© 2004 European Society of Cardiology
Relation of myocardial histomorphometric features and left ventricular contractile reserve assessed by high-dose dobutamine stress echocardiography in patients with idiopathic dilated cardiomyopathy
evi
aaaaakovia,*
a Dr. Aleksandar D. Popovi Cardiovascular Research Center, Dedinje Cardiovascular Institute, Belgrade University Medical School Milana Tepia 1, 11040 Belgrade, Serbia and Montenegro, Yugoslavia
b Centro Nazionale di Riserche Pisa, Italy
* Corresponding author. Tel.: +381 11 360 16 69; fax: +381 11 2666 445. E-mail address: neskovic{at}hotmail.com
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionReferences |
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Background: This study was designed to determine the relationship between histomorphometric features and contractile reserve assessed by high-dose dobutamine stress echocardiography in patients with idiopathic dilated cardiomyopathy.
Methods: Twenty-four consecutive patients (21 men, aged 43.4±8.7 years) with idiopathic dilated cardiomyopathy underwent dobutamine stress echocardiography. Wall motion score index, ejection fraction, cardiac power output and end-systolic pressure/volume ratio were used as indices of left ventricular contractility. Left ventricular endomyocardial biopsy specimens (3–5 per patient) were routinely processed and stained with Masson trichrome, interstitial fibrosis and myocyte diameter were calculated quantitatively.
Results: Myocyte diameter and interstitial fibrosis showed strongest correlation with change in wall motion score index (r=–0.667, p<0.001, and r=–0.567, p=0.004, respectively), followed by change in ejection fraction (r=–0.603, p=0.002, and r=–0.467, p=0.021, respectively). Interstitial fibrosis showed no correlation with change of cardiac power output and end-systolic pressure/volume ratio, whereas myocyte diameter was associated with change of both indices (r=–0.565, p=0.004, and r=–0.455, p=0.025).
Conclusions: Contractile reserve elicited by high-dose dobutamine is strongly related to the degree of histological disruption in patients with idiopathic dilated cardiomyopathy.
Key Words: Dilated cardiomyopathy • Dobutamine stress echocardiography • Contractile reserve • Morphometry
Received June 26, 2003; Revised September 19, 2003; Accepted January 9, 2004
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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A number of studies have suggested that the direct assessment of left ventricular contractile reserve during pharmacological or exercise stress testing may improve the prognostic evaluation of patients with heart failure due to dilated cardiomyopathy [1,2]. Dobutamine stress echocardiography is an established methodology for the assessment of patients with dilated cardiomyopathy of ischemic origin [3,4]. However, the significance of left ventricular contractile reserve assessed by high-dose dobutamine in patients with diffusely affected myocardium, as seen in idiopathic dilated cardiomyopathy, is poorly defined. Although myocardial morphology is considered to be a descriptor of the degree of myocardial damage, as well as a predictor of future cardiac events in patients with idiopathic dilated cardiomyopathy, [5] currently, there are no studies on the association of myocardial morphology and contractile reserve assessed by high-dose dobutamine. Since the understanding of the nature of this association may be an important step forward, we designed the present study to assess the relationship between various indices of left ventricular contractile reserve elicited by high-dose dobutamine and myocardial histomorphometric features in patients with idiopathic dilated cardiomyopathy.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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2.1. Study patients
Between February and December 1998, 72 patients with idiopathic dilated cardiomyopathy were referred to our institution for diagnostic evaluation. Diagnosis of idiopathic dilated cardiomyopathy was performed by echocardiography if there was no evidence of alcohol intake, arterial hypertension, toxin exposure, myocarditis, hypertrophic cardiomyopathy, valvular heart disease and/or significant coronary artery disease (defined as
50% diameter stenosis of the major epicardial vessel). Patients entered the study if they met the following criteria: (1) left ventricular end-diastolic diameter60 mm; (2) ejection fraction
35%; (3) adequate echocardiographic window (defined as visualization of at least 13/16 segments of the left ventricle), and (4) diagnostic endomyocardial biopsy. The study protocol was approved by Dedinje Cardiovascular Institute Ethics Committee, and the investigation conformed with the principles outlined in the Declaration of Helsinki. Of the 72 referred patients, 48 patients did not meet the study entry criteria. The majority of the excluded patients (36/48) did not have an endomyocardial biopsy, because biopsies were performed at the discretion of the attending physician. Of the remaining 12 excluded patients, six had left ventricular ejection fraction>35%, four did not have adequate echocardiographic window, and two refused to participate in the study. Importantly, there was no difference between these two groups of patients with respect to major demographic, clinical and functional data. The final study group therefore consisted of 24 patients (21 men, mean age 43.4±8.7 years).
On admission, four patients (16.7%) were in New York Heart Association class I, 13 patients (54.2%) were in class II, five patients (20.8%) were in class III, and two patients (8.3%) were in class IV heart failure. The mean duration of symptoms was 15±28 months, ranging from 1 to 134 months. Eight patients (33.3%) were in atrial fibrillation, whereas 16 (66.6%) were in normal sinus rhythm. The patients were taking the following medications: digoxin 11/24 (46%), ACE inhibitors 23/24 (96%), diuretics 20/24 (83%), beta-blockers 16/24 (67%) and coumadin 12/24 (50%).
2.2. Echocardiography
All examinations were performed with a Hewlett-Packard Sonos 2500 machine (Andover, MA), using a 2.5 MHz transducer, and were stored on video tape for later analysis. Left ventricular end-diastolic diameter was measured in parasternal long-axis view using M-mode echocardiography, whereas left ventricular end-diastolic volume, end-systolic volume and ejection fraction were determined from apical two- and four-chamber views using the Simpson's biplane formula. Tracing of endocardial borders in end-diastole and end-systole was performed on the Hewlett-Packard Sonos 2500 machine in the technically best cardiac cycle. The volumes were normalized for body surface area and expressed as indexes.
Aortic velocity–time integral was measured by pulsed wave Doppler in the apical five-chamber view with the sample volume placed just beyond the valve annulus. Modal flow velocities were traced after quiet expiration in three or five consecutive beats for patients in normal sinus rhythm or atrial fibrillation, respectively, and then averaged. Aortic diameter was measured at the annular level in parasternal long-axis view using two-dimensional echocardiography. Cardiac output was calculated using standard equation:
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2.3. Dobutamine stress echocardiography
Dobutamine stress echocardiography was performed in all patients in incremental stages lasting 5 min each, with an initial dose of 5 mcg/kg/min, which was increased to 10 mcg/kg/min, then to 20 and 30 mcg/kg/min and, finally, to the maximal dose of 40 mcg/kg/min. The infusion was discontinued before the maximal dose was reached if 85% of the maximal predicted heart rate for the age group was achieved, or symptomatic nonsustained or sustained ventricular tachycardia were observed. The investigative nature of the procedure was explained to the patients and informed consent was obtained from all patients. Beta-blockers were stopped 48 h prior to dobutamine testing in all patients.
2.4. Contractile reserve
Wall motion score index, ejection fraction, cardiac power output and end-systolic pressure/volume ratio were considered as indices of left ventricular contractility. Contractile reserve was defined as the difference between the values of these indices obtained at peak dobutamine dose during the test and the baseline values.
2.4.1. Wall motion score index
Left ventricular wall motion score index was calculated using a 16-segment model of the left ventricle. Wall motion for each segment was graded semiquantitatively as normokinesia=1, hypokinesia=2, akinesia=3 and diskinesia=4. Wall motion score index was calculated by summing the scores for each segment and dividing by the number of analyzed segments. Segments that were not adequately visualized were excluded from the analysis.
2.4.2. Ejection fraction
Calculation of the ejection fraction was performed as described previously.
2.4.3. Cardiac power output
The mean arterial pressure, in mm Hg, was calculated as:
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2.4.4. End-systolic pressure/volume ratio
Since it has been shown that mean arterial pressure underestimates end-systolic pressure, we calculated end-systolic pressure, in mm Hg, using a previously validated equation [7]:
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2.5. Cardiac catheterization and endomyocardial biopsy
Cardiac catheterization was performed in all patients 24 h prior to dobutamine stress echocardiography. All patients were unsedated and received no medications for at least 12 h before the procedure. Right and left heart catheterization was performed by femoral approach using standard 7 French fluid-filled catheters. Baseline intracardiac pressures were recorded, then coronary angiography and left ventricular angiography were performed. Stenosis of the major coronary artery diameter>50% was considered significant.
At the end of the catheterization procedure, left ventricular endomyocardial biopsies were performed using King's College bioptome, and three to five tissue specimens were taken from the infero- and/or posterolateral wall and fixed in phosphate buffered 10% formalin at room temperature. The biopsy specimens were embedded in paraffin and cut in semithin sections, which were stained with hematoxylin–eosin and Masson trichrome.
2.6. Histomorphometric analysis
Histomorphometric analysis was performed using light microscopy with 400x magnification. At least three fields of each section were digitized and stored for further analysis. Interstitial fibrosis was computed using commercially available software (Leica Qwin Standard, version 2.2, Leica Technology, Rijswijk, The Netherlands) for each field of each specimen and then averaged to obtain a single value per patient. Particular attention was paid to excluding fixation artifacts, blood vessels and endocardial plaque from the analysis. Myocyte diameter was calculated using the same digitized fields which were used for the previous analysis. All longitudinally cut myocytes with nuclei were measured at the nuclear level using computer software (ImageTool, version 2.0, University of Texas Health Science Center, San Antonio, TX) and then averaged [8].
Values for both interstitial fibrosis and myocyte diameter were dichotomized with respect to median value and assigned zero points if lower than median value or one point if median value or higher. The newly assigned values were summated and the patients were divided into three groups. Patients with zero points were considered to have mild histomorphometric changes, while patients with one and two points were considered to have moderate or severe histomorphometric changes, respectively (Fig. 1A–C).
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2.7. Statistical analysis
All data are expressed as mean±standard deviation. Parametric or nonparametric (Kruskal–Wallis) one-way analysis of variance was used for comparisons between the groups, depending on the presence or the absence of normal distribution and variance homogeneity in each group. Simple linear regression was used to assess the relationship between individual histomorphometric and contractile reserve indices.
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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3.1. Study patients
Each of the three groups of patients, divided according to histomorphometric changes (see Methods), consisted of eight patients. Baseline demographic, clinical, echocardiographic and histomorphometric characteristics of these patients are shown in Table 1. Briefly, patients with severe histomorphometric changes were older, more frequently were female and more frequently were in New York Heart Association classes III and IV compared to patients with more favorable histomorphometric findings. On the other hand, patients with mild changes had lower baseline end-diastolic and end-systolic volume indices. There was no difference in hemodynamic variables between the groups.
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3.2. Dobutamine stress echocardiography
Submaximal heart rate was not reached in 13/24 (54.7%) patients. However, there was no difference in indices of contractile reserve between the patients who reached and those who did not reach submaximal heart rate (Table 2). No test was stopped due to complex ventricular arrhythmias.
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3.3. Contractile reserve indices
Values for baseline and peak dobutamine indices of left ventricular contractility, as well as their change, are shown in Table 3. With increased severity of morphologic changes over the groups, there was a significant trend towards a decrease in baseline and peak dobutamine ejection fraction (p<0.001 and p<0.01, respectively), as well as in baseline and peak end-systolic pressure/volume ratio (p<0.001 and p<0.01, respectively). On the other hand, baseline and peak wall motion score index increased over the groups (p<0.01 and p<0.001, respectively). These differences were translated into the lower contractile reserve indices (defined by ejection fraction, end-systolic pressure/volume ratio and wall motion score index), as the severity of morphologic changes increased (p<0.05 for all). In contrast, there was no difference among the groups in contractile reserve derived from cardiac power output as well as in its baseline and peak dobutamine values (p=NS for all).
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3.4. Histomorphometry and contractile reserve
In order to evaluate the association between histomorphometric features and contractile reserve, we correlated the percentage of interstitial fibrosis and myocyte diameter with contractile reserve assessed by change in wall motion score index, ejection fraction, end-systolic pressure/volume ratio and cardiac power output (Table 4). Myocyte diameter demonstrated a stronger association with dobutamine-induced changes in contractility indices than interstitial fibrosis. Both myocyte diameter and interstitial fibrosis showed strongest correlation with change in wall motion score index (r=–0.667, p<0.001, and r=–0.567, p=0.004, respectively; Figs. 2 and 3), followed by change in ejection fraction (r=–0.603, p=0.002, and r=–0.467, p=0.021, respectively).
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, moderate histomorphometric changes; 
, severe histomorphometric changes).
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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As there is no consensus on the definition of contractile reserve indices, different studies have defined them ad libitum [9–11]. Ideally, contractile reserve should reflect both the amount and the quality of contracting myocardium. Bearing this in mind, we assessed the relationship of various contractile reserve indices and histologic markers of myocardial impairment. The markers used in this study were selected since interstitial fibrosis should be inversely related to the amount of contracting myocardium, while myocyte diameter should be a robust measure of its quality. Indeed, it has been shown that an increase in fibrosis and reduction in the volume fraction of myofibrils are morphologic correlates of left ventricular dysfunction in patients with idiopathic dilated cardiomyopathy [12]. Also, it appears that myocyte hypertrophy may not be related to augmentation in contractile material, but rather to myocardial degeneration which is accompanied by compromised cardiac function [13,14].
4.1. Dobutamine stress echocardiography
It has been shown that patients with dilated cardiomyopathy have a decreased response to low-dose dobutamine which is related to abnormal left ventricular geometry, with patients with severe alterations showing no response [15]. Therefore, it appears that low-dose dobutamine does not recruit full-contractile potential, especially in patients with severe heart failure, in whom Beta-receptor down regulation is the most prominent [16]. We believe that the use of high-dose dobutamine and prolongation of each stage of dobutamine infusion (5 min rather than the usual 3 min) may be necessary to evoke full-contractile reserve.
4.2. Histomorphometric findings and contractile reserve: general considerations
In the present study, the severity of histomorphometric changes parallel the patient's functional status and baseline left ventricular ejection fraction. Both of these parameters have been shown to be strong univariate predictors of survival [17,18]. This is in keeping with previous reports that histomorphometric findings carry independent prognostic information in patients with idiopathic dilated cardiomyopathy [5]. Moreover, we have shown that patients with both moderate and severe histologic changes had lower contractile reserve than patients with mild changes, suggesting that the presence of either advanced fibrosis or significantly increased myocyte diameter or both have an adverse effect on contractile reserve assessed by high-dose dobutamine. These observations are also supported by the correlation between histomorphometric features and all contractile reserve indices, except cardiac power output.
These are interesting findings because it seems that decreased contractile reserve elicited by high-dose dobutamine may be a sensitive method for detection of the degree of myocardial histological derangement. However, contractile reserve indices are not equally related to the myocardial histology, since myocyte diameter consistently demonstrated stronger correlation with contractile reserve indices than interstitial fibrosis. Indeed, we believe that these data may provide further insight into recently published findings, suggesting a close correlation between left ventricular hypertrophy, response to high-dose dobutamine and spontaneous late recovery of left ventricular function and geometry in patients with recent onset idiopathic dilated cardiomyopathy [19].
4.3. Histomorphometric findings and contractile reserve: specific considerations
There are a number of studies dealing with left ventricular contractile indices. However, these studies are different with respect to the studied population, the method used to elicit left ventricular contractile response and the indices of contractile reserve.
4.3.1. Wall motion score index
Our findings suggest that the change in wall motion score index reflects myocardial histologic properties more accurately than other contractile reserve indices, which provides a sound rationale for the use of this index in the clinical setting. A recent study has indicated that the magnitude of dobutamine-induced change in wall motion score index has major prognostic implications in patients with idiopathic dilated cardiomyopathy [20], but further studies are needed in order to confirm these findings.
4.3.2. Ejection fraction
Because of its multifactorial nature, ejection fraction is not an ideal index of contractility and its use in the assessment of contractile reserve was challenged on that basis. Although this is certainly true from the hemodynamic standpoint, our results demonstrate that change in ejection fraction correlates well with myocardial morphology, suggesting that it may reflect the histologic basis of left ventricular contractile properties, at least in patients with idiopathic dilated cardiomyopathy. Data on prognostic usefulness have been conflicting, but it appears that contractile reserve expressed through change in ejection fraction may have prognostic significance [2,11,21].
4.3.3. End-systolic pressure/volume ratio
To our knowledge, end-systolic pressure/volume ratio has not previously been used in the assessment of contractile reserve in patients with dilated cardiomyopathy. The rationale for using pressure/volume ratio is that it reflects left ventricular end-systolic stiffness [22]. Our data show that end-systolic pressure/volume ratio has only a moderate correlation with myocyte diameter, and no correlation with the amount of interstitial fibrosis. These observations imply that end-systolic/pressure volume ratio may be of limited value in the assessment of contractile reserve in patients with idiopathic dilated cardiomyopathy.
4.3.4. Cardiac power output
The usefulness of cardiac power output, whether mean or peak, in the assessment of patients with left ventricular dysfunction is somewhat controversial [2,10]. In our study, cardiac power output did not correlate with interstitial fibrosis and had only a marginal correlation with myocyte diameter. The reasons for this are not clear, but potential explanations may include: (1) well-known limitations in the measurement of cardiac output using aortic velocity–time integral, which may present a significant source of error in the calculation of cardiac power output, and (2) crucial impact of mean arterial pressure on this index of contractility. Indeed, in our study, both intra- and inter-observer variability were highest for calculation of cardiac power output (5% and 7%, respectively), whereas correlation of mean arterial pressure at baseline and at peak dobutamine infusion with myocyte diameter (r=–0.381, p=0.07, and r=–0.393, p=0.006, respectively) and interstitial fibrosis (r=– 0.287, p=0.18, and r=–0.247, p=0.25, respectively) was weak.
4.4. Previous studies
To our knowledge, there are no other studies specifically designed to evaluate the association between myocardial histology and left ventricular contractile reserve. A recent study by Dagdeviren et al. [23] suggested that contractile reserve and outcome in patients with idiopathic dilated cardiomyopathy can be predicted by videodensitometric myocardial texture analysis of posterior wall and septum. These findings are in line with the results of our study, indicating that there must be a link between morphology and function. However, videodensitometry can only provide indirect information about myocardial histology.
4.5. Future directions
Further studies are needed to establish whether this close link between certain indices of contractile reserve and myocardial histology has similar implications in terms of prognosis.
4.6. Limitations of the study
Endomyocardial biopsy, by definition, gives regional information, but is commonly used to predict overall histology. In order to avoid sampling variability and to standardize the source of histomorphometric information, biopsy specimens in all patients were taken from the inferobasal and/or inferolateral segments of the left ventricle.
4.7. Conclusion
Our data demonstrate that contractile reserve indices assessed by dobutamine stress echocardiography correlate with myocardial histomorphometric features, suggesting that contractile reserve is strongly related to the degree of histological disruption in patients with idiopathic dilated cardiomyopathy.
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