cardiac reserve during isoproterenol stress in patients with aortic valve disease before and after...

Cardiac reserve during isoproterenol stress in

patients with aortic valve disease before and

after corrective surgery

Franz Schwarz, M.D. Willem Flameng, M.D. Jochen Thormann, M.D. Roland Ensslen, M.D. Michael Sesto, M.D. Martin Schlepper, M.D. Bad Nauheim and Giessen, West Germany

In a recent report Bailey and associates’ empha- sized that survival after aortic valve replacement in patients with aortic regurgitation depends upon the extent of left ventricular hypertrophy. Bolooki and Kaiser2 showed that preoperative cardiac function is one of the important determinants of early postoperative survival in patients with aortic valve disease and severe hypertrophy. However, a close relation between left ventricular hypertrophy and function has not been defined previously.“. 4 Further, it is questionable to which extent different types of overload can influence myocardial contra&lity.” Since hypertrophy compensates an increased cardiac stress, we believe that the investigation of cardiac reserve is best suited to study the relation between cardiac hypertrophy and ventricular function. Studies investigating reserve force of the hypertrophied heart muscle are scarce indeed. Bolen and col- league@ found a deterioration of cardiac function during afterload stress in seven patients with severe aortic regurgitation, two of which, however, had associated coronary artery disease. Lee and co-workers’ reported a reduced function during exercise in severe aortic stenosis but not in moderate stenosis. A relation between left ventricular muscle mass and reserve force was not established in these studies.

From the Kerckhoff-Clinic, Bad Nauheim, and from the Department of Cardiovascular Surgery, Justus Liebig University, Giesaen, West GelTIlany.

Received for publication Aug. 30, 1976.

Accepted for publication Dec. 10, 1976.

Reprint requests: F. Schwarz, M.D., 6350 Bad Nauheim, Kerckhoff- Klinik, Benekestrasse 6-8, W. Germany.

The purpose of the present study was to quan- titate left ventricular function at rest and during isoproterenol infusion in patients with aortic valve disease and to correlate the reserve force of the left ventricle with the degree of left ventric- ‘ular hypertrophy.

Methods

1. Patients. Preoperative studies were performed in 3.5 patients undergoing right and left heart catheterization for diagnosis and evaluation of valvular heart disease. There were ten females and 25 males. Each patient gave informed consent for the conduction ‘of the study. No patients received premeditation before catheterization. The patients with aortic valve lesions represent a consecutive nonselected series.

The control group consists of nine patients without evidence of valvular or myocardial heart disease. They all had normal coronaroangio- grams. The mean age in this group was 47.3 years (range 36 to 58 years).

Twelve patients with predominant aortic stenosis had a mean age of 43.4 years (range 14 to 59 years). Average aortic valve area was 0.68 cm.?/ M.? (range 0.40 to 1.29 cm.‘/M.‘) and average peak systolic pressure gradient was 78.3 mm. Hg (range 40 to 120 mm. Hg). Aortic root angiography was performed in all these patients and revealed additional aortic incompetence in eight patients estimated as l+ (out of a maximum of 3+ ). No patients had additional mitral valve disease. The presence and severity of symptoms were assessed from the clinical records. We recorded NYHA functional class, considering

146 February, 1978, Vol. 95, No. 2 OOOZ-8703/78/0295-0146$00.80/O 0 1978 The C. V. Mosby Co.

LV function and cardiac reserve force

typical symptoms associated with aortic valve disease: angina, syncope and dyspnea. Seven patients of this group were in Class II, four in Class III, and one in Class IV. Selective coronaro- angiography was performed in all patients, except the child of 14 years, and showed coronary arteries without obstructions.

Twelve patients had predominant aortic regurgitation. Their mean age was 38 years (range 16 to 63 years). All patients had massive regurgitation scored as 3+ from aortic root angiography. Average aortic valve area in this group was 2.19 cm.?/M.’ (range 1.41 to 2.9 cm.“/M.*). Six patients had additional peak systolic pressure gradients between 6 and 20 mm. Hg. Two patients had additional mild mitral incompetence without mitral stenosis. Five patients were in Class II and seven in Class III. In the six patients above 40 years of age coronaryangiography showed no abnormalities.

Two patients had mixed aortic valve lesions with massive aortic regurgitation of 3+, aortic valve areas of 1.15 and 1.25 cm.2/M.2 and peak systolic pressure gradients of 48 and 50 mm. Hg. Additional mild mitral incompetence was present in one patient. Both patients were in Class III and had coronary arteries without obstructions.

Pre- and postoperative studies were performed in another series of six patients. Four of them had preoperatively predominant aortic stenosis with an average aortic valve area of 0.58 cm.2/M.2 (range 0.42 to 0.70 cm.*/M.‘) and a peak systolic pressure gradient of 116 mm. Hg (range 64 to 186 mm. Hg). Mild additional (1 + out of a maximum of 3+) aortic regurgitation was found in two of these four patients. The remaining two patients had a massive aortic regurgitation of 3+ with aortic valve areas of 1.7 and 2.3 cm.‘/M.Z and peak systolic pressure gradients of 12 and 30 mm. Hg. The postoperative evaluation was carried out 9.2 -+ 3.3 months (mean + SEM) after aortic valve replacement (Bjork-Shiley prosthesis).

2. Conduction of the study. Heart rate, left atria1 pressure, left ventricular pressure (8F Brockenbrough catheter, transseptal approach) and aortic pressure (8F pigtail catheter, femoral artery) were recorded before use of contrast material, using Statham P23Db pressure transducers at the midchest position. Thereafter 50 ml. Uro- grafin 76 were injected into the left ventricle using the Brockenbrough catheter while cineangiograms were exposed at 48 frames/set. on

ENDDIASTOLIC 1 VOLUME ml

600

400

200

1

y-3.29 f 1.0 X

w r =O.QQ, ~‘0.001

+TcTTTr . .

1 200 400

80. EJECTION .s

20 40 60 60

MONOPLANE

Fig. 1. C!I&XU%O~ between end-diastolic volume, end- systolic volume and ejection fraction deasured by single ljlane (monoplane) and biplane angiography. r = correlation coefficient.

a 35 mm. film (RAO position). Simultaneously the ECG and the aortic pressure were recorded tith a paper speed of 100 mm./sec. on an oscil- lomink direct writing system. Ventriculography Was repeated after a waiting period of at least 25 minutes during continuous infusion of 0.3 pg/Kg. body weight/min. isoproterenol. The Brocken- brough catheter was withdrawn into the left atrium and ventriculography was performed by injection into the atrium. Thereafter selective cinecoronarography was performed using the Judkins technique.

American Heart Journal 147

Schwarz et al.

Table I. Comparison of cardiac function before and during isoproterenol infusion between patients with predominant aortic stenosis and patients with predominant aortic regurgitation (both groups had comparable degrees of ventricular hypertrophy)

HR VCF (beats LVSP A oPd EDV EF (circumfer. MLAP LVEDP AVA

LVMMI /min.) (mm. Hg) (mm. Hg) (ml./M.2) (%) /sec.) (mm. Hg) (mm. Hg) (cm.‘/M.‘)

Rest Aortic stenosis

(n=ll) ’ Aortic

regurgitation (n = 8)

P value Isoproterenol

Aortic stenosis (n = 11)

Aortic regurgitation (n = 8)

P value

226.5 84.0 k ao.7* t 11.7 223.5 79.5

t 67.6 t 12.6

196.4 71.5 2 30.3 f 15.2 155.3 64.3

f 15.4 +- 14.6

127.9 63.4 1.05 c 67.7 -+ 16.3 i 0.40

171.8 58.8 0.94 -t 34.7 rt 12.8 rt 0.23

14.4 -t 9.0 11.0

t 5.2

20.6 t 10.0

17.9 t 6.4

0.68 F 0.26

2.18 c 0.40

ns. n.s. to.01 <O.OOl n.s. n.s. n.s. ns. n.s. ns.

226.5 130.9 f 80.7 k 13.6 223.5 122.9

k 67.6 k 23.6

254.0 t 49.2 174.5

+ 18.1

66.0 f 15.2

57.0 rt 14.3

118.6 68.9 1.72 i 77.9 I 16.3 -+ 0.62 151.8 70.5 1.81

f 38.5 t 10.6 r 0.40

16.0 * 11.5

9.2 z!z 7.3

18.8 Tk 13.9

9.9 + .5.1

0.74 * 0.31

2.63 + 1.29

(0.001 ns. ns. n.s. U.S. n.s. n.s. n.s. n.s. <O.Ol

Abbreviations: LVMMI = left ventricular muscle maae index (Gin/M.” of body surface area); HR = heart rate; LVSP = left ventricular systolic Fmaaure; AoPd = diastolic aortic pressure; EDV = end-diastolic volume; EF = ejection fraction; VCF = mean fiber shortening rate; MLAP = mean left atria1 pressure; LVEDP = left ventricular end-diastolic preaaure; AVA = aortic valve area. *Data are mean values f standard deviation.

3. Angiographic methods. Quantitative ventriculography was done using a sphere calibration technique and the area length methods modified for the RAO position.g-‘l End-diastolic and end- systolic volumes were derived from the largest and smallest silhouettes of the left ventricle using the apex and the aortic root as reference points. Ventriculographic images selected for analysis were taken from the first four sinus beats follow- ing contrast material injection. Heart rate did not change more than 5 b.p.m. during ventriculography as compared to heart rate measured during pressure recordings. All volume data were corrected according to the formula of Sandler and Dodge.* To assess ventricular function, ejection fraction was determined as stroke volume divided by end diastolic volume times 100 per cent. The minor equator (D) was calculated as D = 4 area/ ?T x L where L is the long axis of the ventricle. The percentage shortening of minor equator was determined as end-diastolic minus end-systolic divided by end-diastolic equator. Mean circumferential fiber shortening rate was calculated as percentage shortening of minor equator divided by ejection time as measured from the aortic pulse during ventriculography. Ventricular volumes were determined by single plane as well as biplane ventriculography in 25 patients in order to compare both methods. Left ventricular

wall thickness was measured in the RAO projec- tion as proposed by Falsetti and colleagues.” Left ventricular mass was determined according to Rackley and associates.‘” Aortic valve area was calculated utilizing a modification of the Gorlin formulaI after Bathe and co-workerslS: aortic valve area = Q/ 37.8 4 PPSG + 10, where &= cardiac output divided by the systolic ejection period, PPSG = peak-to-peak left ventricular-to-aortic pressure gradient. Cardiac output was calculated as angiographic stroke volume tunes heart rate. Valve areas determined by this method were found to be greater than those reported by others using the Fick principle’6, l7 but agree closely with values obtained by Lewis and colleaguesi and by Kennedy” using the angiographic technique. We believe that this method is preferable because even in “pure” aortic stenosis we found frequently mild regurgitation during aortic root angiography. Statistical analysis was carried out using the Student t test and linear regression analysis.

Results

Comparison of monoplane and biplane volumes for normal and enlarged ventricles showed an excellent correlation (r = 0.994) for end-diastolic volumes ranging from 134 to 645 ml. (Fig. 1). A similar correlation (r = 0.996) was found for end-

148 February, 1978, Vol. 95, No. 2


REST ISOPROTERENOL

22.

mean fiber 1.8’ . shortening rate ,,4,

circ/sec ,,@

so

eject ion fraction so

%

40

2c

I’ . . . . ‘.

6.. . OS .... . l . . : l

?s l . .I.. . . . . s

\

8“;. ;..

l . ..-. . . . . . . . . . . .

l . . . . L.

. . ‘.

. . . .

. . , , l

. .

r=O.62 r =O. 84

200 400 6ocl 200 400 800

left ventricular mass g/r?

0 = normals l = aortic valve

disease

Fig. 2. Correlation between left ventricular muscle mass and mean fiber shortening rate (upperpanel) or ejection fraction (lower panel) during rest (left) and during isoproterenol infusion (right). r = correlation coefficient. The open circles represent values of normal patients, closed circles represent values for patients with aortk valve disease.

systolic volumes over the range of 26 to 425 ml. pressure were not significantly different and for ejection fractions (r = 0.973) over a range (p > 0.05) between both groups either at rest or of 34 to 84 per cent. during isoproterenol infusion.

Eleven out of twelve patients wit,h predomi- It is therefore justified to correlate the ejection nant aortic stenosis and 8 out of 12 patients’with fraction and mean fiber shortening rate to the left predominant aortic regurgitation were selected ventricular muscle mass irrespective of the type according to their left ventricular mass to achieve of overload, as shown in Fig. 2. During rest the two groups with nearly identical and therefore correlation for mean fiber shortening rate was comparable degree of hypertrophy (Table I). Left poor (r = 0.57, p -C 0.001) but improved during ventricular peak systolic pressure and aortic isoproterenol (r = 0.74, p < 0.001). Both these valve area were significantly different between regression lines are significantly different both groups (p < 0.01). Heart rate, diastolic (p < 0.01). The relation between muscle mass aortic pressure, end-diastolic volume, ejection and ejection fraction was poor at rest (r = 0.62, fraction, mean fiber shortening rate, mean left p < 0.001) but also improved considerably during atria1 pressure, and left ventricular end-diastolic isoproterenol (r = 0.84, p < 0.001).


Schwarz et al.

Table II. Left ventricular function in normal patients and in patients before and after aortic valve replacement under resting conditions and during isoproterenol stress

HR VCF LVMMI (beats LVSP AoPd EDV EF (circumfer. MLAP LVEDP AVA

9 1min.j (mm. Hg) (mm. Hg) (mZ.lM.‘) @) /sec.) (mm. Hg) (mm. Hg) (cm.fM2)

Rest Normals

(n = 9) Before aortic

valve replacement (n = 6)

Before vs. Normals

After aortic valve replacement

(n = 6) After vs.

Before After vs.

tiormals Isoproterenol

Normals (N = 9)

After aortic valve replacement (n = 6)

After vs. Normals

87.3

it: 22.6$

315.6

t 62.1

to.001

146.9

+ 43.5

87.3

I 22.6

146.9

f 43.5

to.05

72.0

k 10.2

80.3

+- 11.0

n.s.

77.6

+ 8.2

ns.

ns.

142.0

+ 11.9 144.8

k6.1

ns.

125.8 71.6

z!z 11.3 f 9.3

188.7 55.0

+ 56.9 k6.2

<0.05 to.01

143.3 74.5

k 13.3 ra.2

n.s. CO.01

to.05 ns.

128.8 67.6

z!z 16.1 _’ 9.4

183.3 62.0

f 12.2 c6.5

to.001 n.s.

91;9 68.1

i 26.9 5 7.9

223.0 48.0

I71.7 * 15.9

CO.01 CO.05

95.7 68.3

2 14.7 zk 11.2

to.01 to.05

n.s. n.s.

74.1 85.0

F 21.2 F 5.4

92.2 76.5

+ 18.5 -t 6.9

ns. <0.05

1.19

kO.18

0.63

k 0.27

<O.OOl

1.29

f 0.39

CO.05

n.s.

2.43

kO.10

2.03

-+ 0.24

co.01

9.1 10.4

t 2.8 t 4.5

25.3 29.3

2 11.7 k9.9

< 0.05 <O.Ol

8.8 13.2

” 3.5 r+ 1.7

to.05 to.01

n.s. n.s.

4.2 6.1

+- 1.3 f 2.9

9.8 9.3

t4.7 t 5.0

CO.05 n.s.

1.68

-c 0.46

1.07

kO.79

n.s.

1.30

kO.31

n.s.

ns.

2.32

_t 0.48

1.20

k0.36

<O.OOl

“Abbreviations 88 in Table I. tData are mean values k standard deviation. &eft ventricular muscle mass index (LVMMI) measured in Gm.lM.’ of body surface area.

A poor but significant (r = 0.47, p < 0.01) inverse relation was found between left ventricular end-diastolic pressure and ejection fraction at rest. This correlation, however, wokened during isoproterenol infusion (r = 0.44, p < 0.05). A similar inverse relation between mean left atria1 pressure and ejection fraction was observed at rest (r = 0.56, p < C@Ol) atid improved during &3oproterenol (r = 0.66, p C O.OOl), suggesting that mean left atria1 pressure roughly reflects pump function of the left v&tricle in aortic valve disease.

Table II shows the results in patients before and nine months after.aortic valve replacement as compared to the contiol group. Left ventricular muscle mass, which was significantly elevated before surgery (p < O.OOl), decreased after valve replacement (p < 0.01, if sets of paired observations were compared), but remained abnormally elevated (p < 0.05). Resting values of

ejection fraction, mean fiber shortening rate, and mean left atria1 pressure which were pathologic before surgery normalized after valve replacement. Cardiac reserve tested during isoproterenol infusion after surgery revealed an abnormal response of ejection fraction, mean fiber shortening rate and mean left atria1 pressure as compared to normal patients (p < 0.05). Fig. 3 indicates that the persisting hypertrophy after corrective surgery is associated with an incomplete restoration of cardiac reserve suggesting that the relation between mass and reserve remains valid after surgery.

Discussion

Some methological problems need discussion: first of all it has to be considered that monoplane angiography may result in erroneous measure- ments of left ventricular volumes. Cohn and colleagueP found good agreement of monoplane

150 February, 1978, Vol. 95, No. 2


and biplane angiography in normal patients and in patients with coronary artery disease without evidence of asynergy. Our observation was that monoplane and biplane angiograms correlate excellently in ventricles with aortic valve disease without coronary artery disease (Fig. 1). This is mainly due to the fact that ventricular geometry in aortic valve disease remains nearly normal. The ejection fraction and the mean circumferential fiber shortening rate3” were used in this study to define left ventricular function at rest and during isoproterenol stress. Peterson and co- worker9 compared isovolumic and ejection phase indices in normal and diseased hearts and found that in patients with diffuse myocardial involvement, ejection phase contractile indices offer a preferable mode for assessing myocardial function. The ejection phase indices showed superior senstitivity for identifying normal and abnormal patients with minimal individual overlap, whereas isovolumic indices although separat- ing normal and diseased hearts, showed consid- erable overlap of individual values. The ejection fraction measured at rest has prognostic significance in the surgical treatment of valvular heart disease since patients with depressed ejection fractions have a poorer short term prognosis than patient with normal ejection fractions3? It was further shown that the evaluation of the contractile reserve determined by the ejection fraction after postextrasystolic potentiation or during epinephrine infusion helped to establish a close relation between ventricular function and prognosis in patients with coronary artery diseasees3

Isoproterenol as a beta-stimulating drug enhances left ventricular performance in normal and diseased hearts.‘9-2P Quinones and colleagueP described an augmentation of contractility as measured from an increase of mean circumferential fiber shortening rate of 58 per cent during isoproterenol infusion in normal individuals. Geha and associateP found a significant increase of contractile behavior in normal and hypertrophied dog hearts. In the present study we used isoproterenol to evaluate cardiac reserve.

Left ventricular function and reserve were not different between chronic pressure and chronic volume overload if patients with nearly identical left ventricular muscle masses are compared. Mehmel and co-workers5 using a similar approach found no differences of Vpm between two groups of patients with chronic pressure and volume

I SOPROTERENOL

left ventricular mass

S/m2

pea05

mean fiber

2.

&;;tening

c i rc/sec 1

pco.05

eject ion 80 fraction .:.:.:.:.

% 6o y:::::: >:.:.:.:

llllIl :.:.:.:..

::::::::: 40 :::::::::

. ..'..... .*...a.*. .-it.-. . . . . 20 g.:.:.: . . . . :.:.:.:.:

.:.:.:.:. ..*..

Fig. 3. Left ventricular muscle mass and reserve function in normal patients and in patients after aortic valve replacement. Left ventricular muscle mass is still significantly increased nine months after surgery. Reserve function (mean fiber shortening rate and ejection fraction) is reduced in these hypertrophied hearts. The columns represent mean values k S.E.M.

overload but with comparable muscle masses. They concluded that in advanced hypertrophy contractility is reduced irrespective of the stimulating factor. Our results support this concept. Therefore, we related left ventricular function to the degree of hypertrophy, irrespective of the type of aortic valve lesion. Under control conditions this relation was poor probably due to the compensatory capacity of the hypertrophied ventricle,24 and the Frank-Starling mechanism.2s When, however, the hypertrophied hearts were forced to mobilize their reserve, a close inverse relationship between muscle mass and reserve force was found (Fig. 2). Thus, stress could demonstrate a depression of cardiac reserve when


Schwarz et al.

differences at rest were only slight or absent. This suggests that changes in the development of hypertrophy occur which may be responsible for the loss of contractile reserve in these hearts. Spann and colleaguesZ6 found in hypertrophied isolated cat papillary muscles that hypertrophy in the absence of cardiac failure was associated with a depression of contractility per unit of myocardium. Gunning and associatesz’ concluded from experiments in’hypertrophied cat papillary muscles due to pressure overload that the depressed contractility is associated with an augmented myocardial oxygen consumption. Strauer and TauchertZ8 found an inefficient energy utilization in the isolated hypertrophied; human ventricular myocardium. These results point out that biochemical correlates at the cellular level may be involved in the process leading to mechanical dysfunction in advanced cardiac hypertrophy. A second mechanism may be responsible for the decline of contractile reserve with increasing severity of hypertrophy. Marchetti and colleagues2” described a reduced coronary reserve in dogs with moderate hypertrophy due to volume overload. This suggests that myocardial perfusion may also be responsible for the impairment of contractile reserve in hypertrophied hearts.

Comparison of pre- and postoperative evaluation in six patients with advanced aortic valve disease and severe left ventricular hypertrophy shows a drastic reduction of left ventricular muscle mass after surgery to 53 per cent of the preoperative value. This regression, however, is incomplete if compared to normal patients. An incomplete regression of left ventricular hypertrophy was also observed by Kennedy and co- worker@ in patients with homograft aortic valve replacement, and by Papadimitriou and asso- ciate@ in dogs after closure of a large aortocaval fistula. Cardiac function at rest, which was severely compromised before surgery, normalized completely in our patients after successful correction of overload; contractile reserve, however, was still depressed. This demonstrates that after correction of overload by aortic valve replacement the hearts shifted upwards and to the left on the mass function curve shown in Fig. 2, indicating improved cardiac performance. It has to be considered, however, that Bjork-Shiley prostheses produce an increased afterload which may be responsible for the incomplete regression

of left ventricular hypertrophy and the incomplete restoration of contractile reserve.

Summary

The relations between left ventricular (LV) hypertrophy as estimated by LV mass and LV function and between LV hypertrophy and cardiac reserve were evaluated in 26 patients with aortic valve disease and in nine normal patients who served as controls. Ejection fraction (EF) and mean circumferential fiber shortening rate (VCF) served as indices of LV function. Reserve force of the left ventricle was tested by ventriculography during infusion of 0.3 pg/Kg. body weight/min. isoproterenol. EF and VCF were not significantly different (p > 0.05) either at rest or during isoproterenol infusion if patients with aortic stenosis were compared to patients with aortic regurgitation having comparable LV masses. Therefore we correlated the EF and VCF to the LV mass of all patients irrespective of the type of aortic valve lesion. Poor but significant inverse correlations were found at rest between LV mass and EF (r = 0.62) and between LV mass and VCF (r = 0.57). These correlations improved considerably during isoproterenol: r = 0.84 for EF and r = 0.74 for VCF.

LV function was evaluated in another six patients with aortic valve disease before and nine months after successful aortic valve replacement by Bjork-Shiley prostheses. LV mass before surgery was 3.6 times control and decreased after surgery to 1.7 times control (p < 0.01) which is still significantly elevated (p < 0.05). EF and VCF which were depressed before surgery (p < 0.05, p < 0.001) normalized after surgery (p > 0.05) but were reduced during isoproterenol infusion if compared to controls (p < 0.05). Thus, stress ventriculography in aortic valve disease could demonstrate a linear decrease of cardiac reserve with increasing severity of hypertrophy when resting function was normal or depressed only slightly. Regression of hypertrophy was incomplete 9 months after correction of overload and LV function, which was depressed before surgery, normalized at rest but was impaired during stress suggesting that cardiac reserve was not fully restored.

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152 February, 1978, Vol. 95, No. 2


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cardiac reserve during isoproterenol stress in patients with aortic valve disease before and after...

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