated
Clrcumferentlal
4 ,
6;
position. Good correlation Ijetween the L\volumes calculated from biplane and single plane frames has lIeen ol)served in Ollr lal)oratory* as IveIl as 1)~ others.” The I=?.~() position \vas selected because it allo\vcd us to study the mitral valve and ascertain the existence of mitral insufficiency during the same injection lvithout detriment to the good correlation \\-ith biplane L\- volumes (r : .830; S.E.E., 19.S ml.). It shoul~~ 1~ noted tllat in general the largest volu~ues
d;=
Stress,
where
EFT
VENTRKIJLAR
used
WALL END
in the determination
STRESS
DIASTOLIC
AT THE
single
plarlc
d2
PRi --jy
- 62
Fig. 1. Shows the calculations sumptions they are based on.
II)-
of stress
EQUATOR-ELLIPSOIDAL
STRESS
P= lntralumlnal Pressure R,= Outer Radius Ri= Inner Radius h = R,- Ri
at the “equator”
vs MEAN
of the heart
CIRCUMFERENTIAL
and
the aa-
METHID;;
END SYSTOLIC STRESS
I ,’
MEAN
Fig. 2. Relationship of left ventricular ferential) and total ellipsoidal stress. time-consuming formula.
CIRCUMFERENTIAL
stress calculated by the simple formula used in the Lest (meall circllmThe excellent correlation makes justitiable the we of the simple, ICY>
Sl~vocc7rdinl
‘l‘lic
radii
\vere derived
of the area of an ellipse3:
froni
the formula
RI = $.
_I
Cl;all thickness (h) was calculated I>>’ simple estimation of the jvidth at several points to obtain an average value. This technique of determining L\’ wall thickness gives almost identical values4 with the metllod descrilled 1)y Rackley and associ;ttes.” l’ressures I\-ere obtained immediately before the angiograms I,y means of Ko. 7 S 1H catheters, 100 cm. long, directly connected to a Statham 1’131111 transducer \vllich \vas calil)rated before each procedure, balanced lIefore each run, and referenced to a zero level 5 cm. I>elow the angle of Louis \\rith the patient supine, and rccorded on an optical recorder at a paper speed of 200 mm. per second. The maximal rate of rise of the left ventricular pressure (d/>/dr) \\x obtained \\-ith an R-C differentiating circuit.’ Stress (Fig. 1) n-as calculated at the eqilator of the left ventricle by the formula: P . Ii1 ~~-.-- \vhere P = L\,- pressure, II
RI = inner
radius,
This
and h = wall
thickness.
Fig. 3. ERG, Electrocardiogram; the lelt ventricular pressure;
I.I.P.,
Ao, aortic integrated
calcu-
7.57
rontrtlctility
lation of circuiilferential stress or a.2 \vas selected because it is the largest stress at the equator of the ventricle and c;kulation is simple. There is excellent correlation with the results obtained with more complicated formula9 (Fig. 2). Stress \vas expressed in dynes per square centimeter and tension \vas expressed as stress X wall thickness ((~2 X 12) in dynes per centimeter. Integrated isometric pressure (IIP) was obtained by planimetric integration of the area beneath the isovolumetric phase of the left ventricular pressure tracing (between the end-diastolic point and the opening of the aortic valve) (Fig. 3) divided 1,) the isovolumetric contraction time. Integrated isometric stress ([IS) was calculated as IIS
= g%’
. The
radius
and
n-all
h
thickness used for these calculations were those calculated from the end-diastolic volumes. Although these values change somewhat during the isovolumetric phase of contractiong-” the variations are small and they should not significantly alter the results. Observations in our laboratory using cineangiography have sholvn that RI and h change less than 4 and :! mm., respectiveI\., during this cardiac phase.
pressure; I, V, left ventricular pressure; dp/dt, iwvolumetric pressure (shadowed area).
first
derivative
of
TabIe
I. Clinical
muteriul
’
’
Patient
Lesion
and qmntitative
Age
B.S.1.
(Al.‘)
NO.
1 2 3 4 5 6
19 27 22 12 25 18 47 29 34 28 37 39 32 50 42 62 12 23 45 30 31 17 2.5 46 17 8 54 60 38 41 34 40 17 49 40 48 35 40 37 2 .i 31 22 31 21 40 42 53 21 18 45 36 65 38
7 8 9 10 11 12 13 14
15 16 17 18 19 20 21 22 23 24 25 26 ‘7 18 2Y 30 31 .z2 33 3-t 35 .16 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53
1.G 1.93 1.75 1.14 1 .I9 1.9 1 .79 1.70 1.51 1.41 1.69 1.45 1.45 2.05 1.68 1.82 1.08 1.38 1.81 1.45 1.87 1.86 2.25 1.75 1.65 0.64 1.62 1.74 2.15 1.65 1 58 2.12 1.45 1.76 1.82 1.56 1.72 1.72 1.95 1.68 1.95 1.53 1.86 2.0-l 1.64 1.82 1.72 1 80 1.55 1.62 1.23 2.04 1.49
datu
E.Il. I;. , (?d./M.~) 81 69 55 61 102 97 51 63 85 42 77 62 74 190 R22 159 200 180 159 434 17.1 183 125 165 258 310 329 100 1 .ZY 123 75 116 114 144 1st 2.19 250 12’) 102 162 178 95 .z 19 129 3% 341 80 8.i 04 97 82 SY 82
38 26 24 31 42 32 29 17 3.5 19 24 16 28 79 147 59 1.54 1.13 128 190 98 144 89 1.1 1 170 222 214 40 56 4.1 16 66 c 2 .a 35 Y2 115 170 56 36 65 108 40 210 31 142 198 26 27 5.z 4-l 34 22 38
43 43 31 30 60 65 22 47 so 23 53 46 46 21 175 100 46 47 31 240 7s 39 36 34 82 88 115 60 83 80 59
so 89 109 59 124 80 74 66 97 71 54 109 97 1X1 143 53 58 41 53 48 37 44
0.53 0.63 0.57 0.49 0.58 0.67 0.44 0.74 0.59 0.55 0.69 0.74 0.62 0.11 0.54 0.63 0 23 0 26 0.19 0 55 0 45 0.21 0.29 0.21 0.32 0.29 0 .z5 0.60 0.60 0. 6.5 0.79 Il.43 0.78 0,76 0, 39 Il. 52 0.32 0.57 0.65 0. 61) 0.40 0.57 0.34 0.76 0.46 0.43 0.67 0.68 0.44 0.54 0.59 0 6.3 0.54
.x11 77 .98 70 85 1 30 97 7.3
65 .7.! 91 85 76 it, 1’2.3 7.3 : XI., .77 80 72 5x 1 IX 1 5’) I 14 90 00 1 31 9 0 92 0 x2 0 78 1 2-l 1.16 0.05 1 ..I’
II i I 2 1 7x 0.99 1.85 1 78 0 80 1 56 05 1 .i(J 1 .zo
1 00 I 10 0.X9 I .37 0. 79 1 .I)5 1 40
Abbreuialions:
integrated
End-diastolic isovolometric stress:
B.D.V.,
volume; %I., stroke volume; E.S.V.. end-systolic N. normal; MS, mitral stenosis; MD. myocardial
index; Kl;.. ejertvd fraction; IL wall thickness; mitral insufficiency; AI. aortic disease; MI,
Myomudiul
contrnctilit~~
7 59
I
RI (rnr. J 2 7 2.7 2.3 2.2 3.1 3.1 2.2 2.8 2.7 1.9 2.7 2.. 3 2 0 3 2 4.4 .3 6 .? 5 1.7 3.6 6.5 1.8 z.‘; 4.7 3 9 4.6 3.7 42 2.8 4.0 .i. 1 A.6 I.2 2.9 .s. 4 .i 3 .(.8 .z 8 .i 2 .z 0 .z 4 4.0 ‘.6 4.7 3 3 .i 9 4 3 2.7 3.0 2.9 2 9 2.8 2.2 3 0 RI. inner fnsuffidency;
k/RI
dP/dt
0.39 0.29 0.42 0.32 0.28 0.49 0.44 0.26 0.24 0 37 0.3‘4 0.36 0.27 0.24 0.28 0. 20 0.23 0.21 0.22 u.11 0.21 0.32 0.43 0.29 0.21 0.16 0.31 0.32 0.23 0.26 0 30 0.39 0.40 0.28 0.37 0.18 0.31 0.56 0.33 0.54 0.45 0.31 0.33 0.29 0.33 0.30 0.60 0.37 0.30 0.47 0.28
1125 1250 1625 1200 1680 1880 1730 187.5 2000 1200 1100 1460 1200 940 1500 1380 1150 650 1400 1050 1300 750 670 1100 850 850 1100 900 2100 1400 12.50
E.D.S. (dynes. f03)
1200 2300 1000 2000 13.50 1550 2700 1250 1550 2420 1250 1850 17.50 2700 16.50 2990 1750 1320 1500 1370 2 100
0.47 E.D.S.,
end-diastolic
1
P.S.T. (dynes. I@)
18 47 16 12 24 25 9 10 5.5 11 20 15 5 39 110 138 234 724 146 169 89 223 31 86 90 221 66 4.5 127 30 58 7 53 29 21 32 25 5 4.5 25 30 34 52 18 125 26 9 29 3.5 43 28
1720
Il.47
radius of curvature; AS, aortic stenosis.
i
214 22.5 192 12.5 255 256 188 176 207 156 187 161 174 4.58 232 188 427 420 5 10 390 27s 427 336 396 351 310 340 250 301 2.56 159 275 1.58 208 380 290 3.50 242 336 278 497 230 52.5 270 350 33.5 316 290 33.5 304 2.50 336 447
2i
11 stress;
P.S.T..
(
peak
systolic
I.I.P. 1 I.I.S. 1 (dynes. 103) (dynps. IO3) ~ 30 30 28 23 2.5 35 29 38 31 24 24 37 29 31 53 31 42 54 50 36 36 66 31 45 43 33 60 42 28 26 33 31 27 26 33 31 28 29 28 16 33 31 29 .32 40 54 38 30 37 4.5 26 30 43
tension;
I.I.P.,
134 140 89 96 120 94 86 194 1 70 86 94 1 .38 143 171 2.55 205 246 345 306 431 22.5 275 95 “03 2 75 266 250 140 159 13.1 147 107 90 124 120 210 118 68 114 .w 97 132 115 147 160 240 8.1 107 160 130 12.Z 8.5 122 integrated
isovolumetric
$5
8.33 8.94 18.25 12.50 13.99 19 91 20.14 9.67 11 76 14 03 11.72 10 61 8.40 5.46 5.87 6.74 4.68 1.89 4.58 2 44 5.77 2.72 7.03 5 41 3.09 3.20 4.4 6.4 13.21 10 56 8.5 16.07 13.37 18.51 8.8 9.5 12 22.8 ‘3.6 32.1 16.0 18.3 10.89 12.6 11 11 19.96 27.84 10.93 10.17 12.24 16.19 17.25 preswre;
I.I.S..
760
Hermann,
Table
II.
Singh,
Statistical
analysis
Am. Heart J. June. 1969
and Drrmmnnn
qf calculated
datu Group II
mean 1 SD.
12.9 3.9 1
S.E.M.
Ejected fraction mean 1 S.D.
S.E.M. First derivative mean
.,zs .lS .0-i
312 86
End-diastolic mean
p < .OOl
stress (dynes/cm.* 20 l-1 2.8
1 S.D.
S.E.M. h/Ii
.6O
.08 p < .oos .03 (dp/dt) 1486
1 SD. S.E.M.
4.6 1.5 .41
p < .005
1000 260 67
Group III
Groups
I and III
15.3 5.9 1.1
p < .005
.5-l p < ,005
.57 .12 .os
.14 .03 1764 518 103
p < .oos
hlI 1602 424 103
AI 1891 544 181
AS 1811 539 204
42 33 10
40 32 10
26 11 4
. 103)
p < ,005
127 69 17
.Z6 29 5.9
p < ,001
I
mean 1 S.D. S.E.M. End-diastolic mean
.34 .07
.02 volume (ml./M.*)
1 S.D.
S.E.M. Abbvesiafions: aortic
.24 .07 .Ol
p < ,005
SD., stenosis.
70 16 4.6
Standard
p < .005
deviation;
S.1C.M..
206 99 25
standard
36 .lO .02
p < .oos 146 76 15
p < .os
error
Results The values of the measuretuents and calculations obtained are listed in Table I. The maximal rate of rise of the left ventricular pressure (dg/dt) has been considered a good deternlinant of ventricular contractility.12~‘3 It has also heen observed to be a function of the heart rate, peak ventricular pressure, and probably enddiastolic volurne.13s’4 The analysis of the first derivative from the patients presented herein (Table II) indicates that there is a significant difference between all groups (p < .OOl). The lowest values were found in patients with myocardial disease. I-lo\~ever, there is a large spread of values in this group as demonstrated by the large standard deviation (S.D. 260). The poor clinical diagnostic value of this determination alone is thus clearly evident. End-diastolic stress (E.II).S.) uxs sig-
of the
mean;
.30 .03 .02
MI.
mitral
.38 .09 .02
150 54 18
insufficiency;
AI,
191 88 29
aortic
insufficiency;
.10 .1 0 .O.? 87 7 2
AS.
nificantly higher in the nlyocardial disease group (p < .OOJ) and this was mainly due to the elevated end-diastolic pressures associated with relatively thin left ventricular walls as shown by the significantly snialler h/XI ratio (p < .OOS). Although the \\a11 thickness (h) was sortiewhat greater in (;roup III, there was no statistically significant difference from those values ol)tained in patients with primary or artel-iosclerotic myocardial disease (Ckoup II). When the ratio dp/dt,lIIS was examined, significantly lower values (,p < .oo.jj \vere ol)served in the myocardial disease group (4.6 f 1.7 S.I).). Values obtained for Group I were (12.9 f 3.9 S.11.) and (;roup III (15.3 * 5.9 S.U.). Fig. 4 sho\vs the maxinlal and nlininlal vall,es
of tile
(Et!!t IIS
index
calwlated
for
32-
r
32.1
3121-
12dp/dt IIS
8-
42-
1:ig. 4. Histogram WY of this ratio
showing for patients
I maximal with
N
and minimal
tnyocardial
values
diseaqe ( AiII)
each type of lesion. There 1~3s a clear statistical difference between patients with myocardial disease and the other groups (Table I I). The ejected fraction (E. F.) was significantly lower (p < .OOS) in Group II than in the others (.35 •t .15 and .57 f .12, respectively). Four patients (SOS. 15, 16, 20, and 28) with a normal E. F.4,15s’6 were included in this group since there u as clinical and pathologic evidence of myocardial disease. On the other hand, several patients with a low E. F. could not be included in (;roup II since there was no evidence of myocardial disease, and therefore they had to be included in other groups. Discussion End-diustolic stress in myocardial diseclse. Sandler and Dodge” studied tension and stress in the left ventricular muscle in man and have shown that tension and stress increase at a greater rate than the left ventricular pressure, exceeding pressure by as much as 60 to 250 per cent. The greatest stress values \\.ere observed in patients with large end-diastolic volumes. They con-
dP/df
of rr.s .
.
Normal
MS Mitral
stenosis
MI
Mitral
insufficiency
AS
Aorttc
stenosis
Al
Aartic
insufficiency
MD
Myacardiol
for each group
are observed.
S.E.X..
disease
studied. Standard
Significant error
low
val-
of the mean.
eluded that stress and tension are functions of volume, shape, and \vall thickness as well as pressure. In two of their patients with idiopathic myocardial hypertrophy, the values of stress found \\-ere not significantl> different from the end-diastolic stress values obtained in another patient with valvular insufficiency and large left ventricular chambers. In our group of patients with xnyocardiaj disease, the end-diastok stress (initial stress) \~as significantly higher than in the other groups, including the group of patients \I-ith valvular insufficiency and large chamber volumes. Calculations of stress during systole were not determined, since they are subject to error which is inherent in the measurement of a contracted, irregular ventricular wall. The observation8 that wall stress may remain normal in spite of increased wall thickness and elevated tension or pressure was again observed in our study, and lends support to the hypothesis that hypertrophy may occur as a consequence of increased pressure or tension in order to keep wall stress within normal limits. This can be observed in our control groups. However,
the patients I\-ith rn?ocnrdial disease represent just the opposite situation. Although the diastolic pressures are higher than the otlier groups, the wall thickness is not signiticantl>greater. Hence, the left ventricular end-diastolic wall stress is higher. Our data suggest that in patients with myocat-dial disease the left ventricular hypertrophy necessary to maintain left ventricular ~211 stress at a normal level cannot be achieved and the ideal relationship between volume, pressure, and wall thickness cannot be sustained by the diseased ventricular
gone corrective heart surgery free of cardiovascular complications. As expected, tllc ejected fraction is low (Table 11) in patients with evidence of myocardial disease. I low ever, four patients I\-erc included in this group \\:ith normal ejected fractions. Tivo had evidence of severe diffuse coronar!. artery- disease and ml,ocardial fibrosis and one had an old anteroseptal myocardial infarction. Patient 16 with an E.F. of .6.1 had evidence of acute mitral regurgitation secondary to rupture of papillary muscle. He did not survive surgery, and exnmination of the heart revealed ;I large area of fibrosis on the left ventricular ~\-a]]. The possibilities of error in estimating tliese values arc several. Sanniarco and assoc.iates’7 llavc observed that the sudden injection into the ventricular chamt)er 0i ;L large volume of contrast material produws an increase of 5 to 13 per cent in cnddiastolic volume and 10 to 30 per cenr in stroke volume during the fihning period. The ejected fraction is conseyuently ovt’restimated. These changes can l)e very significant at larger end-diastolic volumes and the ejected fraction is then an exaggeration of the wtual value. On the other hand, if
muscle.
Ejected -fraction, a controverskl index of myocnrdiul diseuse. T-sing the area-length method of Dodge and associates3 to calculate the left ventricular volumes, differobtained ditierent normal ent autliors4~‘“~‘6 ejected fraction values ranging from .67 to .58 k .0X. These values compare well \vitll those found here. However, when the patients \\-ith valvular disease are studied, a larger standard deviation is observed, due to the inclusion in this group of patients \\-it11 low ejected fractions who did not shop evidence of myocardial disease by any other standard. They have successfully under-
r:
IO
0 Myocardial 1L
-.701
disease
I 100
I
200
I
PEAK LEFT VENTRICULAR f;ig. 5. Ejected fraction plotted as a function found for all patients studied is shown.
of peak
I
300
systolic
I
I
500
400
TENSION (dynes x IO31 tension
for Groups
1, IT, and
I I I. The
correlation
dl~~ofrtrdirrl ronfractilit~
763
tlic initial velocity and the extent of fibershortening are progressively decreased. Fig. 5 show3 this relationship (r : - .701) for all patients. Relatively good correlation for clinical purposes was observed in patients with normal left ventricles (r = - .555) and the highest reciprocity (r : - 307) existed in patients with myocardial disease (Fig. 6). On the basis of this 0l)servation 14.e can safely assume that an>- increase in peripheral resistance in patients with myoc;wdial damage should have a deleterious effect on the function of the left ventricle as ;I punlp. On the other hand, patients wit11 aortic stenosis Lvho exhibit a I)oor ejected fraction should be thoroughly evaluated hefore being denied the henelits of surgtr) since the ventricular disfunction might be at least partially revcrsihle. ‘l‘liis IUS Iwen our experience with four paticiits of this nature. All of them successfull!toleraled open-heart surgery and one sl~o\~ed ;L ilorma1 ejected fraction in a postoperative study L\-Ilen the gradient across the valve ~vas reduced from 90 to 25 mn~. Hg across tllc prosthetic valve.
t11c volumes are calculated from films obt;\ined at a rather slow speed (4 to 8 per s;cToIld)) the end-systolic point can l)e missed and the calculation of the E. F. is tlren uilderestimated. Still another variable is introduced nhen volumes are determined 1))‘ single plane films which produce falsely lligh values in large Ilearts and low values in smaller ones,4 thus decreasing and increasing, respectivel>-, the resultant ejected fraction. ‘Tllc large standard deviation of the ciccted fraction calculated in these patients C;LI~ IX explained by the above errors, and tlie relative value of this parameter as a I&s for the diagnosis and prognosis of I);.ttients becomes apparent. Although the ejected fraction has been observed to be r-tkted to the stroke volume and to ;t cerr;tin extent to the end-diastolic volumes in normal hearts,15 the data presented herein strongly suggests that this pzlrameter is ,1ls0 an inverse function of the peak left \.enlricular systolic tension. This is not surprising when one considers the experiinental \Vork, using strips of papillary IIILISC~C%~’ and intact hearts,‘,?3~24 that has repeatedly shown that during isotonic c.ontraction, as the afterload is increased,
r.
1
r:
-.807
y: 82.81-.136x
.\”
60-
$ 2
50-
Et w”
40-
I8
30-
a 20 I IO{ I 100
200I
PEAK LEFT Fig, 6. Relationship of ejected fraction 11). The best reciprocity between these
300I
400I
VENTRICULAR
TENSION
5001
1 600
(dynes x IO31
and peal; systolic tension in patients two parameters is found in this group
nith myocardial of patients.
dkense
(Group
764
Hermann,
Singh,
and Lhmmctnn
rate of rise of the left ventricular pressure (dp/dt) during isovolutnetric contraction is related to the rate of change of ~~41 tento reflect sion ,? and 11x5 heeti olk5erved changes in the ititensit~~ of the active state.“:‘~?” Since at an> tiiuscle letigth the rate of tension developtnent is ;I function of the force velocity relation,?t an estiittation of cotitractilit~. is then possible. In this stud!., the first derivative of the left ventricular pressure and tension Itas been found to he poorly correlated to other parameters such as initial fiber length (circumference), end-diastolic and peak systolic
pressures, and heart rate and the diagnost-ic significance in tttan~~ individual cases I-F mains obscure. Although its usefulness to indicate changes in ttt>aw-dial COIJ ttxc‘tilityZ,?h-ZY . ts not questioned, contradictor>, values of dp:‘dt \vere found in the patients studied here tnaking this deterrninath equivocal frown the clinical standpoint. In the intact hearts of dogs, Reeves and associates2 found the ratio of dp, dt to enddiastolic
pressure
to
IF
a
good
hdex
25-
20-
X
Normal
A
Mitral
stenosis
A
Mitral
insufficiency
l
Aorfic
stenosis
o
Aortic
insufficiency
0
Myocordlal
0 0
X .
.
A
disease
-i-F&
15dp/dt IIS
At
-
X A
.
:
:
90
l
A0
1
A
A
IO-
. b A .x
X .-_-----_-------
A
---_-_--
------. A 0
0
5-
0
S.D. &
I
.I0
I .30
I .20
I .40
I 50
EJECTED Fig.
7. I~‘fenn values
and
standard
deviations
(.UJ.)
expected
for
the
dpldt __ I.I.S.
ratio
and clearly
separates
I .70
I .80
and ;$,
ratio
I 60
FRACTION
of ejected
with myocardial disease and the other groups. The overlap of these two groups of patients is evident. ‘The horizontal value
of
contractility defined 1)~ the rate of change in force tneasured 114.a strain gauge sutured to the left ventricular \\all. Siegel and Son-
fraction
are shown
for patients
of the standard deviations of the ejected fraction dotted line has been drawn at the lowest normal the patients
with
m).ocardial
disease.
nrnblick,’ studying isometric contractions of isolated papillary muscles in cats and intact left ventricles in dogs, found that the ratio dpldt to integrated isometric tension (I.I.T.) \\-a~ independent of changes in til)er length, remains constant for any given slate of contractility, and varies in a proportional manner to changes in the maxi1na1 velocity that shortening the muscle would achieve if carrying no load (17 max.). These ratios \vere analyzed and the relation dp;‘dt ~ 1.l.S.
\~as ol)served
to correlate
\\-ell \vith
clinical and pathologic findings in the patients studied; thus this ratio constitutes nlore useful index of myocardial impairment tl~an other parameters measured. Fig. 7 shows a comparison between tllis ratio and the ejected fraction. All p;~tients n-ith clinical or pathologic indication of m~wrardial
disease
sho\ved
a loa
dpl’dt -1.1. s.
ratio. [‘sing this index, it is possil)le to differentiate clearly this group with diseased myocardium from the other patients \vith relatively low ejected fractions and no evidence of irreversible myocardial damage. The fact that patients from (;roup III tolerated the corrective surgery \\-ell suggests that a high value of this index carries ;I good prognosis. Whether the large variations in ejected fraction okerved in this study are due to possible errors in the estiIllation of this value (vi& .SUP~U), the deI)ressive action of the pressure volume injeciat?,“” or the fact that soim patients \t.ith valvular al ~normalities \\-et-e in sul)clinical Ileart failure at the time of the study is not clear. If the pi<. . .
ratio
reflects
changes
IK~X., is independent of variation length alone, and constant for contractility,’ it would be possible index to define more clearly the status of the myocardium, and nostic value observed herein lvould apparent ,
in \.
of filter a given l\-ith this inotropic its diagthen be
Summary In 33 patients terization, the
maximal rate of rise of the left ventricular pressure and the integrated isovolumetric stress was observed to I)e an excellent index of contractility. A clearer separation of patients I\-ith evidence of myocardial disease ~‘as possillle with this index than \vith other parameters assessed. The ejected fraction (tiller-shortening) \\-a~ noticed to be an inverse function of the peak systolic tension (afterload) as expected from extensive experimental work. Tlie highest reciprocity 1~3s olmrved in patients with nlyocardial disease, indicating the prold~le deleterious effect of an incrcnsing peripheral resistance in this type of patient. End-diastolic stress \vas found to lie significantly higher in patients I\-ith evidence of nlwcardial damage, due to a relatively tllinner nlyocardial \\a11 in this group.
1. Siegel, J. H., and Sonne~~blick, E. f-1.: fsomet-rictime tension relationships as an index of nlyocnrdinl contractility, Circulation lies. 12597. 1963. T. J., Hefner. I,. I*., Jones, \V. IS., 2. Reeves, Coghlan, C., I’tieto, G., and Carroll, J.: The hemodyumics determinants of the rate oi change in pressure in the left ventricle during isometric cmtractioll, .ZU. HL’AK,~ J. 60:745. 1960. ,1 Dodge, H. -I‘., Sandier, H., Uallew, I). ii’., a11tl la-d, J. I).: The use of biplane angiocardiography for the measurement of left ventric-ulnr v&me in man, AM. ~~KAHT J. 60:762, 1960. 4. Hemann, H. J., and f3nrtle. S. l-1.: I
9.
IO.
studied at cardiac catlierelationship I)et\\:een the
11.
12.
13.
11.
15.
16.
17.
18.
19. 20.
R. H., Jr., and Gilmore, J. I’.: Left ventricular circumference changes in right heart by-passed Drenarations. :Itn. I. I’hssiol. 211:681. 1966. h&on, 1). T., Br;L;lnxxjd, E., Ro+, J., Jr., ;tnd Morrow, X. C. : L)iagnohtic value of the first and second derivatives of the xterial pressure pulse in aortic valve disease zund hvpertrouhic subnortic stenosis, Circulation 30:90,-1964. Gleason. 11’. I... and Bmunwald. E.: Studies 011 the first derivatixre of the ventricular pressure pulse in man, J. Clin. Invest. 41:80, 1662. \Vallace. A. G.. Skinner. AI. S.. Tr.. md 1Titchell. J. N. : Hemodynamic determinants of the masima1 rate of rise of left vcntricrllnr pressure, .qm. J. I’h>siol. 205~30, 19h.i. BartIe, S. H., Sann~m-o, itI. E., md I~II~KIIIII, J. I;., Jr. : Ejected fraction: au index of nlyocardial fullction, .2m. J. Cxdiol. 15:1X, 1965. Keuned>-, J. \\.., HasIcy, 11‘. .I., FigIcy, 11. I)., l>udge, If. ‘I‘., and B~~~E;III~II, J. Ii.: Quantitative ~lllgioc;~rdiogmph~. ‘The normal left ventricle in man, Circlllatioit 34:272, 1966. S;mmxco, 31. E., I;ronek, I<., I’hilips, C. 11., and I)avila, J. C.: Continllous measurement of left vcntriculnr ~wlumc in the dog. Il. CompariFOII of \vashout and Iradiographic technique3 with XI external dimension method, =\m. J. Cardiol. 28:5X1, 1966. Abbott. 13. C.. :Irld ‘\Iurt~n~;rerts. \\‘. 1;. H. Al.: ;\ stud;: of illritrophic mechnu&s in the papillary preparntioll, J. &cl. PhJxiol. 42:533, 1959. Sonnenblicli, E Il. : Implications of nluicle mechanics in the heart, Fed. I’n~c. 21:975, 1962. Sonncnblick, E. 1-I.: 11eternliu;mt~ of active state in heart n~usclc. Force, velocity, instnnta,_I
Ileous muscle length atid time. Fed. l’rcx-. (Suppl.) 24:1396, ib65. 21. Sonnenblick, E. H.: Force-velocity relations irl mammalian heart muscle, .\m. J. I’h! siol. 202:931, 1962. 22. Sounenblick, E. H., Brallnwvald, E., ;md \IoI-row, A. (;.: Contractile properties of human heart muscle: studies on myocnrdial tnechanicc of surgically excised papillary ~n~~sclcs, J. Clin. Invest. 44:966, 1965. 2.3. I.evine. I. J., and Britmln, S. .i.: l‘orce \~lo( it y relations in the illtact dog heart, J, Clill Jiwest. 43:1383, 1961. ‘4. ‘I‘;tylo~-, R. R., lio-;~, J.. (‘well. J. \\... .III~I
2s.
26.
27. 28.
20.
30.
t;Lct, sedated dog, -Circulation Res. 21:99, 1067. Reeves;, 7’. J., alld IIefner, I.. I,.: Isometric: contraction and contractility in I he intact mcltl~nlnlia ventricle, AXI. Heas~ J. 64~525, 196,. Sonne~~blick, f<. II., AIorrow, .\. G., and \\rlli,mls, J. I;. : IIffects of he,rri I-.lte on the (I).n;iulic?; of force devel~ynrnt ill the int.icl hc~m:u~ velltriclc, Circulation 33:9-&S, 1966. I:rank;, 0.: %tIr I)ynnniili de5 IIcrrniuskel~, %t>chr. Biol. 32:37O, 189.5. P,lttcrsr)n, S. I\~., I’ipcr, If., c~lid ‘itarling, E. I I.: ‘l‘hc regulation of the heart beat, J. Ph! yiol. 48:-165, 1914. I\-iggrrs, C. J.: Some ixtors controlling the sh:lpc of the pressure curve ill the right VVIItrick, :\m. J. Ph>xiol. 33:382, 1911. R;thuntooln, S. H., Duffy, J. l’., :III~ ~\wii, II. J. C.: \Tcntricular performance after nngiogr,lph!., Circlllntion 35:70, 1967.
of myocardial
contractility
in man
Hector J. Hermann, X.0.* Rrxjindnr Singla, M.D. J. Francis Dammann, M.D. Charlottesville, Til.
Methods
W
ith the analysis of the isometric contraction of isolated papillar) muscle and intact left ventricle, an assesstnent of myocardial contractility can I)e made independent of fiber length or its function as a pump.’ Experimental studies suggest that the ratios between the first derivative and end-diastolic pressure2 and integrated isometric tension’ are constant for a given inotropic state. If so, these ratios should give better indices of contractility than the paratneters routineI!evaluated in most clinical laboratories. Furthermore, clinical and experimental observations indicate that the ratio of stroke volume to end-diastolic volume, enddiastolic pressure, estimation of stroke \\,ork, and determination of the first and second derivative of the left ventricular pressure are of value used serially in the individual patient, but are of uncertain diagnostic significance in comparing one patient to another. In the present study, the isovolumetric phase of the left ventricular contraction 11as been analyzed in 53 patients with sevrral tJ.pes of heart disease in order to assess the significance and relative value of those caxperitnental findings.
*.\ddress correspondence to: IIector riat IIospital, 250 East Superior
I ‘01. Ti. No.
6. pp. 75576/j
JWIC, 1969
J. Herman. St., Chicago,
Fifty-three patients were selected for this study and divided into three different groups. Only those in whom the diagnosis had been established by detailed cardiac catheterization were included. Group I. The control group of 13 patients consisted of 6 patients without evidence of valvular or myocardial disease who underwent cardiac catheterization because of the presence of functional murmurs, and 7 patients with pure mitral stenosis. The existence of mitral insufliciency was ruled out by cineangiography and the patients were considered to have no abnormalities involving the left ventricle. Group 11. This group included 15 patients with unequivocal myocardial disease of different etiology. Eight fulfill the criteria for idiopathic primary myocardiopathy, and 7 had evidence of advanced arteriosclerotic heart disease. Except for 3 patients (Nos. 15, 16, and 20), the patients in this group had no evidence of valvular disease. Grolip 111. This group n-as comprised oi 25 patients ~vith a single valvulnr lesion causing either severe degrees of tttitral or aortic insufficiency or aortic stenosis. Left ventricular angiograms were 01,.
hI.tI., IXrector. Ill. 60611,
Cardiovascular
American
laboratory,
Heart
Chicago
Jnurnal
Wesley
hlrmo-
755
756
Hermmn,
Sing-h, and Dtrmmnnn
tained with the injection of 40 to 60 ml. of a 7.5 per cent solution of sodium and methylglucamine diatrizoate (Renovist, Squil)l)) into the left ventricle (L\:) or left atrium (LA), and biplane films (Elema-Schonander, Stockholm, Sweden) or single plane tine exposed at 6 or 30 frames per second, respectively. Volumes were calculated using the ellipsoid reference figure and the area length method of Dodge and associates” and corrected 11). the regression equation : I-,, = IrC . .936 - 3.6. (‘ineangiograms I\-ere obtained with the patients in the RAO
Mean
overestimated
Clrcumferentlal
4 ,
6;
position. Good correlation Ijetween the L\volumes calculated from biplane and single plane frames has lIeen ol)served in Ollr lal)oratory* as IveIl as 1)~ others.” The I=?.~() position \vas selected because it allo\vcd us to study the mitral valve and ascertain the existence of mitral insufficiency during the same injection lvithout detriment to the good correlation \\-ith biplane L\- volumes (r : .830; S.E.E., 19.S ml.). It shoul~~ 1~ noted tllat in general the largest volu~ues
d;=
Stress,
where
EFT
VENTRKIJLAR
used
WALL END
in the determination
STRESS
DIASTOLIC
AT THE
single
plarlc
d2
PRi --jy
- 62
Fig. 1. Shows the calculations sumptions they are based on.
II)-
of stress
EQUATOR-ELLIPSOIDAL
STRESS
P= lntralumlnal Pressure R,= Outer Radius Ri= Inner Radius h = R,- Ri
at the “equator”
vs MEAN
of the heart
CIRCUMFERENTIAL
and
the aa-
METHID;;
END SYSTOLIC STRESS
I ,’
MEAN
Fig. 2. Relationship of left ventricular ferential) and total ellipsoidal stress. time-consuming formula.
CIRCUMFERENTIAL
stress calculated by the simple formula used in the Lest (meall circllmThe excellent correlation makes justitiable the we of the simple, ICY>
Sl~vocc7rdinl
‘l‘lic
radii
\vere derived
of the area of an ellipse3:
froni
the formula
RI = $.
_I
Cl;all thickness (h) was calculated I>>’ simple estimation of the jvidth at several points to obtain an average value. This technique of determining L\’ wall thickness gives almost identical values4 with the metllod descrilled 1)y Rackley and associ;ttes.” l’ressures I\-ere obtained immediately before the angiograms I,y means of Ko. 7 S 1H catheters, 100 cm. long, directly connected to a Statham 1’131111 transducer \vllich \vas calil)rated before each procedure, balanced lIefore each run, and referenced to a zero level 5 cm. I>elow the angle of Louis \\rith the patient supine, and rccorded on an optical recorder at a paper speed of 200 mm. per second. The maximal rate of rise of the left ventricular pressure (d/>/dr) \\x obtained \\-ith an R-C differentiating circuit.’ Stress (Fig. 1) n-as calculated at the eqilator of the left ventricle by the formula: P . Ii1 ~~-.-- \vhere P = L\,- pressure, II
RI = inner
radius,
This
and h = wall
thickness.
Fig. 3. ERG, Electrocardiogram; the lelt ventricular pressure;
I.I.P.,
Ao, aortic integrated
calcu-
7.57
rontrtlctility
lation of circuiilferential stress or a.2 \vas selected because it is the largest stress at the equator of the ventricle and c;kulation is simple. There is excellent correlation with the results obtained with more complicated formula9 (Fig. 2). Stress \vas expressed in dynes per square centimeter and tension \vas expressed as stress X wall thickness ((~2 X 12) in dynes per centimeter. Integrated isometric pressure (IIP) was obtained by planimetric integration of the area beneath the isovolumetric phase of the left ventricular pressure tracing (between the end-diastolic point and the opening of the aortic valve) (Fig. 3) divided 1,) the isovolumetric contraction time. Integrated isometric stress ([IS) was calculated as IIS
= g%’
. The
radius
and
n-all
h
thickness used for these calculations were those calculated from the end-diastolic volumes. Although these values change somewhat during the isovolumetric phase of contractiong-” the variations are small and they should not significantly alter the results. Observations in our laboratory using cineangiography have sholvn that RI and h change less than 4 and :! mm., respectiveI\., during this cardiac phase.
pressure; I, V, left ventricular pressure; dp/dt, iwvolumetric pressure (shadowed area).
first
derivative
of
TabIe
I. Clinical
muteriul
’
’
Patient
Lesion
and qmntitative
Age
B.S.1.
(Al.‘)
NO.
1 2 3 4 5 6
19 27 22 12 25 18 47 29 34 28 37 39 32 50 42 62 12 23 45 30 31 17 2.5 46 17 8 54 60 38 41 34 40 17 49 40 48 35 40 37 2 .i 31 22 31 21 40 42 53 21 18 45 36 65 38
7 8 9 10 11 12 13 14
15 16 17 18 19 20 21 22 23 24 25 26 ‘7 18 2Y 30 31 .z2 33 3-t 35 .16 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53
1.G 1.93 1.75 1.14 1 .I9 1.9 1 .79 1.70 1.51 1.41 1.69 1.45 1.45 2.05 1.68 1.82 1.08 1.38 1.81 1.45 1.87 1.86 2.25 1.75 1.65 0.64 1.62 1.74 2.15 1.65 1 58 2.12 1.45 1.76 1.82 1.56 1.72 1.72 1.95 1.68 1.95 1.53 1.86 2.0-l 1.64 1.82 1.72 1 80 1.55 1.62 1.23 2.04 1.49
datu
E.Il. I;. , (?d./M.~) 81 69 55 61 102 97 51 63 85 42 77 62 74 190 R22 159 200 180 159 434 17.1 183 125 165 258 310 329 100 1 .ZY 123 75 116 114 144 1st 2.19 250 12’) 102 162 178 95 .z 19 129 3% 341 80 8.i 04 97 82 SY 82
38 26 24 31 42 32 29 17 3.5 19 24 16 28 79 147 59 1.54 1.13 128 190 98 144 89 1.1 1 170 222 214 40 56 4.1 16 66 c 2 .a 35 Y2 115 170 56 36 65 108 40 210 31 142 198 26 27 5.z 4-l 34 22 38
43 43 31 30 60 65 22 47 so 23 53 46 46 21 175 100 46 47 31 240 7s 39 36 34 82 88 115 60 83 80 59
so 89 109 59 124 80 74 66 97 71 54 109 97 1X1 143 53 58 41 53 48 37 44
0.53 0.63 0.57 0.49 0.58 0.67 0.44 0.74 0.59 0.55 0.69 0.74 0.62 0.11 0.54 0.63 0 23 0 26 0.19 0 55 0 45 0.21 0.29 0.21 0.32 0.29 0 .z5 0.60 0.60 0. 6.5 0.79 Il.43 0.78 0,76 0, 39 Il. 52 0.32 0.57 0.65 0. 61) 0.40 0.57 0.34 0.76 0.46 0.43 0.67 0.68 0.44 0.54 0.59 0 6.3 0.54
.x11 77 .98 70 85 1 30 97 7.3
65 .7.! 91 85 76 it, 1’2.3 7.3 : XI., .77 80 72 5x 1 IX 1 5’) I 14 90 00 1 31 9 0 92 0 x2 0 78 1 2-l 1.16 0.05 1 ..I’
II i I 2 1 7x 0.99 1.85 1 78 0 80 1 56 05 1 .i(J 1 .zo
1 00 I 10 0.X9 I .37 0. 79 1 .I)5 1 40
Abbreuialions:
integrated
End-diastolic isovolometric stress:
B.D.V.,
volume; %I., stroke volume; E.S.V.. end-systolic N. normal; MS, mitral stenosis; MD. myocardial
index; Kl;.. ejertvd fraction; IL wall thickness; mitral insufficiency; AI. aortic disease; MI,
Myomudiul
contrnctilit~~
7 59
I
RI (rnr. J 2 7 2.7 2.3 2.2 3.1 3.1 2.2 2.8 2.7 1.9 2.7 2.. 3 2 0 3 2 4.4 .3 6 .? 5 1.7 3.6 6.5 1.8 z.‘; 4.7 3 9 4.6 3.7 42 2.8 4.0 .i. 1 A.6 I.2 2.9 .s. 4 .i 3 .(.8 .z 8 .i 2 .z 0 .z 4 4.0 ‘.6 4.7 3 3 .i 9 4 3 2.7 3.0 2.9 2 9 2.8 2.2 3 0 RI. inner fnsuffidency;
k/RI
dP/dt
0.39 0.29 0.42 0.32 0.28 0.49 0.44 0.26 0.24 0 37 0.3‘4 0.36 0.27 0.24 0.28 0. 20 0.23 0.21 0.22 u.11 0.21 0.32 0.43 0.29 0.21 0.16 0.31 0.32 0.23 0.26 0 30 0.39 0.40 0.28 0.37 0.18 0.31 0.56 0.33 0.54 0.45 0.31 0.33 0.29 0.33 0.30 0.60 0.37 0.30 0.47 0.28
1125 1250 1625 1200 1680 1880 1730 187.5 2000 1200 1100 1460 1200 940 1500 1380 1150 650 1400 1050 1300 750 670 1100 850 850 1100 900 2100 1400 12.50
E.D.S. (dynes. f03)
1200 2300 1000 2000 13.50 1550 2700 1250 1550 2420 1250 1850 17.50 2700 16.50 2990 1750 1320 1500 1370 2 100
0.47 E.D.S.,
end-diastolic
1
P.S.T. (dynes. I@)
18 47 16 12 24 25 9 10 5.5 11 20 15 5 39 110 138 234 724 146 169 89 223 31 86 90 221 66 4.5 127 30 58 7 53 29 21 32 25 5 4.5 25 30 34 52 18 125 26 9 29 3.5 43 28
1720
Il.47
radius of curvature; AS, aortic stenosis.
i
214 22.5 192 12.5 255 256 188 176 207 156 187 161 174 4.58 232 188 427 420 5 10 390 27s 427 336 396 351 310 340 250 301 2.56 159 275 1.58 208 380 290 3.50 242 336 278 497 230 52.5 270 350 33.5 316 290 33.5 304 2.50 336 447
2i
11 stress;
P.S.T..
(
peak
systolic
I.I.P. 1 I.I.S. 1 (dynes. 103) (dynps. IO3) ~ 30 30 28 23 2.5 35 29 38 31 24 24 37 29 31 53 31 42 54 50 36 36 66 31 45 43 33 60 42 28 26 33 31 27 26 33 31 28 29 28 16 33 31 29 .32 40 54 38 30 37 4.5 26 30 43
tension;
I.I.P.,
134 140 89 96 120 94 86 194 1 70 86 94 1 .38 143 171 2.55 205 246 345 306 431 22.5 275 95 “03 2 75 266 250 140 159 13.1 147 107 90 124 120 210 118 68 114 .w 97 132 115 147 160 240 8.1 107 160 130 12.Z 8.5 122 integrated
isovolumetric
$5
8.33 8.94 18.25 12.50 13.99 19 91 20.14 9.67 11 76 14 03 11.72 10 61 8.40 5.46 5.87 6.74 4.68 1.89 4.58 2 44 5.77 2.72 7.03 5 41 3.09 3.20 4.4 6.4 13.21 10 56 8.5 16.07 13.37 18.51 8.8 9.5 12 22.8 ‘3.6 32.1 16.0 18.3 10.89 12.6 11 11 19.96 27.84 10.93 10.17 12.24 16.19 17.25 preswre;
I.I.S..
760
Hermann,
Table
II.
Singh,
Statistical
analysis
Am. Heart J. June. 1969
and Drrmmnnn
qf calculated
datu Group II
mean 1 SD.
12.9 3.9 1
S.E.M.
Ejected fraction mean 1 S.D.
S.E.M. First derivative mean
.,zs .lS .0-i
312 86
End-diastolic mean
p < .OOl
stress (dynes/cm.* 20 l-1 2.8
1 S.D.
S.E.M. h/Ii
.6O
.08 p < .oos .03 (dp/dt) 1486
1 SD. S.E.M.
4.6 1.5 .41
p < .005
1000 260 67
Group III
Groups
I and III
15.3 5.9 1.1
p < .005
.5-l p < ,005
.57 .12 .os
.14 .03 1764 518 103
p < .oos
hlI 1602 424 103
AI 1891 544 181
AS 1811 539 204
42 33 10
40 32 10
26 11 4
. 103)
p < ,005
127 69 17
.Z6 29 5.9
p < ,001
I
mean 1 S.D. S.E.M. End-diastolic mean
.34 .07
.02 volume (ml./M.*)
1 S.D.
S.E.M. Abbvesiafions: aortic
.24 .07 .Ol
p < ,005
SD., stenosis.
70 16 4.6
Standard
p < .005
deviation;
S.1C.M..
206 99 25
standard
36 .lO .02
p < .oos 146 76 15
p < .os
error
Results The values of the measuretuents and calculations obtained are listed in Table I. The maximal rate of rise of the left ventricular pressure (dg/dt) has been considered a good deternlinant of ventricular contractility.12~‘3 It has also heen observed to be a function of the heart rate, peak ventricular pressure, and probably enddiastolic volurne.13s’4 The analysis of the first derivative from the patients presented herein (Table II) indicates that there is a significant difference between all groups (p < .OOl). The lowest values were found in patients with myocardial disease. I-lo\~ever, there is a large spread of values in this group as demonstrated by the large standard deviation (S.D. 260). The poor clinical diagnostic value of this determination alone is thus clearly evident. End-diastolic stress (E.II).S.) uxs sig-
of the
mean;
.30 .03 .02
MI.
mitral
.38 .09 .02
150 54 18
insufficiency;
AI,
191 88 29
aortic
insufficiency;
.10 .1 0 .O.? 87 7 2
AS.
nificantly higher in the nlyocardial disease group (p < .OOJ) and this was mainly due to the elevated end-diastolic pressures associated with relatively thin left ventricular walls as shown by the significantly snialler h/XI ratio (p < .OOS). Although the \\a11 thickness (h) was sortiewhat greater in (;roup III, there was no statistically significant difference from those values ol)tained in patients with primary or artel-iosclerotic myocardial disease (Ckoup II). When the ratio dp/dt,lIIS was examined, significantly lower values (,p < .oo.jj \vere ol)served in the myocardial disease group (4.6 f 1.7 S.I).). Values obtained for Group I were (12.9 f 3.9 S.11.) and (;roup III (15.3 * 5.9 S.U.). Fig. 4 sho\vs the maxinlal and nlininlal vall,es
of tile
(Et!!t IIS
index
calwlated
for
32-
r
32.1
3121-
12dp/dt IIS
8-
42-
1:ig. 4. Histogram WY of this ratio
showing for patients
I maximal with
N
and minimal
tnyocardial
values
diseaqe ( AiII)
each type of lesion. There 1~3s a clear statistical difference between patients with myocardial disease and the other groups (Table I I). The ejected fraction (E. F.) was significantly lower (p < .OOS) in Group II than in the others (.35 •t .15 and .57 f .12, respectively). Four patients (SOS. 15, 16, 20, and 28) with a normal E. F.4,15s’6 were included in this group since there u as clinical and pathologic evidence of myocardial disease. On the other hand, several patients with a low E. F. could not be included in (;roup II since there was no evidence of myocardial disease, and therefore they had to be included in other groups. Discussion End-diustolic stress in myocardial diseclse. Sandler and Dodge” studied tension and stress in the left ventricular muscle in man and have shown that tension and stress increase at a greater rate than the left ventricular pressure, exceeding pressure by as much as 60 to 250 per cent. The greatest stress values \\.ere observed in patients with large end-diastolic volumes. They con-
dP/df
of rr.s .
.
Normal
MS Mitral
stenosis
MI
Mitral
insufficiency
AS
Aorttc
stenosis
Al
Aartic
insufficiency
MD
Myacardiol
for each group
are observed.
S.E.X..
disease
studied. Standard
Significant error
low
val-
of the mean.
eluded that stress and tension are functions of volume, shape, and \vall thickness as well as pressure. In two of their patients with idiopathic myocardial hypertrophy, the values of stress found \\-ere not significantl> different from the end-diastolic stress values obtained in another patient with valvular insufficiency and large left ventricular chambers. In our group of patients with xnyocardiaj disease, the end-diastok stress (initial stress) \~as significantly higher than in the other groups, including the group of patients \I-ith valvular insufficiency and large chamber volumes. Calculations of stress during systole were not determined, since they are subject to error which is inherent in the measurement of a contracted, irregular ventricular wall. The observation8 that wall stress may remain normal in spite of increased wall thickness and elevated tension or pressure was again observed in our study, and lends support to the hypothesis that hypertrophy may occur as a consequence of increased pressure or tension in order to keep wall stress within normal limits. This can be observed in our control groups. However,
the patients I\-ith rn?ocnrdial disease represent just the opposite situation. Although the diastolic pressures are higher than the otlier groups, the wall thickness is not signiticantl>greater. Hence, the left ventricular end-diastolic wall stress is higher. Our data suggest that in patients with myocat-dial disease the left ventricular hypertrophy necessary to maintain left ventricular ~211 stress at a normal level cannot be achieved and the ideal relationship between volume, pressure, and wall thickness cannot be sustained by the diseased ventricular
gone corrective heart surgery free of cardiovascular complications. As expected, tllc ejected fraction is low (Table 11) in patients with evidence of myocardial disease. I low ever, four patients I\-erc included in this group \\:ith normal ejected fractions. Tivo had evidence of severe diffuse coronar!. artery- disease and ml,ocardial fibrosis and one had an old anteroseptal myocardial infarction. Patient 16 with an E.F. of .6.1 had evidence of acute mitral regurgitation secondary to rupture of papillary muscle. He did not survive surgery, and exnmination of the heart revealed ;I large area of fibrosis on the left ventricular ~\-a]]. The possibilities of error in estimating tliese values arc several. Sanniarco and assoc.iates’7 llavc observed that the sudden injection into the ventricular chamt)er 0i ;L large volume of contrast material produws an increase of 5 to 13 per cent in cnddiastolic volume and 10 to 30 per cenr in stroke volume during the fihning period. The ejected fraction is conseyuently ovt’restimated. These changes can l)e very significant at larger end-diastolic volumes and the ejected fraction is then an exaggeration of the wtual value. On the other hand, if
muscle.
Ejected -fraction, a controverskl index of myocnrdiul diseuse. T-sing the area-length method of Dodge and associates3 to calculate the left ventricular volumes, differobtained ditierent normal ent autliors4~‘“~‘6 ejected fraction values ranging from .67 to .58 k .0X. These values compare well \vitll those found here. However, when the patients \\-ith valvular disease are studied, a larger standard deviation is observed, due to the inclusion in this group of patients \\-it11 low ejected fractions who did not shop evidence of myocardial disease by any other standard. They have successfully under-
r:
IO
0 Myocardial 1L
-.701
disease
I 100
I
200
I
PEAK LEFT VENTRICULAR f;ig. 5. Ejected fraction plotted as a function found for all patients studied is shown.
of peak
I
300
systolic
I
I
500
400
TENSION (dynes x IO31 tension
for Groups
1, IT, and
I I I. The
correlation
dl~~ofrtrdirrl ronfractilit~
763
tlic initial velocity and the extent of fibershortening are progressively decreased. Fig. 5 show3 this relationship (r : - .701) for all patients. Relatively good correlation for clinical purposes was observed in patients with normal left ventricles (r = - .555) and the highest reciprocity (r : - 307) existed in patients with myocardial disease (Fig. 6). On the basis of this 0l)servation 14.e can safely assume that an>- increase in peripheral resistance in patients with myoc;wdial damage should have a deleterious effect on the function of the left ventricle as ;I punlp. On the other hand, patients wit11 aortic stenosis Lvho exhibit a I)oor ejected fraction should be thoroughly evaluated hefore being denied the henelits of surgtr) since the ventricular disfunction might be at least partially revcrsihle. ‘l‘liis IUS Iwen our experience with four paticiits of this nature. All of them successfull!toleraled open-heart surgery and one sl~o\~ed ;L ilorma1 ejected fraction in a postoperative study L\-Ilen the gradient across the valve ~vas reduced from 90 to 25 mn~. Hg across tllc prosthetic valve.
t11c volumes are calculated from films obt;\ined at a rather slow speed (4 to 8 per s;cToIld)) the end-systolic point can l)e missed and the calculation of the E. F. is tlren uilderestimated. Still another variable is introduced nhen volumes are determined 1))‘ single plane films which produce falsely lligh values in large Ilearts and low values in smaller ones,4 thus decreasing and increasing, respectivel>-, the resultant ejected fraction. ‘Tllc large standard deviation of the ciccted fraction calculated in these patients C;LI~ IX explained by the above errors, and tlie relative value of this parameter as a I&s for the diagnosis and prognosis of I);.ttients becomes apparent. Although the ejected fraction has been observed to be r-tkted to the stroke volume and to ;t cerr;tin extent to the end-diastolic volumes in normal hearts,15 the data presented herein strongly suggests that this pzlrameter is ,1ls0 an inverse function of the peak left \.enlricular systolic tension. This is not surprising when one considers the experiinental \Vork, using strips of papillary IIILISC~C%~’ and intact hearts,‘,?3~24 that has repeatedly shown that during isotonic c.ontraction, as the afterload is increased,
r.
1
r:
-.807
y: 82.81-.136x
.\”
60-
$ 2
50-
Et w”
40-
I8
30-
a 20 I IO{ I 100
200I
PEAK LEFT Fig, 6. Relationship of ejected fraction 11). The best reciprocity between these
300I
400I
VENTRICULAR
TENSION
5001
1 600
(dynes x IO31
and peal; systolic tension in patients two parameters is found in this group
nith myocardial of patients.
dkense
(Group
764
Hermann,
Singh,
and Lhmmctnn
rate of rise of the left ventricular pressure (dp/dt) during isovolutnetric contraction is related to the rate of change of ~~41 tento reflect sion ,? and 11x5 heeti olk5erved changes in the ititensit~~ of the active state.“:‘~?” Since at an> tiiuscle letigth the rate of tension developtnent is ;I function of the force velocity relation,?t an estiittation of cotitractilit~. is then possible. In this stud!., the first derivative of the left ventricular pressure and tension Itas been found to he poorly correlated to other parameters such as initial fiber length (circumference), end-diastolic and peak systolic
pressures, and heart rate and the diagnost-ic significance in tttan~~ individual cases I-F mains obscure. Although its usefulness to indicate changes in ttt>aw-dial COIJ ttxc‘tilityZ,?h-ZY . ts not questioned, contradictor>, values of dp:‘dt \vere found in the patients studied here tnaking this deterrninath equivocal frown the clinical standpoint. In the intact hearts of dogs, Reeves and associates2 found the ratio of dp, dt to enddiastolic
pressure
to
IF
a
good
hdex
25-
20-
X
Normal
A
Mitral
stenosis
A
Mitral
insufficiency
l
Aorfic
stenosis
o
Aortic
insufficiency
0
Myocordlal
0 0
X .
.
A
disease
-i-F&
15dp/dt IIS
At
-
X A
.
:
:
90
l
A0
1
A
A
IO-
. b A .x
X .-_-----_-------
A
---_-_--
------. A 0
0
5-
0
S.D. &
I
.I0
I .30
I .20
I .40
I 50
EJECTED Fig.
7. I~‘fenn values
and
standard
deviations
(.UJ.)
expected
for
the
dpldt __ I.I.S.
ratio
and clearly
separates
I .70
I .80
and ;$,
ratio
I 60
FRACTION
of ejected
with myocardial disease and the other groups. The overlap of these two groups of patients is evident. ‘The horizontal value
of
contractility defined 1)~ the rate of change in force tneasured 114.a strain gauge sutured to the left ventricular \\all. Siegel and Son-
fraction
are shown
for patients
of the standard deviations of the ejected fraction dotted line has been drawn at the lowest normal the patients
with
m).ocardial
disease.
nrnblick,’ studying isometric contractions of isolated papillary muscles in cats and intact left ventricles in dogs, found that the ratio dpldt to integrated isometric tension (I.I.T.) \\-a~ independent of changes in til)er length, remains constant for any given slate of contractility, and varies in a proportional manner to changes in the maxi1na1 velocity that shortening the muscle would achieve if carrying no load (17 max.). These ratios \vere analyzed and the relation dp;‘dt ~ 1.l.S.
\~as ol)served
to correlate
\\-ell \vith
clinical and pathologic findings in the patients studied; thus this ratio constitutes nlore useful index of myocardial impairment tl~an other parameters measured. Fig. 7 shows a comparison between tllis ratio and the ejected fraction. All p;~tients n-ith clinical or pathologic indication of m~wrardial
disease
sho\ved
a loa
dpl’dt -1.1. s.
ratio. [‘sing this index, it is possil)le to differentiate clearly this group with diseased myocardium from the other patients \vith relatively low ejected fractions and no evidence of irreversible myocardial damage. The fact that patients from (;roup III tolerated the corrective surgery \\-ell suggests that a high value of this index carries ;I good prognosis. Whether the large variations in ejected fraction okerved in this study are due to possible errors in the estiIllation of this value (vi& .SUP~U), the deI)ressive action of the pressure volume injeciat?,“” or the fact that soim patients \t.ith valvular al ~normalities \\-et-e in sul)clinical Ileart failure at the time of the study is not clear. If the pi<. . .
ratio
reflects
changes
IK~X., is independent of variation length alone, and constant for contractility,’ it would be possible index to define more clearly the status of the myocardium, and nostic value observed herein lvould apparent ,
in \.
of filter a given l\-ith this inotropic its diagthen be
Summary In 33 patients terization, the
maximal rate of rise of the left ventricular pressure and the integrated isovolumetric stress was observed to I)e an excellent index of contractility. A clearer separation of patients I\-ith evidence of myocardial disease ~‘as possillle with this index than \vith other parameters assessed. The ejected fraction (tiller-shortening) \\-a~ noticed to be an inverse function of the peak systolic tension (afterload) as expected from extensive experimental work. Tlie highest reciprocity 1~3s olmrved in patients with nlyocardial disease, indicating the prold~le deleterious effect of an incrcnsing peripheral resistance in this type of patient. End-diastolic stress \vas found to lie significantly higher in patients I\-ith evidence of nlwcardial damage, due to a relatively tllinner nlyocardial \\a11 in this group.
1. Siegel, J. H., and Sonne~~blick, E. f-1.: fsomet-rictime tension relationships as an index of nlyocnrdinl contractility, Circulation lies. 12597. 1963. T. J., Hefner. I,. I*., Jones, \V. IS., 2. Reeves, Coghlan, C., I’tieto, G., and Carroll, J.: The hemodyumics determinants of the rate oi change in pressure in the left ventricle during isometric cmtractioll, .ZU. HL’AK,~ J. 60:745. 1960. ,1 Dodge, H. -I‘., Sandier, H., Uallew, I). ii’., a11tl la-d, J. I).: The use of biplane angiocardiography for the measurement of left ventric-ulnr v&me in man, AM. ~~KAHT J. 60:762, 1960. 4. Hemann, H. J., and f3nrtle. S. l-1.: I
9.
IO.
studied at cardiac catlierelationship I)et\\:een the
11.
12.
13.
11.
15.
16.
17.
18.
19. 20.
R. H., Jr., and Gilmore, J. I’.: Left ventricular circumference changes in right heart by-passed Drenarations. :Itn. I. I’hssiol. 211:681. 1966. h&on, 1). T., Br;L;lnxxjd, E., Ro+, J., Jr., ;tnd Morrow, X. C. : L)iagnohtic value of the first and second derivatives of the xterial pressure pulse in aortic valve disease zund hvpertrouhic subnortic stenosis, Circulation 30:90,-1964. Gleason. 11’. I... and Bmunwald. E.: Studies 011 the first derivatixre of the ventricular pressure pulse in man, J. Clin. Invest. 41:80, 1662. \Vallace. A. G.. Skinner. AI. S.. Tr.. md 1Titchell. J. N. : Hemodynamic determinants of the masima1 rate of rise of left vcntricrllnr pressure, .qm. J. I’h>siol. 205~30, 19h.i. BartIe, S. H., Sann~m-o, itI. E., md I~II~KIIIII, J. I;., Jr. : Ejected fraction: au index of nlyocardial fullction, .2m. J. Cxdiol. 15:1X, 1965. Keuned>-, J. \\.., HasIcy, 11‘. .I., FigIcy, 11. I)., l>udge, If. ‘I‘., and B~~~E;III~II, J. Ii.: Quantitative ~lllgioc;~rdiogmph~. ‘The normal left ventricle in man, Circlllatioit 34:272, 1966. S;mmxco, 31. E., I;ronek, I<., I’hilips, C. 11., and I)avila, J. C.: Continllous measurement of left vcntriculnr ~wlumc in the dog. Il. CompariFOII of \vashout and Iradiographic technique3 with XI external dimension method, =\m. J. Cardiol. 28:5X1, 1966. Abbott. 13. C.. :Irld ‘\Iurt~n~;rerts. \\‘. 1;. H. Al.: ;\ stud;: of illritrophic mechnu&s in the papillary preparntioll, J. &cl. PhJxiol. 42:533, 1959. Sonnenblicli, E Il. : Implications of nluicle mechanics in the heart, Fed. I’n~c. 21:975, 1962. Sonncnblick, E. 1-I.: 11eternliu;mt~ of active state in heart n~usclc. Force, velocity, instnnta,_I
Ileous muscle length atid time. Fed. l’rcx-. (Suppl.) 24:1396, ib65. 21. Sonnenblick, E. H.: Force-velocity relations irl mammalian heart muscle, .\m. J. I’h! siol. 202:931, 1962. 22. Sounenblick, E. H., Brallnwvald, E., ;md \IoI-row, A. (;.: Contractile properties of human heart muscle: studies on myocnrdial tnechanicc of surgically excised papillary ~n~~sclcs, J. Clin. Invest. 44:966, 1965. 2.3. I.evine. I. J., and Britmln, S. .i.: l‘orce \~lo( it y relations in the illtact dog heart, J, Clill Jiwest. 43:1383, 1961. ‘4. ‘I‘;tylo~-, R. R., lio-;~, J.. (‘well. J. \\... .III~I
2s.
26.
27. 28.
20.
30.
t;Lct, sedated dog, -Circulation Res. 21:99, 1067. Reeves;, 7’. J., alld IIefner, I.. I,.: Isometric: contraction and contractility in I he intact mcltl~nlnlia ventricle, AXI. Heas~ J. 64~525, 196,. Sonne~~blick, f<. II., AIorrow, .\. G., and \\rlli,mls, J. I;. : IIffects of he,rri I-.lte on the (I).n;iulic?; of force devel~ynrnt ill the int.icl hc~m:u~ velltriclc, Circulation 33:9-&S, 1966. I:rank;, 0.: %tIr I)ynnniili de5 IIcrrniuskel~, %t>chr. Biol. 32:37O, 189.5. P,lttcrsr)n, S. I\~., I’ipcr, If., c~lid ‘itarling, E. I I.: ‘l‘hc regulation of the heart beat, J. Ph! yiol. 48:-165, 1914. I\-iggrrs, C. J.: Some ixtors controlling the sh:lpc of the pressure curve ill the right VVIItrick, :\m. J. Ph>xiol. 33:382, 1911. R;thuntooln, S. H., Duffy, J. l’., :III~ ~\wii, II. J. C.: \Tcntricular performance after nngiogr,lph!., Circlllntion 35:70, 1967.