Left ventricular hypertrophy and mortality after aortic valve replacement for aortic stenosis

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VALVULAR DISEASE

Left Ventricular Hypertr - -_ Ti .Lyand wic J

_a,'air y

After Aortic Valve

Replacement for Aortic Stc-. osis A fligli Risk Subgroup Identified by Preoperative Relative Wall Thickness DAVID A . ORSINFI .T .1, MD, GERARD P . AURIGEMMA, IUD, FACC, STEPHEN BATTISTA, M STEVEN KRENDEL, BS, WILLIAM H . GAASCH, MD . FACC Worcester, Massachusetts

Objectives . We investigated the relation between the extent and pattern of left ventricular hypertrophy and surgical outcome in 54 patients undergoing aortic valve replacement for severe aortic sleftos6. Background. Previous `work from our laboratory has demon . strated that a subgroup of patients, mostly elderly women with Doppler evidence of abnormal intracaviiary llow acceleration, had an unexpectedly high in-hospital mortality rate after aortic valve replacement for aortic stenosis . We hypothesized that marked concentric hypertrophy, rather than the Doppler signal itself, was related to the poor outcome . Methods. A retrospective analysis of the clinical, hemodynamic and echocardiographic data in patients who survived aortic valve replacement versus those who died in the hospital was performed .

Results . There were no differences between the 42 survivors and 12 nonsurvivors with regard to the clinical or hemodynamic variables . Of the echocardiographic variables analyzed, diastolic relative wall thickness was found to be significantly different between the two groups . Patients who died had significantly greater relative wall thickness (mean ± SD) than those who survived (0.72 ± 0.38 vs . 0.56 it 0.15, p = 0.04). Analysis by gender demonstrated that the relation between ventricular geometry and mortality held true only for women . Conclusions . We conclude that excessive ventricular hypertrophy, manifested as a markedly increased relative wall thickness, is associated with a significantly increased risk of postoperative mortality after aortic valve replace nient for aortic stenosis .

Left ventricular hypertrophy in patients with aortic stenosis is generally characterized by an increased myocardial mass and a, hange in ventricular geometry that preserves a normal relation between systolic wall stress and ejection fraction . Thus, the development of concentric hypertrophy is generally considered to be an appropriate and beneficial adaptation that compensates for high intracavitary pressure (1,2) . After valve replacement, left ventricular systolic pressure falls, a systolic unloading occurs and, at least initially, ejection fraction increases (3) . In some patients an abnormal high velocity intrp ,.avitary Doppler flow signal appears (4,5) . This flow phenomenon appears to represent a postoperative unloading effect in hypertrophic hearts and does not necessarily signify left ventricular outflow obstruction (6,7) . After aortic valve replacement, patients with intracavitary flow acceleration appear to have increased postoperative compli-

cations and an increased early mortality rate (4) . However, it would seem unlikely that intracavitary flow acceleration itself might be responsible for these malefic consequences in the early postoperative period . A more likely muse of postoperative morbidity is the presence of marked or excessive left ventricular hypertrophy . We therefore designed the present study to test the hypothesis that the pattern and extent of hypertrophy, as determined by preoperative echocardiography, was related to the high postoperative morbidity and mortality rates seen in patients undergoing aortic valve replacement for aortic stenosis .

From the Noninvasive Laboratory, Division of Cardiology, University of Massachusetts Medical Center and the Division of Cardiology, Medical Center of Central Massachusetts, Worcester, Massachusetts . This study was presented in part at this 4lst Annual Scientific Session of the American College of Cardiology, Dallas, Texas, April 1992 . Manuscript received December 17, 1992 ; revised manuscript received April 28, 1993, accepted June 9, 1993. Address for comes 2Qndance : Dr. Gerard P. Aurigemma, Division of Cardiology, University of Massachusetts Medical Center, 55 Lake Avenue North, Worcester, Massachusetts 01655 . 01993 by the American College of Cardiology

(J Am Coll Cardiol 1993,22 .1679-83)

Methods Study patients . All patients who underwent aortic valve replacement for severe aortic stenosis from dune 1987 to October 1990 were identified . Patients with previous aortic valve surgery and those undergoing concomitant mitral valve surgery were excluded . A total of 164 patients were thus identified . Fifty-four patients had complete preoperative echocardiographic studies and constitute the current study group . Data from 28 of these patients have been reported elsewhere (4) . Echocardiographic data were reviewed by an investigator unaware of clinical and catheterization data . Clinical and demographic data were obtained from a review of the patients' hospital records . 0735-1097193/$6,00

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ORSINELLI ET AL . LEFT VENTRICULAR HYPERTROPHY AND AORTIC VALVE REPLACEMENT

Table 1 . Clinical/Hemodynamic Data

Age (q) Gender (% male) AVA (cm2) Mean gradient (mm Hg) CAD (%) Ejection fraction (%) LVEDP (mm Hg) Cardiac index (liters/min per m 2 )

Total (n = 54)

Survivor (n = 42)

Nonsurvivor (n = 12)

p Value*

71 ± 12 44 0.60 ± 0.23 59 ± 24 46 62 18 18 ±8 2 .3 0.6

70 ± 12 48 0.61 ± 0.24 59 ± 23 48 61 20 1 8 2 .2 0.6

72 ± 11 33 0 .59 ± 0 .16 59 ± 26 42 65 20 IS 5 2.5 0.6

NS NS NS NS NS NS NS NS

*SurvivoT versus nonsurvivor . Values presented are mean value ± SD or percent . AVA = aortic valve area; CAD - coronary artery disease ; LVEDP - left ventricular end-diastolic pressure.

Echocardiography . M-mode, two-dimensional and Dopp-

ler echocarfiography were performed using commercially available equipment (Hewlett-Packard series 77020A, HewlettPackard Medical Products) . Standard apical, parasternal and subcostal views were obtained . Two-dimensionally guided M-mode recordings were obtained from the parasternal window, and strip chart recordings were made at a paper speed of so mm/s . From the M-mode recordings, the following measurements were made using American Society of Echocardiography standards (8) : interventricular septal thickness, posterior wall thickness, left ventricular end-diastolic dimension and left ventricular end-systolic dimension . Left ventricular mass was calculated from the M-mode measurements using the formula described previously by Troy et al . (9) and modified by Devereux et al . (IM and was indexed to body surface area. Diastolic relative wall thickness was calculated as twice the posterior wall thickness divided by the left ventricular end-diastolic dimension (i 1) . Chlbe cacheatake. Left and right heart catleteriza, tion was performed using fluid-filled catheters, and pressure measurements were recorded in a standard fashion . Cardiac output determinations were performed using either the Fick principle for oxygen or the thermodilution method . The Gorlin equation was used to calculate the aortic valve area (12) . Left ventricular ejection fraction was calculated using the area-length method from the right anterior oblique ventriculogrant (13) . Coronary artery disease was defined as the presence of a _>50% stenosis involving a major coronary artery . StatistieL Continuous variables are express ,.-d as mean value ± SD . Comparisons between continuous variables were performed using a two-tailed unpaired Student t test . DiO'Iotomous variables were compared using contingency table and chi-square analysis . A p value of < 0.05 was taken as statistically significant .

Results

St* paftlL There were no significant differences in age, gender or in-hospital mortality between the 54 study

patients and the remaining 110 patients who underwent aortic valve replacement during the cAy period and did not have preoperative echocardiography . Thus, the 54 study patients are representative of our larger experience with aortic stenosis and aortic valve replacement . Hemodynamic data (Table 1) . The patient group had severe aortic stenosis (mean valve area 0 .60 ± 0 .23 cm2 , mean transvalvular gradient 59 ± 24 mm Hg) and preserved left ventricular systolic function (ejection fraction 62 t 18%) . Among the 54 study patients, 12 patients (22%) died in the hospital . There were no differences between survivors and nonsurvivors in terms of age, gender, aortic valve area, mean transvalvular aortic gradient, presence of coronary artery disease, left ventricular ejection fraction, left ventricular end-diastolic pressure or cardiac index . 1kbwKardNqpph1bc data (Table 2) . The study population had increased left ventricular wall thickness with normal left ventricular chamber dimensions . The mean relative wall thickness was 0 .60 ± 0 .23 . The mean left ventricular mass was 282 ± 77 g, and the mass index was 159 ± 43 g/m 2 . Of the echocardiographic variables evaluated, only the enddiastolic relative wall thickness proved to be significantly different between survivors and nonsurvivors . Patients who died in the hospital had a significantly higher relative wall thickness (0.72 ± 0,38 vs . 0 .56 ± 0.15, p = 0 .04) . When defining a markedly increased relative wall thickness, a value of 0.66 was found to be the best partition value for the overall study group in terms of discriminating between survivors and nonsurvivors . Using this cut point, relative wall thickness values of >0 .66 were associated with a trend toward increased mortality (42% vs . 179o, p = 0 .07) Gender differences (Table 3). We analyzed our mortality data by gender in view of recent work demonstrating gender differences in elderly patients with pressure overload hypertrophy due to aortic stenosis (14-16) . Among the 30 women, there were no differences between survivors and nonsurvivors with regard to age, any hemodynamic variable or the presence of coronas ; disease . However, women who died in the hospital had significantly greater septal thickness, posterior wall thickness and relative wall thickness and smaller left ventricular systolic and diastolic dimensions (Table 3) .



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Table 2 . Echocardiographic Data Total In = 54)

Survivor (a = 42)

Nonsurvivor

ST (mm) PWT (mm)

15 ± I

15±3

16±5

NS

14 ± 3

15 ± 4

LVEDD (mm) LVESD (mm)

47 ± 8

13 ± 3 48±7

29 ± 10

30±9

46±9 26±14

0.06 NS

LV mass (g)

282 ± 77

277 ± 79

301 ± 70

LV mass index (g/m 2 )

159 ± 43

157 ± 45 0 .56±0 .15

166 ± 34 0.72±0 .38

1 .1 ±0 .2

1 .1 ±0 .2

37 ± 14

47 ± 24

RWT STIPWT % Fractional shortening

0.60 ± 0 .23 L! ± 0 .2 39 ± 17

In = 12)

p Value*

NS NS NS 0.04 NS 0.09

*Survivor versus nonsurvivor . Values presented are mean value ± Sly, LV = left ventricular ; LVEDI3 left ventricular end-diastolic dimension ; LVESD = left ventricular end-systolic dimension, PWT = posterior left ventricular wall thickness : KWT = relative wall thickness . ST - interventricular septal thickness .

Among women with relative wall thickness values >0 .66, the mortality rate was 63% 15 of 8) versus 14% (3 of 22) in women with values <0 .66 (p = 0 .007) . A similar analysis of the 24 men failed to demonstrate any significant differences between survivors and nonsurvivors with regard to age, hernodynamic variables or the presence of coronary disease . With respect to echocardiographic variables, with the exception of septal thickness (15 ± 3 imi in those who lived vs . 12 ± 2 mm in those who died, p < 0 .05), there were no significant differences between the men who lived and those who died . Impact of coronary artery disease . We attempted to determine the influence of coronary artery disease on left ventricular geometry, in view of recent work highlighting the impact of epicardial coronary disease on left ventricular structure in aortic stenosis (17) . There were no differences between the 2' patients with and the 29 without coronary artery disease, . .j any hemodynamic or echocardiographic variable examined . When the subgroup of 25 patients with coronary artery disease was analyzed, several differences emerged between the patients who survived and those who died in the hospital . The patients with coronary artery disease who died had higher relative wall thickness (0 .88 ± 0 .55 vs . 0 .57 ± 0 .19, p = 0.04), higher ejection fraction (81 ± 7% vs . 59 ± 16%,

1) = 0 .02) and a higher cardiac index (2 .8 ± 0 .6 liters/m2, p = 0.01) . When the group was classified into patients with and without markedly increased relative wall thickness (relative wall thickness >010, patients with a high relative wall thickness had a fivefold increase in mortality (3 142%] of 7 vs . 2 111%] of 18, p = 0 .07) .

Discussion Our principal finding is that a pattern of left ventricular hypertrophy characterized by a marked increase in relative wall thickness is associated with a poor outcome after aortic valve replacement in patients with aortic stenosis . The mean value for relative wall thickness was significantly lower in survivors than in nonsurvivors . This association was present in the study group as a whole, in women and in the subgroup with coronary artery disease . These findings extend our previous observations (4) and suggest that the combination of increased relative wall thickness, high ejection fraction and, in some cases, abnormal intracavitary flow acceleration appears to identify a group of patients with significant morbidity and mortality after aortic valve replacement for aortic stenosis . Moreover, our current findings suggest that there is an important clinical consequence of the recently described gender differ-

Table 3 . Echocardiographic Data in Women Survivor (n = 22)

Nonsurvivor

(n = 30)

ST (mm)

15 ± 4

14 ± 3

PWT (mm) LVEDD (mm)

12±2

18 ± 4 16±4

0.005

13 ± 3 46 ± 7 28 ± 11

47±6

42±8

NS

31±9

21±12

0.03

0.85 ± 0A 0 315 ± 77

0.002 0.04

174 ± 34

NS

11 .2±0 .3

NS

51 ± 24

0 .05

Total

LVESD (mm) RWT

0h1

0 .27

LV mass (g)

266

78

0.53 ± 0.13 248 ± 72

LV mass index (glm') ST/PWT

157 1 .2

46 0.2

150 ± 49 1 .2±0.2

40

20

35 ± 16

% Fractional shortening

(n = 8)

*Survivor versus nonsurvivor . Values presented are mean value ± SD . Abbreviations as in Table 2 .

p Value*

0.002



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ORSINELLI ET AL LEFT VENTRICULAR HYPERTROPHY AND AORTIC VALVE REPLACEMENT

ences in left ventricular structure in left ventricular pressure overload hypertrophy (14-16) . previous studies. Although several investigators (18-23) have reported results of aortic valve replacement for aortic valve disease, no previous study has examined surgical outcome as a function of ventricular geometry . However, a number of observations tend support to our observations . Lytte et al . (18) reported the results of aortic valve replacement in 500 patients . The strongest univariate predictor of operative mortality was female gender, followed by aortic regurgitation and age . This finding is particularly striking in view of the lack of difference in extent of coronary artery disease or vcrltiicttiair 6ly •. ftrction between women and men . Preoperative ejection fraction did not appear to influence in-hospital operative mortality, men undergoing aortic tai et al . (20) reported data on valve replacement, The operative mortality was highest in the u , i up with "preserved" ejection fraction . They also found that left ventricular systolic pressure was inversely related to mortality and speculated that "high left ventricular systolic pressures may be reflective of systemic arterial hypertension, or left ventricular hypertrophy or both" (20) The operative mortality in the present series is higher than in previous series of patients undergoing aortic valve replacement (18-23) . This finding most likely reflects the older age of our study patients than that of patients in most series (1821,23) and, perhaps, the higher proportion of women in our series than in many others (18-23) . We cannot exclude the possibility that the higher mortality rate in patients with a high relative wall thickness is related to factors that were not assessed in our study . Because this is a consecutive series of patiequs, these factors should be evenly divided among all patients . Nonetheless, our findings may not be applicable to centers with a lowe operative mortality rate . Our data cone=t ; sting the impact of coronary disease differ from the findings of Vekshtein et al . (17), who showed that epicardial coronary artery disease was associated with diminished left ventricular systolic function and a lower mass/ volume ratio, We observed no differences in left ventricular geometry between patients with and without coronary disease. However, Vekshtein et al. (17), classified their patients into those with angiographically normal coronaries, nonobstructive disease and obstructive disease and compared patients with any degree of coronary disease to patients without disease . When they compared their patients with obstructive coronary disease to those with either normal coronary arteries or nonobstructive disease, no differences in left ventricular structure were found (17). The reason for the poor surgical outcome in patients with aortic stenosis with a marked increase in relative wall thickness is not apparent. We previously observed that a subset of these patients developed systemic by tension and a low cardiac output state in the early postoperative period despite the presence of a normal left ventricular ejection fraction (4) . On the basis of our experience, ischemic systolic dysfunction (24) does not appear to

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account for the poor outcome in view of the preserved systolic function that we observed (4) . Although the development of left ventricular hypertrophy is generally considered to be a beneficial adaptation to high intracavitary pressures, recent evidence has highlighted the adverse cardiovascular risk associated with left ventricular hypertrophy in hypertensive patients (25-29) . Koren et al . (27) found that a pattern of concentric hypertrophy was associated with the highest risk of adverse events in hypertensive patients . Patients with concentric remodeling (normal left ventricular mass and increased relative wall thickness) also experienced a higher morbidity . Ohali et al . (29) found that left ventricular hypertrophy was associated with increased mortality both in patients with and in patients without coronary disease . There are several potential mechanisms whereby excessive left ventricular hypertrophy may confer increased morbidity and more !ity after aortic valve replacement . First, optimal cardiol , ,;section during ischemic arrest is difficult to achieve in hypertrophic hearts . Second, abnormalities in coronary flow reserve (30,31), which may be especially prominent in hypertrophied hearts, may contribute to ischemia and its consequences . A third potential adverse consequence of left ventricular hypertrophy is an exacerbation of diastolic dysfunction (24,32,33) . Diastolic dysfunction, especially exacerbated by superimposed ischemia, might lead to impaired filling despite elevated pulmonary venous pressure . Impaired diastolic function could explain the hemodynamic sequelae that we observed . This hypothesis is supported by the observation that several patients responded to volume replacement and the addition of calcium channel or betaadrenergic blocking agents, or both (4) . Limitations of the study . The present study has several important limitations . First, it is retrospective, and therefore the clinical data on the patients may be incomplete . Of importance, we were unable to accurately define a history of hypertension or the duration of aortic stenosis in the patient group, both of which could influence the development and pattern of left ventricular hypertrophy . Patients who had preoperative echocardiography represent a subgroup of patients undergoing aortic valve replacement at our institution, and it might be argued that the patients whose condition was more compromised had undergone echocardiography preoperatively . However, there was no significant mortality difference between those who did or did not undergo preoperative echocardiography . Conclusions. In patients with aortic stenosis, a pattern of concentric left ventricular hypertrophy denoted by high relative wall thickness and, on occasion, an abnormal high velocity intracavitary Doppler signal (4) identifies a group of patients with a high risk of postoperative morbidity and mortality. Preoperative echocardiography may thus play a significant role in preoperative risk assessment of patients with aortic stenosis and may also help guide therapeutic interventions in the postoperative period .

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ORSINELLI ET ALEFT VENTRICULAR HYPERTROPHY AND AORTIC VALVE REPLACEMENT

We acknowledge the technical assistance of Andrea Sweeney, RDCS.

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